Ifosfamide

Ifosfamide is an antineoplastic and alkylating agent belonging to the pharmacological class of nitrogen mustards.

The FDA approves ifosfamide to manage and treat various cancers such as sarcoma, lymphoma and lung cancer.

Ifosfamide is rapidly absorbed from the administration site, swiftly entering the bloodstream. It efficiently penetrates the blood-brain barrier, distributing into the cerebrospinal fluid. Additionally, ifosfamide traverses into breast milk. Extensive liver metabolism follows, with subsequent elimination primarily through renal pathways.

Ifosfamide's most common side effects include nausea, vomiting, hair loss, anaemia (low number of red blood cells), and decreased white blood cell count.

Ifosfamide is available as an injectable solution.

The molecule is available in India, Australia, Germany, France, the United States, the United Kingdom, Canada, Italy, Japan and Brazil.

Ifosfamide is an antineoplastic/ alkylating agent belonging to the pharmacological class of nitrogen mustards.

Ifosfamide, an oxazaphosphorine alkylating agent, is a prodrug metabolized in the liver by CYP450 enzymes. Active metabolites, phosphoramide mustard derivatives, and acrolein induce cell damage via interstrand or intrastrand crosslinks, leading to apoptosis. Additionally, they upregulate reactive oxygen species, causing irreparable DNA damage and halting protein formation. Notably, ifosfamide and cyclophosphamide exhibit enhanced anti-tumour activity, and renal function dictates dosage adjustments due primarily to kidney filtration.

Ifosfamide is available as an injectable solution.

Injectable solutions: To be administered parenterally, usually intravenously.

As the physician recommends, take the medication orally once daily, and it can be taken with or without food as directed.

Ifosfamide can be used for the following health conditions:

• Malignant diseases such as pancreatic cancer, ovarian cancer, non-small cell lung cancer, breast cancer and blood cancer
• Germ cell testicular carcinoma

• Malignant diseases: Ifosfamide exerts efficacy against various malignant conditions, including pancreatic cancer, ovarian cancer, breast cancer, non-small cell lung cancer, and blood cancers. Functioning as a potent alkylating agent, ifosfamide disrupts DNA replication, hindering cancer cell proliferation. Its integration into combination therapies or chemotherapy regimens results in tumour shrinkage and enhanced disease management. The drug actively targets rapidly dividing cells, demonstrating its crucial role in treating various malignancies with varied benefits depending on the specific cancer type.
• Germ cell testicular carcinoma: Ifosfamide actively targets and treats germ cell testicular carcinoma by efficiently attacking rapidly dividing cancer cells, resulting in tumour regression. Its inclusion in treatment protocols actively enhances therapeutic responses and improves outcomes for patients with this specific type of testicular cancer.

• Malignant diseases: Ifosfamide exerts efficacy against various malignant conditions, including pancreatic cancer, ovarian cancer, breast cancer, non-small cell lung cancer, and blood cancers. Functioning as a potent alkylating agent, ifosfamide disrupts DNA replication, hindering cancer cell proliferation. Its integration into combination therapies or chemotherapy regimens results in tumour shrinkage and enhanced disease management. The drug actively targets rapidly dividing cells, demonstrating its crucial role in treating various malignancies with varied benefits depending on the specific cancer type.
• Germ cell testicular carcinoma: Ifosfamide actively targets and treats germ cell testicular carcinoma by efficiently attacking rapidly dividing cancer cells, resulting in tumour regression. Its inclusion in treatment protocols actively enhances therapeutic responses and improves outcomes for patients with this specific type of testicular cancer.

Parenterally: Ifosfamide is usually administered parenterally as injection solutions, once daily, with or without food; adjust dosage according to patient response and severity of the condition. Administer ifosfamide via a slow 30-minute IV infusion or a continuous 5-day infusion. Administer Mesna concurrently, comprising 20% of the Ifosfamide dose 15 minutes before, 4 hours after, and 8 hours after Ifosfamide administration. To reduce the risk of hemorrhagic cystitis, ensure adequate hydration (at least 2 L/day) before and for 72 hours post-therapy.

Individuals must adhere strictly to the prescribed dosage and administration schedule. Patients are also advised to consult their healthcare provider about the medication's benefits and potential side effects.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

• Powder with mesna solution: 1g/vial, 3g/vial
• Solution: 1g/20Ml, 3g/60mL

Ifosfamide is available as an injectable solution.

Dose Adjustment in Adult Patients:

Malignant disease

There are different available dose regimens.

Regimen 1: 8–12 g/m2 split equally into single daily dosages over 3–5 days, to be repeated every 2–4 weeks.

Regimen 2: once every three to four weeks, administer a single 24-hour infusion of 5–6 g/m2 (maximum 10 g). Regimen 3: every 3–4 weeks, provide 2-2.4 g/m2 (50–60 mg/kg) every day for five days in a row. to be administered along with mesna and sufficient fluid intake—at least 2 L of oral or IV fluid each day. The patient's blood count, recovery from any side effects, and tolerability influence the dosage, duration of the treatment, and intervals.

