Ifosfamide

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IFOSFAMIDE (IFOSFAMIDE)

Composition:

Active substance: ifosfamide;

1 vial contains 1 g of ifosfamide.

Pharmaceutical form. Lyophilisate for solution for infusion.

Main physicochemical properties: white lyophilized mass.

Pharmacotherapeutic group. Antineoplastic agents. Alkylating agents, nitrogen mustard analogues. ATC code L01A A06.

Pharmacological Properties

Pharmacodynamics

Ifosfamide is a cytotoxic agent belonging to the oxazaphosphorine group. Chemically, it is related to nitrogen mustard and is a synthetic analogue of cyclophosphamide.

Ifosfamide is inactive in vitro and is activated in vivo, primarily in the liver, by microsomal enzymes, transforming into 4-hydroxyifosfamide, which exists in equilibrium with its tautomer, aldoifosfamide. Aldoifosfamide spontaneously degrades into acrolein and the alkylating metabolite isophosphoramide mustard. Acrolein causes the urotoxic effect of ifosfamide. An alternative metabolic pathway involves oxidation and dealkylation of the chloroethyl side chains.

The cytotoxic effect of ifosfamide results from the interaction of its alkylating metabolites with DNA. The primary site of attack is the phosphodiester bonds of DNA. Alkylation leads to strand breaks and cross-linking of DNA strands.

In the cell cycle, progression through the G2 phase is delayed. The cytotoxic effect is not specific to any particular phase of the cell cycle, but is effective throughout the cell cycle.

Cross-resistance cannot be excluded, primarily with structurally related cytostatic agents such as cyclophosphamide, as well as with other alkylating agents. On the other hand, it is known that tumors resistant to cyclophosphamide or recurring after cyclophosphamide treatment often respond to ifosfamide therapy.

Pharmacokinetics

There is a linear relationship between plasma concentration and the administered dose of ifosfamide. Plasma protein binding is low. The volume of distribution approximately corresponds to total body water. After intravenous administration, ifosfamide appears in organs and tissues within several minutes.

Ifosfamide can cross the blood-brain barrier in unchanged form; however, the ability of its active metabolites to cross remains controversial. There are no confirmed data regarding placental transfer or excretion into breast milk. Due to the teratogenicity of ifosfamide demonstrated in animal studies and its structural similarity to cyclophosphamide, it is expected that ifosfamide also crosses the placenta and is excreted into breast milk.

The elimination half-life of ifosfamide and its 4-hydroxymetabolite from plasma ranges from 4 to 7 hours.

Ifosfamide and its metabolites are primarily excreted via the kidneys. After administration of fractionated doses of 1.6–2.4 g/m² body surface area/day for three consecutive days, 57% of the dose is excreted within 72 hours, and after administration of a high single dose of 3.8–5 g/m² body surface area, 80% of the dose is excreted within 72 hours, primarily as metabolites or unchanged ifosfamide. The amount of unchanged ifosfamide excreted reaches 15% and 53%, respectively.

Clinical characteristics.

Indications.

Testicular tumors

In combination with chemotherapy for patients with advanced stage II–IV tumors according to the TNM classification (International Classification of Malignant Tumors) (seminoma and non-seminoma) that have shown insufficient response or no response at all to primary chemotherapy.

Cervical carcinoma (carcinoma of the cervix uteri)

Palliative combined chemotherapy with cisplatin/ifosfamide (without additional combination agents) for stage IVB cervical carcinoma according to the International Federation of Gynecology and Obstetrics (FIGO) classification (when radical surgical treatment or radiation therapy is not feasible), as an alternative to palliative radiotherapy.

Breast cancer

As palliative therapy for advanced, resistant, or recurrent breast cancer.

Non-small cell bronchial carcinoma

As monotherapy or in combination chemotherapy for patients with inoperable or metastatic tumors.

Small cell bronchial carcinoma

In combination chemotherapy.

Soft tissue sarcoma (including osteosarcoma and rhabdomyosarcoma)

As monotherapy or in combination chemotherapy for rhabdomyosarcoma or osteosarcoma when standard treatment is ineffective. As monotherapy or in combination chemotherapy for other soft tissue sarcomas when surgical and radiation therapy are ineffective.

Ewing's sarcoma

In combination chemotherapy when primary cytostatic therapy is ineffective.

Non-Hodgkin's lymphomas

In combination chemotherapy for patients with high-grade non-Hodgkin's lymphomas that have shown insufficient response or no response at all to primary therapy. In combination therapy for patients with recurrent tumors.

Hodgkin's disease

For treatment of patients with Hodgkin's disease, particularly those with progressive disease or early relapse (duration of complete remission less than 1 year), following unsuccessful primary chemotherapy or radiochemotherapy within established combination chemotherapy regimens such as the MINE protocol.

Contraindications.

Ifosfamide is contraindicated in patients:

• with hypersensitivity to ifosfamide or any of its metabolites or other components of the medicinal product;
• with severe bone marrow dysfunction (particularly patients previously treated with cytotoxic agents and/or radiation therapy);
• with bladder inflammation (cystitis);
• with impaired renal function and/or obstruction of the urinary tract;
• with acute infections;
• during pregnancy or breastfeeding (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

Planned concomitant or sequential use of other drugs or treatment modalities that may increase the likelihood or severity of toxic effects (due to pharmacodynamic or pharmacokinetic interactions) requires careful individual assessment of expected benefits and risks.

Patients receiving such combinations should be closely monitored for signs of toxicity to ensure timely intervention.

