Ifosfamide (Powder) Instructions for Use

ATC Code

L01AA06 (Ifosfamide)

Active Substance

Ifosfamide (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent, alkylating compound

Pharmacological Action

Antineoplastic agent of alkylating action, an oxazaphosphorine derivative. The mechanism of action is associated with the alkylation of nucleophilic centers, the formation of cross-links in DNA and RNA molecules, and the blocking of mitotic cell division.

Pharmacokinetics

The active substance is a prodrug (inactive transport form).

A few minutes after intravenous administration, Ifosfamide is detected in organs and tissues. Plasma protein binding is low. The volume of distribution approximately corresponds to the total body fluid volume and reaches 0.5-0.8 L/kg. Unchanged Ifosfamide can penetrate the blood-brain barrier. The ability of active ifosfamide metabolites to penetrate the blood-brain barrier has not been definitively established.

After intravenous administration, Ifosfamide is metabolized into the pharmacologically active metabolite 4-hydroxyifosfamide.

Ifosfamide and its metabolite are excreted mainly by the kidneys. The half-life (T_1/2) of ifosfamide and its 4-hydroxy metabolite is 4-8 hours. After a single administration, about 80% of the ifosfamide dose is excreted within 24 hours. About 80% of the administered dose is excreted as metabolites. A significant amount of unchanged ifosfamide is found in the cerebrospinal fluid, apparently due to the high lipophilicity of the substance. Renal clearance is 6-22 mL/min.

Indications

Malignant testicular tumors, ovarian cancer, cervical cancer, breast cancer, lung cancer (non-small cell and small cell), soft tissue sarcomas (including osteosarcoma and rhabdomyosarcoma), Ewing’s sarcoma, pancreatic cancer, non-Hodgkin’s lymphomas, Hodgkin’s disease.

ICD codes

Dosage Regimen

Administer intravenously as an infusion. Determine the dose and schedule individually based on the specific malignancy, disease stage, and patient’s hematopoietic status.

Calculate the dose based on body surface area (BSA). Typical doses range from 1.2 g/m² to 2.5 g/m² daily for 3 to 5 consecutive days. Repeat treatment cycles every 3 to 4 weeks, or after adequate hematological recovery.

For certain regimens, use higher doses of 3.6 g/m² to 5.0 g/m² daily for one or two days. Adjust the dose for patients with impaired renal function or bone marrow suppression.

Always administer with mesna (sodium 2-mercaptoethanesulfonate) for prophylaxis against hemorrhagic cystitis. Administer mesna as an intravenous bolus injection or infusion concurrently with ifosfamide.

Ensure adequate patient hydration with at least 2 liters of oral or intravenous fluid per day during administration to further reduce the risk of urotoxicity.

Reconstitute the powder with Water for Injections or a compatible solution such as 0.9% sodium chloride. Further dilute the reconstituted solution in 500 mL of a compatible infusion fluid.

Infuse the final solution over a period of 30 minutes to several hours, as directed by the specific protocol. Do not administer as a rapid intravenous injection.

Monitor blood counts, renal function, and urinary sediment before and during each treatment cycle. Withhold therapy if severe myelosuppression (leukocytes < 2,000/mm³ and/or platelets < 50,000/mm³) or severe renal impairment occurs.

Adverse Reactions

Infections and infestations: frequent – infections.

From the hematopoietic system: very common – myelosuppression, leukopenia, neutropenia, thrombocytopenia, anemia.

From the metabolism and nutrition: frequent – anorexia.

From the nervous system: very common – neurotoxicity affecting the CNS; uncommon – peripheral neuropathy.

From the cardiovascular system: uncommon – cardiotoxicity, arterial hypotension.

From the digestive system: very common – nausea, vomiting; uncommon – diarrhea, stomatitis.

From the liver and biliary tract: frequent – increased activity of liver enzymes (ALT, AST, ALP, LDH and GGT), increased bilirubin concentration, jaundice.

From the skin and subcutaneous tissues: very common – alopecia; very rare – dermatitis, papular rash.

From the urinary system: very common – hemorrhagic cystitis, dysuria, frequent urination and other symptoms of bladder inflammation (blood in urine, painful urination), impaired renal function (increased serum creatinine and urea concentrations, decreased creatinine clearance, glucosuria), proteinuria; metabolic acidosis.

General reactions: frequent – phlebitis, neutropenic fever; uncommon – increased fatigue; frequency unknown – dysphoria.

Contraindications

Hypersensitivity to ifosfamide; urinary tract obstruction; severe bone marrow function disorders (especially in patients previously treated with cytotoxic drugs or radiation therapy); cystitis, acute infectious diseases; pregnancy, breastfeeding period.

With caution hypoproteinemia (hypoalbuminemia), electrolyte imbalance, elderly age, immunosuppression, diabetes mellitus, impaired liver function, chronic liver failure, brain metastases, cerebral symptoms, impaired renal function and/or difficulty urinating, active urinary tract infections, chickenpox (including recently contracted or after contact with sick individuals), herpes zoster, prior radiation therapy, debilitated patients.

