Vero-ifosfamide (Powder) Instructions for Use

Marketing Authorization Holder

Veropharm, JSC (Russia)

Manufactured By

Veropharm, LLC (Russia)

ATC Code

L01AA06 (Ifosfamide)

Active Substance

Ifosfamide (Rec.INN registered by WHO)

Dosage Forms

	Vero-Ifosfamide	Powder for solution for injection 1 g: vial 1 pc.
		Powder for solution for injection 2 g: vial 1, 20 or 30 pcs.

Dosage Form, Packaging, and Composition

Powder for solution for injection white or almost white, microcrystalline; a slight specific odor is allowed; powder caking is possible.

1 g – vials of colorless glass (1) – cardboard packs.

Powder for solution for injection white or almost white, microcrystalline; a slight specific odor is allowed; powder caking is possible.

2 g – vials of colorless glass (1) – cardboard packs.

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).

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

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

Ifosfamide and its metabolite are excreted mainly by the kidneys. The 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 treatment schedule individually based on the specific malignancy, disease stage, and patient’s hematological status.

For most solid tumors and lymphomas in adults, common regimens include a daily dose of 1.2 g/m² to 2.5 g/m² body surface area, administered for 3 to 5 consecutive days. Repeat treatment cycles every 3 to 4 weeks, provided hematological recovery has occurred.

For high-dose therapy, administer single doses up to 5 g/m² with adequate supportive care, including vigorous hydration and uroprotection.

Always administer in combination with the uroprotective agent mesna to prevent hemorrhagic cystitis. The total daily mesna dose should equal 60-120% of the total daily ifosfamide dose, administered as intravenous bolus injections or a continuous infusion.

Ensure vigorous hydration with at least 2 liters of fluid per day, either orally or intravenously, to ensure high urinary output and reduce bladder toxicity. Monitor urine output and sediment regularly.

Adjust the dose based on hematological parameters. Withhold therapy if the leukocyte count falls below 2,000/mm³ and/or the platelet count falls below 50,000/mm³.

Reduce the dose in patients with impaired renal function or elderly patients. Exercise extreme caution and consider dose reduction in patients with pre-existing hepatic impairment.

Reconstitute the powder with Water for Injections or bacteriostatic water. Further dilute the resulting solution in 500 ml of a compatible infusion solution, such as 0.9% sodium chloride or 5% glucose. Administer the infusion over a period of 30 minutes to several hours.

In pediatric patients, use established pediatric oncology protocols. Doses typically range from 1.2 g/m² to 3.0 g/m² per day for 3 to 5 days.

Adverse Reactions

Infections and infestations: frequent – infections.

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

From the metabolism: frequent – anorexia.

From the nervous system: very common – neurotoxicity to 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 the urine, painful urination), impaired renal function (increased serum creatinine and urea concentration, 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 dysfunction (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 difficult urination, active urinary tract infections, chickenpox (including recently past or after contact with sick people), herpes zoster, previous radiation therapy, debilitated patients.

Use in Pregnancy and Lactation

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

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

In experimental studies, the teratogenic and embryotoxic effects of ifosfamide have been established.

Use in Hepatic Impairment

It should be used with caution in case of impaired liver function, chronic liver failure.

Use in Renal Impairment

It should be used with caution in patients with impaired renal function.

Pediatric Use

It is possible to use in children according to indications in recommended doses and therapy regimens.

Geriatric Use

It 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. There have been reports of fatal outcomes of myelosuppression and associated development of severe infections while using ifosfamide.

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. At the same time, due to a 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 administration should, if possible, be discontinued.

Before starting treatment with ifosfamide, glomerular and tubular kidney functions should be assessed and their condition monitored during and after treatment. During therapy with ifosfamide, it is necessary to regularly monitor urine sediment for the presence of red blood cells and other signs of uro- or nephrotoxicity. It is recommended to conduct thorough clinical monitoring of serum and urine biochemistry, including phosphorus, potassium and other laboratory parameters used to identify nephrotoxicity and urothelial toxicity. If indicated, appropriate replacement therapy should be prescribed.

The possibility of using ifosfamide in patients with existing kidney damage or reduced kidney function should be considered individually, carefully assessing the ratio of expected benefit to 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 that appear after the use of ifosfamide 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 are the use of high cumulative doses of ifosfamide, the presence of renal pathology, previous or concomitant therapy with potentially nephrotoxic drugs, early age in children (under 5 years), the absence of one kidney both in patients with kidney tumors and in those who underwent irradiation of 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 fractional administration. There is evidence of the development of hemorrhagic cystitis 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 effect of ifosfamide.

Before starting ifosfamide therapy, any urinary tract obstruction, cystitis and other infections of the kidneys and urinary tract, as well as electrolyte imbalance, should be excluded or eliminated.

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 should be paid to adequate hydration and regular bladder emptying.

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

Fatal outcomes of the cardiotoxic effect of ifosfamide have been reported. The risk of developing cardiotoxic effects of ifosfamide is dose-dependent and increases in patients with previous or concomitant treatment with other cardiotoxic drugs or the use of radiation to the heart area and, possibly, in case of impaired renal function. In this regard, special caution should be exercised 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. It is reported that interstitial pneumonitis and pneumosclerosis, as well as other forms of pulmonary toxicity, develop during treatment with ifosfamide.

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 leukemia increases. Other malignant tumors reported after the use of ifosfamide or therapeutic regimens with its use are lymphomas, thyroid cancer and sarcomas.

Ifosfamide has mutagenic potential and genotoxicity to 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 conservation before starting treatment and that they should not conceive children either during therapy or for at least 6 months after its completion. Reliable means of contraception should 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. In this case, genetic counseling is indicated.

Ifosfamide affects the processes of 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 usually not affected.

In boys treated with ifosfamide before puberty, secondary sexual characteristics may develop normally, but oligospermia or azoospermia may also 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 carry out ifosfamide therapy, the condition of these patients should be carefully monitored. Liver damage, especially severe, may be associated with a decrease in the activation of ifosfamide, which may affect the effectiveness of therapy.

Ethanol consumption increases the risk of liver dysfunction.

When selecting the dose and monitoring the toxicity of ifosfamide 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 the ability to drive vehicles and mechanisms

During therapy with ifosfamide, nausea and vomiting, as well as phenomena of encephalopathy, are possible, which may affect the ability to drive a car or work with other mechanisms. Therefore, patients receiving Ifosfamide should avoid driving and other activities that require high concentration and speed of psychomotor reactions.

Drug Interactions

Increased 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.

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

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 appear.

The possibility of increased formation of cytotoxic metabolites in case of previous or concomitant use of carbamazepine, corticosteroids, rifampicin, phenobarbital, benzodiazepines, chloral hydrate, phenytoin and St. John’s wort preparations should be taken into account.

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

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

An increase in the International Normalized Ratio has been observed in patients receiving Ifosfamide and warfarin.

As an immunosuppressant, Ifosfamide can be expected to reduce 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 when used concomitantly with ifosfamide.

Enhancement of ifosfamide myelotoxicity due to interaction with other cytotoxic drugs or radiation should be considered. Concurrent use of ifosfamide and allopurinol or hydrochlorothiazide may also increase the myelosuppressive effect.

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

The therapeutic effect and toxicity of ifosfamide may be enhanced by the concomitant 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 efficacy. Patients being treated with ifosfamide should avoid consuming grapefruit and/or products or drinks 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.