Patients receiving ifosfamide and drugs that reduce its activation should be monitored for potential reduction in therapeutic efficacy and need for dose adjustment.

Enhanced myelotoxicity should be considered due to interactions with other cytostatic agents or radiation therapy, for example, with allopurinol or hydrochlorothiazide.

Due to the immunosuppressive effect of ifosfamide, a reduced response to vaccines should be expected. Administration of live vaccines may lead to vaccine-induced infections.

Coumarin derivatives: increased INR (elevated international normalized ratio) has been reported in patients receiving ifosfamide and warfarin. Concomitant administration of ifosfamide with warfarin may enhance the anticoagulant effect of the latter and thus increase the risk of bleeding.

Concomitant use of nephrotoxic agents such as cisplatin, aminoglycosides, acyclovir, carboplatin, or amphotericin B may enhance the nephrotoxic effect of ifosfamide.

Cumulative effects on the CNS may occur when ifosfamide is used concomitantly with antiemetics, neuroleptics, tranquilizers, sedatives, narcotics, selective serotonin reuptake inhibitors, tricyclic antidepressants, or antihistamines. These agents should be used with particular caution in cases of ifosfamide-induced encephalopathy and, if possible, discontinued altogether.

Ifosfamide treatment may enhance the hypoglycemic effect of sulfonylureas.

When prior or concomitant treatment is administered, the possibility of increased formation of metabolites responsible for cytotoxicity and other types of toxicity (depending on the induced enzymes) should be considered.

CYP 3A4 inhibitors: reduced activation and metabolism of ifosfamide may affect the efficacy of ifosfamide treatment. Inhibition of CYP 3A4 may also lead to increased formation of an ifosfamide metabolite associated with CNS and nephrotoxicity. CYP 3A4 inhibitors include fluconazole, itraconazole, ketoconazole, sorafenib.

Inducers of hepatic and extrahepatic microsomal enzymes in humans (e.g., cytochrome P450 enzymes). The possibility of increased formation of metabolites responsible for cytotoxicity and other types of toxicity (depending on the induced enzymes) should be considered when prior or concomitant treatment with agents such as carbamazepine, corticosteroids, St. John's wort, phenobarbital, phenytoin, rifampicin is administered.

Potentiation of hematotoxicity and/or immunosuppression may result from concomitant use with ACE inhibitors, as they may cause leukopenia and agranulocytosis; with carboplatin, which may increase nephrotoxicity; with cisplatin—cisplatin-induced hearing loss may worsen during concomitant ifosfamide therapy; with natalizumab.

Increased cardiotoxicity may result from the combined effect of ifosfamide and, for example, anthracyclines, or radiation to the cardiac region.

Increased pulmonary toxicity may result from the combined effect of ifosfamide and, for example, amiodarone, G-CSF, GM-CSF (granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor).

Increased risk of hemorrhagic cystitis may result from the combined effect of ifosfamide and, for example, busulfan, or radiation to the bladder.

Increased therapeutic effect and toxicity may occur when ifosfamide is used concomitantly with chlorpromazine, triiodothyronine, or aldehyde dehydrogenase inhibitors such as disulfiram (Antabuse).

Potentiation of the muscle-relaxing effect of succinylcholine.

Alcohol: in some patients, alcohol may increase the severity of ifosfamide-induced nausea and vomiting.

Docetaxel: increased incidence of gastrointestinal toxicity has been reported when ifosfamide is administered prior to docetaxel infusion.

Tamoxifen: concomitant use of tamoxifen and chemotherapy may increase the risk of thromboembolic complications.

Irinotecan: reduced levels of the active metabolite of irinotecan.

Ifosfamide may enhance skin reactions during radiation therapy.

Grapefruit contains a substance that may reduce the activation of ifosfamide and thus its efficacy. For this reason, patients receiving ifosfamide treatment should avoid consuming grapefruit or grapefruit juice.

Special precautions for use.

In individual patients, risk factors for the toxic effects of ifosfamide and their consequences described in this and other sections may be considered equivalent to contraindications. In such cases, an individual assessment of the risks and expected benefits of using the drug is required. If adverse reactions occur, depending on their severity, it may be necessary to modify the dosage or discontinue treatment.

Myelosuppression, immunosuppression, infections

Treatment with ifosfamide may cause myelosuppression and significant suppression of immune responses, which may lead to the development of severe infectious diseases. Fatal outcomes associated with the development of myelosuppression due to ifosfamide administration have been reported.

Myelosuppression induced by ifosfamide may lead to the development of leukopenia, neutropenia, thrombocytopenia (associated with an increased risk of bleeding), and anemia.

Administration of ifosfamide is typically followed by a further decrease in leukocyte count. The maximum reduction in leukocyte count usually occurs approximately in the second week of treatment. Subsequently, the leukocyte count increases again.

Severe myelosuppression is particularly expected in patients who have previously received treatment and/or are receiving concomitant chemotherapy/hematotoxic agents and/or radiation therapy. Concomitant use of other immunosuppressants may increase the severity of immunosuppression caused by ifosfamide (see section "Interaction with other medicinal products and other forms of interaction").

The risk of developing myelosuppression depends on the dose of the drug and increases when a single high dose is administered compared to fractionated administration.

The risk of developing myelosuppression increases in patients with impaired renal function.

Severe immunosuppression has led to the development of serious, sometimes fatal, infections. Cases of sepsis and septic shock have also been reported.

Infections reported in association with ifosfamide use include pneumonia, as well as other bacterial, fungal, viral, and parasitic infections.