Use in Pregnancy and Lactation

Ifosfamide is contraindicated during pregnancy. If use is necessary during lactation, breastfeeding should be discontinued.

Women of childbearing potential should use reliable methods of contraception throughout the entire course of treatment and for 3 months after its completion.

Experimental studies have established the teratogenic and embryotoxic effects of ifosfamide.

Use in Hepatic Impairment

Should be used with caution in patients with impaired liver function, chronic liver failure.

Use in Renal Impairment

Should be used with caution in patients with impaired renal function.

Pediatric Use

Can be used in children according to indications in recommended doses and treatment regimens.

Geriatric Use

Should be used with caution in elderly patients.

Special Precautions

Treatment with ifosfamide can cause myelosuppression and significant suppression of the immune response, which can lead to serious infections, including pneumonia and other bacterial, fungal, viral, or parasitic infections, as well as sepsis and septic shock. Fatal outcomes of myelosuppression and associated development of severe infections during ifosfamide use have been reported.

Ifosfamide should be used with particular caution in patients with impaired bone marrow function, severe immunosuppression, and in the presence of infections.

Given the adverse effects of ifosfamide on the CNS, patients should take antiemetics in a timely manner. However, due to the possible additive effect, drugs acting on the CNS (antiemetics, sedatives, narcotic analgesics, or antihistamines) should be used with particular caution. In case of development of Ifosfamide-induced encephalopathy, their use should, if possible, be discontinued.

Before starting ifosfamide treatment, glomerular and tubular kidney functions should be assessed and monitored during and after treatment. During ifosfamide therapy, urine sediment should be regularly monitored for the presence of red blood cells and other signs of uro- or nephrotoxicity. Thorough clinical monitoring of serum and urine biochemistry, including phosphorus, potassium, and other laboratory parameters used to identify nephrotoxicity and urothelial toxicity, is recommended. Appropriate replacement therapy should be prescribed as indicated.

The possibility of using ifosfamide in patients with existing kidney damage or reduced renal function should be considered individually, carefully assessing the expected benefit versus the potential risk. Renal parenchymal necrosis and tubular necrosis have been observed in patients treated with ifosfamide therapy. Disorders of glomerular and/or tubular kidney function appearing after ifosfamide use are very common. Tubular damage can be detected during ifosfamide therapy, several months or even years after discontinuation of treatment.

Risk factors for the development of nephrotoxicity include the use of high cumulative doses of ifosfamide, the presence of renal pathology, prior or concomitant therapy with potentially nephrotoxic drugs, young age in children (under 5 years), absence of one kidney in patients with kidney tumors, as well as in those who have undergone radiation to the kidney area or unilateral nephrectomy. Caution should be exercised when treating such patients with ifosfamide.

The risk of developing hemorrhagic cystitis increases with the use of high single doses compared to fractionated administration. There are reports of hemorrhagic cystitis developing after a single use of ifosfamide. For the prevention of hemorrhagic cystitis, Ifosfamide must always be used in combination with mesna. Mesna significantly reduces the frequency and severity of hemorrhagic cystitis and does not affect the therapeutic action of ifosfamide.

Before starting ifosfamide therapy, any urinary tract obstructions, cystitis and other infections of the kidneys and urinary tract, as well as electrolyte imbalances, must be excluded or corrected.

With long-term use of ifosfamide, it is very important to ensure regular monitoring of kidney function, diuresis, and urine sediment, especially in children. Particular attention must be paid to adequate hydration and regular bladder emptying.

In case of nephropathy development and further continuation of ifosfamide therapy, irreversible kidney damage should be expected. When deciding to continue ifosfamide treatment, the ratio of expected benefit to potential risk should be carefully assessed.

Fatal outcomes of ifosfamide cardiotoxicity have been reported. The risk of developing cardiotoxic effects of ifosfamide is dose-dependent and increases in patients with prior or concomitant treatment with other cardiotoxic drugs or the use of radiation to the heart area and, possibly, with impaired renal function. In this regard, special caution is necessary when using ifosfamide in patients with risk factors for cardiotoxicity and in patients with heart disease. Regular monitoring of electrolyte balance is required.

Fatal cases of pulmonary toxicity leading to respiratory failure have been noted. Interstitial pneumonitis and pneumosclerosis, as well as other forms of pulmonary toxicity, are reported to develop during ifosfamide treatment.

Like any cytotoxic therapy, treatment with ifosfamide is associated with the risk of developing secondary tumors and their precursor cells. Secondary malignancy can develop even several years after the cessation of chemotherapy. In particular, the risk of developing myelodysplastic changes and their progression to acute leukemias is increased. Other malignant tumors reported after the use of ifosfamide or therapeutic regimens containing it include lymphomas, thyroid cancer, and sarcomas.

Ifosfamide has mutagenic potential and genotoxicity towards male and female germ cells. Women should not become pregnant during ifosfamide treatment. If pregnancy is detected during therapy, genetic counseling is strongly recommended. Men who are to be prescribed Ifosfamide should be informed about sperm cryopreservation before starting treatment and that they should not father children either during therapy or for at least 6 months after its completion. Reliable contraceptive methods must be used during ifosfamide treatment. The duration of the contraception period after chemotherapy should be determined in accordance with the prognosis of the underlying disease and the parents’ desire to have children. Genetic counseling is indicated in this case.