Reactivation of latent infections may occur. Reactivation of various viral infections has been reported in patients receiving ifosfamide treatment. Infectious diseases should be treated appropriately.

In some cases of neutropenia, antimicrobial prophylaxis may be appropriate (at the discretion of the treating physician).

In the event of neutropenic fever, antibiotics and/or antifungal agents should be administered.

Careful monitoring of hematological parameters is recommended. Leukocyte count, platelet count, and hemoglobin levels should be determined before each administration of the drug and at regular intervals after administration.

Ifosfamide should be used with caution in all patients with severe bone marrow dysfunction, severe immunosuppression, or existing infection.

Encephalopathy and neurotoxic effects on the CNS

Administration of ifosfamide may cause encephalopathy and other neurotoxic effects.

Neurotoxic effects on the CNS caused by ifosfamide may occur within several hours or days after administration and in most cases resolve within 48–72 hours after discontinuation of ifosfamide. Symptoms may persist for a longer period. Recovery is sometimes incomplete. Fatal outcomes due to neurotoxic effects on the CNS have been reported. If neurotoxicity develops, ifosfamide administration should be discontinued.

Symptoms of neurotoxicity may include: confusion, somnolence, coma, hallucinations, blurred vision, psychotic behavior, extrapyramidal symptoms, urinary incontinence, and seizures.

Neurotoxic effects on the CNS are likely dose-dependent. Risk factors for ifosfamide-induced encephalopathy include hypoalbuminemia, impaired renal function, reduced performance status, pelvic organ disease (e.g., presence of a tumor in the lower abdomen, extensive abdominal disease), and prior or concomitant nephrotoxic therapy, particularly with cisplatin.

Careful monitoring of the patient's condition is required in cases of potential neurotoxic effects of the drug and other neurotoxic effects.

Due to the potential for additive effects, medicinal products acting on the CNS (such as antiemetics, sedatives, opioids, or antihistamines) and other substances acting on the CNS (such as alcohol) should be used with particular caution or, if necessary, discontinued in the event of ifosfamide-induced encephalopathy.

Patients receiving ifosfamide treatment should be closely monitored for symptoms of encephalopathy, especially if they have an increased risk of developing encephalopathy.

Methylene blue may be used for the treatment and prevention of ifosfamide-induced encephalopathy.

Cardiotoxicity, use in patients with cardiac diseases

Manifestations of cardiotoxicity reported during ifosfamide treatment include supraventricular or ventricular arrhythmias, including atrial/supraventricular tachycardia, atrial fibrillation, pulseless ventricular tachycardia; decreased QRS segment voltage and ST segment or T-wave changes; toxic cardiomyopathy leading to congestive heart failure and arterial hypotension; exudative pericarditis, fibrinous pericarditis, and epicardial fibrosis.

Cases of ifosfamide-associated cardiotoxicity with fatal outcomes have been reported.

The risk of developing cardiotoxic effects depends on the dose of the drug. It is increased in patients who have received prior or concomitant treatment with other cardiotoxic agents or radiation therapy to the heart area, and possibly in patients with impaired renal function.

Particular caution should be exercised when administering ifosfamide to patients with risk factors for cardiotoxicity and to patients with pre-existing heart diseases.

Renal and urothelial toxicity

Ifosfamide has nephrotoxic and urotoxic effects.

Glomerular and tubular kidney function should be assessed and monitored before, during, and after therapy.

Urine sediment should be regularly examined for the presence of erythrocytes and other signs of uro/nephrotoxicity.

Careful clinical monitoring of serum and urine biochemical parameters is recommended, including phosphorus, potassium, and other laboratory parameters suitable for detecting nephrotoxicity and urothelial toxicity.

Appropriate replacement therapy should be administered as indicated.

Nephrotoxic effects

Cases of renal parenchymal and tubular necrosis have been reported in patients receiving ifosfamide treatment.

Cases of impaired renal function (glomerular and tubular) after ifosfamide administration are very common. Manifestations include decreased glomerular filtration rate and increased serum creatinine levels, proteinuria, enzymuria, cylindruria, aminoaciduria, phosphaturia, and glucosuria, as well as renal tubular acidosis. Cases of Fanconi syndrome, renal rickets, and growth retardation in children, as well as cases of osteomalacia in adults, have also been reported.

Dysfunction of the distal tubules impairs the kidney's ability to concentrate urine.

Syndrome resembling SIADH (syndrome of inappropriate antidiuretic hormone secretion) has been reported during ifosfamide administration.

Tubular damage may become apparent during treatment and for months or even years after discontinuation of treatment.

Glomerular or tubular insufficiency may resolve over time, remain stable, or progress over several months or years even after completion of ifosfamide treatment. Cases of acute tubular necrosis, acute renal failure, and chronic renal failure secondary to ifosfamide treatment have been reported; a case of nephrotoxicity with fatal outcome has also been documented.

The risk of developing clinical manifestations of nephrotoxicity increases with, for example, high cumulative doses of ifosfamide; pre-existing renal dysfunction; prior or concomitant treatment with potentially nephrotoxic agents; younger age of children (especially under 5 years); and reduced nephron reserve, as seen in patients with kidney tumors, those who have undergone kidney irradiation, or those who have had a unilateral nephrectomy.

The risks and benefits expected from ifosfamide treatment should be carefully weighed when considering the use of ifosfamide in patients with pre-existing renal dysfunction or reduced nephron reserve.

Urothelial effects

Administration of ifosfamide is associated with urotoxic effects, which can be reduced by prophylactic use of mesna.

Manifestations of urotoxicity resulting from cyclophosphamide, another cytotoxic agent in the oxazaphosphorine group, include hemorrhagic cystitis (including severe forms associated with ulceration and necrosis), hematuria, which may be severe, signs of urothelial irritation (e.g., painful urination, sensation of incomplete bladder emptying, frequent urination, nocturia, urinary incontinence), and development of bladder fibrosis, decreased bladder capacity, telangiectasia, recurrent hematuria, and signs of chronic bladder irritation.

Cases of pyelitis and ureteritis have been reported following cyclophosphamide administration.

Hemorrhagic cystitis requiring blood transfusion has been reported following ifosfamide administration. Fatal cases of urothelial toxicity and the need for cystectomy due to fibrosis, bleeding, or secondary malignancies have been reported with cyclophosphamide use.

Experience with cyclophosphamide has shown that hematuria usually resolves within a few days after discontinuation of treatment, although it may persist.

The risk of developing hemorrhagic cystitis depends on the dose of the drug and increases when single high doses are administered compared to fractionated administration.

Cases of hemorrhagic cystitis have been reported after administration of a single dose of ifosfamide.

If cystitis associated with microhematuria or macrohematuria occurs during treatment with Ifosfamide, treatment should be interrupted until the patient's condition normalizes.

All types of urinary tract obstructions should be excluded or corrected before initiating treatment (see section "Contraindications").

To accelerate diuresis and reduce the risk of toxic effects on the urinary tract, an adequate amount of fluid should be administered (intravenously or by infusion) during or immediately after drug administration.

To prevent hemorrhagic cystitis, ifosfamide must be used in combination with mesna.

Ifosfamide should be used with caution in all patients with active urinary tract infections.

Prior or concomitant radiation therapy for bladder diseases or treatment with busulfan may increase the risk of developing hemorrhagic cystitis.

Genotoxicity

Ifosfamide exerts genotoxic and mutagenic effects on male and female germ cells. Therefore, women and men are advised to avoid conception during ifosfamide therapy. If pregnancy occurs during treatment, the woman should undergo genetic counseling. The duration of contraception after completion of chemotherapy should be determined based on the prognosis of the underlying disease and the desire to have children. Genetic counseling should also be performed.

Men are advised to use reliable contraceptive methods for 6 months after completion of therapy. Men should be informed before ifosfamide treatment about the possibility of sperm cryopreservation.

Data from animal studies with cyclophosphamide, another cytotoxic agent in the oxazaphosphorine group, show that the effect of the drug on oocytes during follicular development may lead to reduced implantation rates and viable pregnancies and increased risk of developmental abnormalities. This effect should be considered in the case of planned conception or pregnancy after discontinuation of ifosfamide therapy. The exact duration of follicular development in humans is unknown but may last more than 12 months.

Effects on fertility

Ifosfamide affects oogenesis and spermatogenesis. Cases of amenorrhea, azoospermia, and sterility in both sexes have been reported.

The development of sterility is likely dependent on the dose of ifosfamide, duration of therapy, and the functional status of the gonads during treatment. In some patients, sterility may be irreversible.

Female patients

Amenorrhea has been reported in female patients receiving ifosfamide treatment. Additionally, oligomenorrhea has been reported with cyclophosphamide, another cytotoxic agent in the oxazaphosphorine group.

The risk of prolonged amenorrhea induced by chemotherapy increases in older women.

In girls who received ifosfamide treatment during the prepubertal period, secondary sexual characteristics may develop normally with preservation of a regular menstrual cycle.

In girls who received ifosfamide treatment during the prepubertal period, fertility may be restored later.

Girls whose ovarian function was preserved after completion of treatment have an increased risk of premature menopause.

Male patients

Oligospermia or azoospermia may develop in men receiving ifosfamide treatment.

Sexual function and libido are generally not impaired in these patients.

In boys who received ifosfamide treatment during the prepubertal period, secondary sexual characteristics may develop normally, but oligospermia or azoospermia is possible.

Some degree of testicular atrophy may occur.

In some patients, azoospermia may be reversible, but recovery of spermatogenesis may take several years after discontinuation of therapy.

Pulmonary toxicity

Cases of interstitial pneumonitis and pulmonary fibrosis have been reported during ifosfamide treatment. Other forms of pulmonary toxicity have also been reported. Cases of pulmonary toxicity leading to respiratory failure and fatal outcomes have been documented.

Secondary malignancies

As with all other cases of cytotoxic therapy, ifosfamide treatment is associated with a risk of developing secondary malignancies and their precursors as long-term complications.

The risk of myelodysplastic changes, some of which may progress to acute leukemias, is increased. Other malignancies reported after ifosfamide use or ifosfamide-containing regimens include lymphoma, thyroid cancer, and sarcomas.

Secondary malignancies may develop several years after completion of chemotherapy.

Development of malignancies has also been reported after in utero exposure to cyclophosphamide, another cytotoxic agent in the oxazaphosphorine group.

Veno-occlusive liver disease

Cases of veno-occlusive liver disease have been reported during chemotherapy regimens including ifosfamide. This condition is also a known complication of cyclophosphamide, another cytotoxic agent in the oxazaphosphorine group.

Anaphylactic/anaphylactoid reactions, cross-sensitivity

Anaphylactic/anaphylactoid reactions have been reported in association with ifosfamide administration.

Reports of cross-sensitivity between cytotoxic agents in the oxazaphosphorine group have been received.

Impaired wound healing

Ifosfamide may affect normal wound healing.