Ifosfamide affects oogenesis and spermatogenesis. Cases of amenorrhea, azoospermia, and infertility in both sexes are known. The development of infertility is likely dependent on the dose of ifosfamide, the duration of therapy, and the state of gonadal function during treatment. In some patients, the developed infertility may become irreversible. The development of amenorrhea has been reported in patients receiving Ifosfamide.

Continuous chemotherapy increases the risk of amenorrhea in older women. In girls treated with ifosfamide before puberty, secondary sexual characteristics, regular menstruation, and the ability to conceive may subsequently develop normally. However, in girls with preserved ovarian function after completion of treatment, there is an increased risk of developing premature menopause.

In men treated with ifosfamide, oligospermia or azoospermia may develop, although sexual function and libido are generally not affected.

In boys treated with ifosfamide before puberty, secondary sexual characteristics may develop normally, but oligospermia or azoospermia may develop. Some degree of testicular atrophy is also likely to develop.

Azoospermia may be reversible in some patients, although recovery of normal spermatogenesis may take several years. According to available observations, men who received ifosfamide treatment subsequently became fathers.

Ifosfamide may affect the process of normal wound healing.

The possibility of using ifosfamide in patients with hepatic insufficiency should be considered individually. When deciding to conduct ifosfamide therapy, these patients should be carefully monitored. Liver damage, especially severe, may be associated with reduced activation of ifosfamide, which may affect the effectiveness of therapy.

Ethanol consumption increases the risk of developing liver function disorders.

When selecting the dose and monitoring ifosfamide toxicity in elderly patients, reduced function of the liver, kidneys, heart, and other organs, as well as concomitant diseases or the use of other types of therapy, should be taken into account.

Effect on ability to drive vehicles and operate machinery

During ifosfamide therapy, nausea and vomiting, as well as encephalopathy phenomena, are possible, which may affect the ability to drive a car or operate other machinery. Therefore, patients receiving Ifosfamide should avoid driving vehicles and engaging in other activities requiring high concentration and speed of psychomotor reactions.

Drug Interactions

Enhanced hematotoxicity and/or immunosuppression is possible with the combined use of ifosfamide and ACE inhibitors, carboplatin, cisplatin, and natalizumab. The combination of ifosfamide with anthracyclines or with radiation to the heart area may lead to increased cardiotoxicity.

Combined use of ifosfamide and amiodarone, G-CSF (granulocyte colony-stimulating factor), GM-CSF (granulocyte-macrophage colony-stimulating factor) may increase pulmonary toxicity.

Increased nephrotoxicity may result from the combined use of ifosfamide with acyclovir, aminoglycosides, amphotericin B, carboplatin, and cisplatin.

Combined use of ifosfamide with busulfan, as well as with radiation to the bladder area, may lead to an increased risk of developing hemorrhagic cystitis.

With the combined use of ifosfamide with antiemetics, antihistamines, narcotic analgesics, and sedatives, additional side effects from the CNS may occur.

The possibility of enhanced formation of cytotoxic metabolites should be considered in case of prior or concomitant use of carbamazepine, corticosteroids, rifampicin, phenobarbital, benzodiazepines, chloral hydrate, phenytoin, and St. John’s wort preparations.

Concomitant use of ifosfamide and inhibitors of the CYP3A4 isoenzyme, such as ketoconazole, fluconazole, and itraconazole, may lead to increased formation of ifosfamide metabolites possessing CNS neurotoxicity and nephrotoxicity.

In cases where Ifosfamide was administered before docetaxel infusion, increased gastrointestinal toxicity was noted.

In patients receiving Ifosfamide and warfarin, an increase in the international normalized ratio was noted.

It can be expected that Ifosfamide, being an immunosuppressant, reduces the body’s response to vaccination. The use of live vaccines may lead to vaccine-induced infection.

Concomitant use of tamoxifen and ifosfamide may increase the risk of thromboembolic complications.

Cisplatin-induced hearing loss may be exacerbated by the simultaneous use of ifosfamide.

The formation of active metabolites of irinotecan may be reduced with simultaneous use with ifosfamide.

Enhanced myelotoxicity of ifosfamide due to interaction with other cytotoxic drugs or radiation should be taken into account. Simultaneous use of ifosfamide and allopurinol or hydrochlorothiazide may also increase the myelosuppressive effect.

Prior or simultaneous use of nephrotoxic drugs, such as cisplatin, aminoglycosides, acyclovir, and amphotericin B may enhance the nephrotoxic effects of ifosfamide and, consequently, hematotoxicity and neurological toxicity.

The therapeutic effect and toxicity of ifosfamide may be enhanced by the simultaneous use of chlorpromazine, triiodothyronine, or inhibitors of aldehyde dehydrogenase such as disulfiram.

Grapefruit contains a substance that causes inhibition of cytochrome P450 isoenzymes and therefore may reduce the metabolic activation of ifosfamide and, consequently, its effectiveness. During treatment with ifosfamide, patients should avoid consuming grapefruit and/or products or beverages containing this fruit.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.