Alopecia

Alopecia is a very common, dose-dependent phenomenon occurring as a result of ifosfamide administration.

Chemotherapy-induced alopecia may progress to complete hair loss.

Hair may regrow, although it may differ in texture or color.

Nausea and vomiting

Administration of ifosfamide may cause nausea and vomiting.

Current guidelines for the use of antiemetic agents should be considered for the prevention and reduction of nausea and vomiting.

Alcohol consumption may increase the intensity of chemotherapy-induced nausea and vomiting.

Stomatitis

Administration of ifosfamide may cause the development of stomatitis (inflammation of the oral mucosa).

Current guidelines should be considered for the prevention and reduction of stomatitis symptoms.

Paravenous administration of the drug

The cytotoxic effect of ifosfamide occurs after its activation, which primarily takes place in the liver. Therefore, the risk of tissue damage following accidental paravenous administration of the drug is low.

In case of accidental paravenous administration of ifosfamide, the infusion should be immediately stopped, and the extravasated ifosfamide solution should be aspirated using the cannula at the site of occurrence; other measures should also be taken if necessary.

Use in patients with impaired renal function

In patients with impaired renal function, especially those with severe renal impairment, reduced renal excretion may lead to increased plasma levels of ifosfamide and its metabolites, thereby increasing toxicity (particularly neurotoxicity, nephrotoxicity, hematotoxicity), which should be considered when determining the dosing regimen for these patients.

Use in patients with impaired hepatic function

Impaired hepatic function, especially severe impairment, may be associated with reduced activation of ifosfamide. This may reduce the efficacy of ifosfamide treatment.

The presence of hepatic dysfunction in a patient should be considered when selecting the drug dose and interpreting the response to the selected dose.

Impaired outflow in the efferent urinary tract, cystitis, as well as infections and electrolyte imbalances, should be excluded or corrected before initiating treatment.

Like all cytotoxic agents, Ifosfamide should generally be used with caution in debilitated patients or elderly patients, as well as in patients who have previously received radiation therapy.

Particular caution is also indicated in patients with weakened immune defenses, for example, in cases of diabetes mellitus or chronic liver or kidney disorders.

The condition of patients with brain metastases, cerebral symptoms, and/or impaired renal function should be regularly monitored.

Use during pregnancy or breastfeeding

Pregnancy

Administration of ifosfamide during organogenesis has been shown to cause fetotoxic effects in mice, rats, and rabbits, and therefore may cause fetal harm when administered to pregnant women.

There are only very limited data on ifosfamide treatment during pregnancy. Cases of fetal growth retardation and neonatal anemia have been reported after administration of chemotherapy regimens including ifosfamide during pregnancy. Numerous congenital abnormalities have been reported after administration of the drug during the first trimester of pregnancy. Data from animal studies with cyclophosphamide, another cytotoxic agent in the oxazaphosphorine group, suggest that the increased risk of pregnancy loss and developmental abnormalities may persist after discontinuation of the drug as long as oocytes/follicles exposed to the drug during any stage of maturation remain.

Furthermore, cyclophosphamide exposure has been reported to cause miscarriages, developmental abnormalities (after exposure during the first trimester of pregnancy), and effects in newborns such as leukopenia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis.

Given the results of animal studies, reports in humans, and data on the mechanism of action of the substance, the use of ifosfamide during pregnancy, especially during the first trimester, is not recommended.

In each individual case, the benefits of treatment and potential risks to the fetus should be weighed.

A physician's consultation regarding pregnancy termination is mandatory in cases of life-threatening indications for treatment during the first trimester of pregnancy.

After the first trimester of pregnancy, if chemotherapy cannot be delayed and the child is desired, all information about the low but non-zero risk of congenital abnormalities in the child should be provided.

If ifosfamide is administered during pregnancy or if a woman becomes pregnant during or after treatment with this drug, the patient should be informed about the potential risk to the fetus.

Breastfeeding

Ifosfamide passes into breast milk and may cause neutropenia, thrombocytopenia, decreased hemoglobin concentration, and diarrhea in infants. Ifosfamide is contraindicated during breastfeeding.

Fertility

Ifosfamide affects oogenesis and spermatogenesis. This may lead to infertility in both sexes. Administration of ifosfamide may cause transient or persistent amenorrhea in women and oligospermia or azoospermia in boys during the prepubertal period.

Men should be informed before ifosfamide treatment about the possibility of sperm cryopreservation.

Genotoxicity

Ifosfamide exerts genotoxic and mutagenic effects on male and female germ cells. Therefore, women and men are advised to avoid conception during ifosfamide therapy.

Men are advised to avoid conception for 6 months after completion of therapy.

Women and men should use effective contraceptive methods during ifosfamide therapy and for 6 months after completion of treatment.

Ability to affect reaction speed when driving or operating machinery

Ifosfamide may negatively affect the ability to drive or operate machinery due to encephalopathy, as well as due to nausea and vomiting, particularly when used concomitantly with medicinal products acting on the CNS or alcohol consumption.

Administration and Dosage

Ifosfamide must be administered only by an experienced oncologist familiar with the use of this drug. The dose should be individually adjusted.

The dose, duration of treatment, and intervals between treatment cycles depend on the indication, combination therapy regimen, and individual patient needs, taking into account general health status, organ function, and blood counts.

When used in combination with other agents having similar toxicity, dose reduction or extended intervals between treatments may be necessary.

Where appropriate, hematopoietic growth factors (colony-stimulating factors and erythropoiesis-stimulating agents) may be used to reduce the risk of myelosuppressive complications and/or to facilitate adherence to the prescribed dosing schedule. For information on potential interactions between this drug and granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF), see section «Interaction with other medicinal products and other forms of interaction».

To promote diuresis and reduce the risk of urothelial toxicity, adequate fluid intake (oral or via infusion) must be ensured during and immediately after drug administration (see section «Special precautions for use»).

To prevent hemorrhagic cystitis, ifosfamide must be administered in combination with mesna.

Recommended Doses

Fractionated administration is the most common regimen for monotherapy in adult patients.

Fractionated administration: 1.2–2.4 g/m² body surface area (up to 60 mg/kg body weight) daily for 5 consecutive days as intravenous infusion.

Administer by intravenous infusion over a period of 30 minutes to 2 hours, depending on the volume infused.

Prolonged infusion: 5 g/m² body surface area (=125 mg/kg body weight), as a high single dose, is usually administered via a 24-hour prolonged infusion.

The total dose per cycle must not exceed 8 g/m² body surface area (=200 mg/kg body weight). Compared to fractionated administration, administration of ifosfamide as a high single dose may result in more severe hematological, urological, nephrological, and CNS toxicity.

The ready-to-use ifosfamide solution must not exceed a concentration of 4%. As with any other cytostatic agent, blood counts must be monitored before each chemotherapy cycle and between cycles. Depending on blood test results, dose adjustments may be required.

Treatment cycles may be repeated every 3–4 weeks. The intervals between cycles depend on the recovery of blood counts and resolution of adverse reactions or associated symptoms.

Regular monitoring of blood counts, kidney function, urinary tract status, and urine analysis is required. Antiemetic agents may be used, taking into account all potential adverse CNS effects when administered in combination with ifosfamide. In case of fever and/or development of leukopenia, antibiotics and/or antifungal agents should be administered prophylactically. Adequate diuresis must be maintained. Careful oral hygiene is essential.

During prolonged ifosfamide treatment, adequate diuresis and regular monitoring of kidney function are necessary. This is particularly important for children. In cases of nephropathy, continued ifosfamide treatment may lead to irreversible kidney damage. The risk-benefit ratio of treatment must be carefully evaluated. The drug should be used with caution in patients with a single kidney, impaired kidney function, or those previously treated with nephrotoxic agents such as cisplatin. In such patients, the frequency and severity of myelotoxicity, nephrotoxicity, and cerebral toxicity may be increased.

Due to its alkylating effect, ifosfamide is a mutagenic and potentially carcinogenic substance. Therefore, contact with skin and mucous membranes should be avoided.

Special Dosage Recommendations

Elderly Patients

Dose selection for elderly patients requires caution due to the higher prevalence of impaired liver, kidney, heart, and other organ functions, as well as concomitant diseases or other medications. Increased vigilance for the development of toxicity is needed; dose adjustment should be considered.

Patients with Impaired Kidney Function

In patients with impaired kidney function, especially those with severe renal impairment, reduced renal excretion may lead to increased plasma levels of ifosfamide and its metabolites. This may increase toxicity (particularly neurotoxicity, hematotoxic effects, and nephrotoxic effects) and must be considered when determining the dosing regimen for these patients.

Ifosfamide and its metabolites are dialyzable. For patients requiring dialysis, consideration should be given to scheduling an appropriate interval between ifosfamide administration and dialysis.

Patients with Impaired Liver Function

In patients with impaired liver function, especially those with severe hepatic impairment, reduced ifosfamide activation may occur. This may affect the efficacy of ifosfamide treatment. Low serum albumin levels or impaired liver function are considered risk factors for CNS toxicity. Impaired liver function may increase accumulation of metabolites, which is presumed to lead to CNS toxic effects. This must be taken into account when selecting the drug dose and interpreting the response to the chosen dose.

Dosage Reduction Recommendations for Patients with Myelosuppression

When used in combination with other cytostatic agents as part of combination chemotherapy, the dosing regimen should be adapted to the corresponding treatment protocol. When used in combination with other myelotoxic agents, the dosing regimen should be adjusted as necessary.

Note. Due to the urotoxic effect of ifosfamide, the drug should always be administered in combination with mesna. Mesna does not affect other types of toxicity or the therapeutic effects of ifosfamide. If cystitis associated with micro- or macrohematuria occurs during ifosfamide treatment, therapy must be suspended until the patient's condition normalizes.

Preparation of infusion solution

When preparing an ifosfamide solution, safety procedures for handling cytostatic agents must be followed.

Skin reactions may occur following accidental exposure to ifosfamide. To minimize the risk of dermal exposure, waterproof gloves should always be worn when handling vials and solutions containing ifosfamide. If the ifosfamide solution comes into contact with the skin or mucous membranes, the skin should be washed immediately with soap and water, and mucous membranes should be flushed thoroughly with copious amounts of water.

To prepare a 4% ready-to-use solution, dissolve the dry powder in 25 mL of water for injections.

The substance dissolves within ½–1 minute after addition of the solvent upon vigorous shaking of the vial. If complete dissolution does not occur immediately, the solution should be left to stand for several minutes.

Parenteral preparations should be inspected visually for particulate matter and discoloration prior to administration.

The substance must be completely dissolved before parenteral administration.

For intravenous infusion, the ready-to-use solution should be diluted in 5% glucose solution, 0.9% sodium chloride solution, or Ringer's solution. For example: dilute to a volume of 250 mL for infusion over 30–60 minutes, or to 500 mL for infusion over 1–2 hours. For prolonged 24-hour high-dose ifosfamide infusion, the total dose (5 g/m²) should be diluted in three liters of 5% glucose solution or 0.9% sodium chloride solution.

Children.

According to standard treatment protocols, children and adolescents may receive the same doses as recommended for adults.

Overdose.

There is no specific antidote for ifosfamide. Therefore, extreme caution must be exercised whenever the drug is administered. In cases of overdose, whether intentional (suicidal intent) or accidental, prompt hemodialysis is indicated.

Severe consequences of overdose include dose-dependent toxicities such as central nervous system toxicity, nephrotoxicity, myelosuppression, and mucositis (see section «Special precautions for use»). The severity and duration of myelosuppression depend on the degree of overdose.

Patients who have received an excessive dose should be closely monitored for signs of toxicity. In cases of severe neutropenia, infection prophylaxis with antibiotics should be initiated. In cases of thrombocytopenia, platelet transfusions should be administered as needed. Severe hemorrhagic cystitis may develop in the absence or insufficiency of preventive measures. Uroprotection with mesna is required to prevent or limit urotoxic effects.

Note. There is no risk of tissue damage following accidental paravenous administration of the drug, since the cytotoxic effect of ifosfamide occurs only after its activation in the liver.

Adverse Reactions

The adverse reactions and frequencies listed below are based on data obtained from publications describing the clinical experience of fractionated administration of ifosfamide as monotherapy with a total dose of 4 to 12 g/m² per course.

Frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from available data).

Infections and infestations: common – infections*; uncommon – pneumonia; frequency not known – sepsis (septic shock)**.

Neoplasms benign and malignant (including cysts and polyps): uncommon – secondary tumors, urinary tract cancer, myelodysplastic syndrome, acute leukemia***, acute lymphoblastic leukemia**; frequency not known – lymphoma (non-Hodgkin's lymphoma), sarcoma**, renal cell carcinoma, thyroid cancer, progression of existing malignancy*.

Blood and lymphatic system disorders: very common – myelosuppression****, leukopenia¹, neutropenia, thrombocytopenia², anemia³; frequency not known – hematotoxicity**, agranulocytosis, febrile neutropenia, hemolytic uremic syndrome, disseminated intravascular coagulation, hemolytic anemia, neonatal anemia, methemoglobinemia.

Immune system disorders: rare – hypersensitivity reactions; very rare – anaphylactic shock; frequency not known – angioneurotic edema**, anaphylactic reaction, immunosuppression, urticaria.

Endocrine disorders: rare – syndrome of inappropriate antidiuretic hormone secretion.

Metabolism and nutrition disorders: common – metabolic acidosis, anorexia; rare – hyponatremia, water retention; very rare – hypokalemia; frequency not known – tumor lysis syndrome, hypocalcemia, hypophosphatemia, hyperglycemia, polydipsia.

Psychiatric disorders: uncommon – hallucinations, depressive psychosis, disorientation, excitement, confusion; frequency not known – panic attack, catatonia, mania, paranoia, delirium, bradiphrenia, mutism, mental status changes, echolalia, logorrhea, perseveration, amnesia.

Nervous system disorders: very common – CNS toxicity, encephalopathy, lethargy; uncommon – somnolence, memory disorders, dizziness, peripheral neuropathy; rare – cerebellar syndrome, seizures**; very rare – coma, polyneuropathy; frequency not known – neurotoxicity^3,4 (dysarthria, epileptoid status, reversible posterior leukoencephalopathy syndrome, leukoencephalopathy, extrapyramidal disorders, asterixis, apraxia, dysesthesia, hypesthesia, paresthesia, neuralgia, gait disturbance, fecal incontinence).

Eye disorders: rare – visual disturbances; frequency not known – blurred vision, conjunctivitis, eye irritation.

Ear and labyrinth disorders: frequency not known – deafness, hearing loss, vertigo, tinnitus.

Cardiac disorders: uncommon – cardiotoxicity⁶ (ventricular arrhythmia, ventricular extrasystole, supraventricular arrhythmia, supraventricular extrasystole, heart failure**); frequency not known – arrhythmia (ventricular fibrillation**, ventricular tachycardia**, supraventricular fibrillation, atrial flutter, premature atrial contraction), bradycardia, cardiac arrest**, myocardial infarction, cardiogenic shock**, left bundle branch block, right bundle branch block, pericardial effusion, myocardial hemorrhage, angina pectoris, left ventricular dysfunction, cardiomyopathy**, congestive cardiomyopathy, myocarditis**, pericarditis, myocardial depression, palpitations, reduced ejection fraction**, ECG changes (ST segment, T segment, QRS complex).

Vascular disorders: uncommon – arterial hypotension⁷, bleeding risk; very rare – phlebitis¹⁰; frequency not known – pulmonary embolism, deep vein thrombosis, capillary leak syndrome, vasculitis, arterial hypertension, hypotension, flushing.

Respiratory, thoracic and mediastinal disorders: very rare – interstitial pneumonitis, interstitial pulmonary fibrosis** (manifesting as pulmonary fibrosis), pulmonary edema**; frequency not known – respiratory arrest**, acute respiratory distress syndrome**, pulmonary hypertension**, allergic alveolitis, pneumonitis**, pleural effusion, bronchospasm, dyspnea, hypoxia, cough, respiratory failure.

Gastrointestinal disorders: very common – nausea, vomiting; uncommon – diarrhea, stomatitis, constipation; very rare – pancreatitis; frequency not known – typhlitis, colitis, enterocolitis, intestinal obstruction, gastrointestinal hemorrhage, mucosal ulceration, abdominal pain, hypersalivation.

Hepatobiliary disorders: uncommon – liver function disorders, hepatotoxicity⁸; frequency not known – hepatotoxicity**, fulminant hepatitis**, hepatic veno-occlusive disease, portal vein thrombosis, cytolytic hepatitis, cholestasis.

Skin and subcutaneous tissue disorders: very common – alopecia; rare – papular rash, dermatitis; frequency not known – toxic epidermal necrolysis, Stevens-Johnson syndrome, hand-foot erythrodysesthesia syndrome, radiation dermatitis, skin necrosis, facial swelling, petechiae, rash, macular rash, pruritus, erythema, skin hyperpigmentation, hyperhidrosis, nail disorders.

Musculoskeletal and connective tissue disorders: very rare – rickets, osteomalacia; frequency not known – rhabdomyolysis, growth retardation, myalgia, arthralgia, limb pain, muscle spasms.

Renal and urinary disorders: very common – hematuria, microhematuria, macrohematuria, hemorrhagic cystitis, renal dysfunction¹⁰, kidney structural abnormalities; common – nephropathy, tubular dysfunction; uncommon – urinary incontinence; rare – glomerular dysfunction, tubular acidosis, proteinuria; very rare – Fanconi syndrome; frequency not known – acute renal failure**, chronic renal failure**, tubulointerstitial nephritis, neurogenic diabetes insipidus, phosphaturia, aminoaciduria, polyuria, enuresis, sensation of incomplete bladder emptying.

Pregnancy, puerperium and perinatal conditions: common – spermatogenesis disorders; uncommon – ovarian insufficiency, amenorrhea, decreased blood estrogen levels; rare – azoospermia, oligospermia; frequency not known – infertility, premature menopause, ovarian function disorders, increased blood gonadotropin levels.

Reproductive system and breast disorders: rare – hyperaminoaciduria; frequency not known – fetal growth retardation.

Congenital, familial and genetic disorders: very rare – increased sensitivity to radiation.

General disorders and administration site conditions: very common – fever; common – febrile neutropenia, weakness; uncommon – fatigue; frequency not known – malaise, multi-organ failure**, worsening general condition, injection site reactions*****, chest pain, edema, mucosal inflammation, pain, increased body temperature, chills.

* Includes also reactivation of latent infections, including viral hepatitis, Pneumocystis jiroveci, herpes zoster, Strongyloides, progressive multifocal leukoencephalopathy, and other viral and fungal infections.

** Including cases with fatal outcome.

*** Includes acute myeloid leukemia, acute promyelocytic leukemia, acute lymphoblastic leukemia.

**** Myelosuppression manifests as bone marrow failure.

***** Including edema, inflammation, pain, erythema, tenderness, pruritus.

¹ Terms related to adverse reactions reported regarding leukopenia: neutropenia, granulocytopenia, lymphopenia, and pancytopenia. See below for febrile neutropenia.

² Thrombocytopenia may also be complicated by bleeding. Cases of fatal bleeding have been reported.

³ Includes cases recorded as anemia and decreased hemoglobin/hematocrit levels.

⁴ Cases of encephalopathy with coma and fatal outcome have been reported.

⁵ Central nervous system toxicity has been reported to manifest as: abnormal behavior, affective lability, aggression, excitement, anxiety, aphasia, asthenia, ataxia, cerebellar syndrome, cerebral function failure, cognitive disorder, coma, confusion, cranial nerve dysfunction, depressed level of consciousness, depression, disorientation, dizziness, EEG abnormalities, encephalopathy, emotional blunting, hallucinations, headache, imagery disturbance, lethargy, memory impairment, mood alteration, motor dysfunction, muscle spasms, myoclonus, progressive loss of brainstem reflexes, psychotic reaction, restlessness, somnolence, tremor, urinary incontinence.

⁶ Cases of cardiotoxicity have been reported, manifesting as congestive heart failure, tachycardia, pulmonary edema. Fatal cases have been reported.

⁷ Cases of hypotension leading to shock and fatal outcome have been reported.

⁸ Cases of hepatotoxicity have been reported, manifesting as increased liver enzyme activity, namely serum alanine aminotransferase, serum aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, and lactate dehydrogenase, increased bilirubin levels, jaundice, hepatorenal syndrome.

⁹ The frequency of hemorrhagic cystitis cases is estimated based on the frequency of hematuria cases. Dysuria and pollakiuria were included among hemorrhagic cystitis symptoms.

¹⁰ Renal dysfunction has been reported to manifest as renal failure (including acute renal failure, irreversible renal failure; fatal cases have been recorded), increased serum creatinine, increased blood urea nitrogen, decreased creatinine clearance, metabolic acidosis, anuria, oliguria, glucosuria, hyponatremia, uremia, increased creatinine clearance. Structural kidney abnormalities have been reported to manifest as acute tubular necrosis, parenchymal kidney damage, enzymuria, cylindruria, proteinuria.

¹¹ Includes cases recorded as phlebitis and venous wall inflammation.

¹² Frequency of febrile neutropenia includes cases recorded as granulocytopenic fever.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Incompatibilities.

Currently unknown. Solutions containing benzyl alcohol may reduce ifosfamide stability.

Packaging.

1 g of lyophilisate in a vial; 1 vial per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Venus Remedies Limited.

Manufacturer's address and location of operations.

Hill Top Industrial Estate, Jharmajri, EPIP Phase-I (Extn.), Bhatoli Kalan, Baddi, Distt. Solan, Himachal Pradesh 173205, India.