Germ Cell Testicular Cancer

Prescribed in conjunction with additional antitumor drugs for third-line germ cell testicular cancer

On days 1–5, q3–4 weeks, or after recuperating from hematologic toxicity (>100,000 cells/mm³ platelets or ≥4,000 cells/mm³ WBC), 1.2 g/m²/day IV infusion over 30 minutes

Off-label use includes doses as high as 5 g/m² over 24 hours via continuous IV infusion in combination with other antineoplastic drugs utilized; 2 g/m²/day IV infusion on days 1-3 (MAID regimen, for a total dose of 6 g/m²).

Management

240 mg/m² IV given concurrently at 0, 4, and 8 hours can help prevent hemorrhagic cystitis.

Continue consuming more than two litres of fluid daily by oral or IV hydration.

Observe: CBCs

When undergoing Ifosfamide treatment, adhering to specific dietary restrictions and safety guidelines is crucial. Choose diverse low-fat, protein-rich foods, incorporating seafood, lean meat, poultry, Greek yoghurt, eggs, beans, soy products, and unsalted nuts and seeds. Include vitamin A-rich foods like sweet potatoes, carrots, kale, spinach, and apricots. Avoid strong-smelling foods to prevent aggravating taste disorders. Minimize the intake of fatty, fried, spicy, and overly sweet foods to decrease the risk of nausea. Eliminate refined sugars and carbohydrates from your diet, as tumours typically thrive on glucose. Abstaining from alcohol and quitting smoking contributes to overall health and well-being.

The dietary restriction should be individualized as per patient requirements.

• Patients with diseases that have previously shown resistance to Ifosfamide shouldn't be treated with it. The medication shouldn't be administered to patients who have shown signs of hypersensitivity to Ifosfamide.
• Pregnancy
• Severe myelosuppression

• Severe and potentially fatal myelosuppression leading to infections necessitates vigilant monitoring of blood counts before and at intervals after treatment initiation. Immediate medical attention is essential to mitigate risks.

• Careful monitoring for severe and fatal neurotoxicity is imperative. CNS toxicity and other neurotoxic effects should be actively assessed. In the event of encephalopathy development, prompt discontinuation of therapy is warranted to prevent further complications.

• Urotoxicity poses a significant risk, with potential severe nephrotoxicity leading to renal failure and death. Regular monitoring of serum and urine chemistries is crucial, and using Mesna is recommended to reduce the occurrence of hemorrhagic cystitis.

• Cardiotoxicity, encompassing arrhythmias, ECG changes, and cardiomyopathy, can occur, potentially resulting in death. Caution is advised in patients with cardiac risk factors and those with preexisting cardiac disease. The risk of cardiotoxicity is dose-dependent, emphasizing the importance of careful dosage considerations.

• Pulmonary toxicity, including interstitial pneumonitis and pulmonary fibrosis, may lead to fatal outcomes. Monitoring for signs and symptoms of pulmonary toxicity is essential, with prompt clinical intervention as needed.

• The occurrence of secondary malignancies as late sequelae underscores the necessity for long-term surveillance and regular screenings.

• Anaphylactic/anaphylactoid reactions have been reported, necessitating awareness and readiness for immediate intervention in case of such reactions. Healthcare providers should be prepared to manage potential allergic responses during treatment.

• Healthcare professionals should exercise caution, closely monitor patients, and consider these warnings and precautions to ensure this medication's safe and effective use in clinical settings. Regular communication between healthcare providers and patients is vital for informed decision-making and proactive management of potential risks associated with therapy.

Avoid alcohol consumption while taking Ifosfamide.

Avoid use during breastfeeding.

It is not recommended during pregnancy, especially in the first trimester.

Increase intake of nutrient-rich foods and proteins and limit fat intake.

The adverse reactions related to Ifosfamide can be categorized as:

• Common Effects: Alopecia, nausea, vomiting, leukopenia, hematuria, metabolic acidosis, thrombocytopenia, CNS toxicity, and neurotoxicity.
• Less Common Effects: Infection, nephrotoxicity.
• Rare Effects: Central nervous system toxicity, neurotoxicity, and thrombocytopenia

The clinically relevant drug interactions of Ifosfamide are briefly summarized here.

• Drug interactions: Concomitant use with CYP3A4 inducers (e.g., carbamazepine, phenytoin) increases toxic metabolite formation. CYP3A4 inhibitors (e.g., ketoconazole) may diminish ifosfamide effectiveness. Previous or concurrent busulfan treatment heightens haemorrhagic cystitis risk. ACE inhibitors, carboplatin, cisplatin, and natalizumab intensify haematoxicity. Anthracyclines elevate cardiotoxicity, while amiodarone, granulocyte colony-stimulating factors boost pulmonary toxicity. Nephrotoxicity increases with aminoglycosides, aciclovir, and amphotericin B. Additive CNS effects occur with antiemetics, antihistamines, narcotics, and sedatives. Neurotoxicity rises with aprepitant. IV docetaxel elevates gastrointestinal toxicity. Warfarin raises INR. Tamoxifen use increases thromboembolic risk. Ifosfamide may enhance the hypoglycemic effects of antidiabetic agents and reduce the formation of irinotecan's active metabolite. Concurrent live vaccine use may lead to vaccine-induced infection.
• Food Interaction: Increased toxicity when using St. John's wort. Ifosfamide's effectiveness may be diminished by grapefruit or grapefruit juice. Drinking alcohol may make you more susceptible to hepatic impairment or ifosfamide-induced nausea and vomiting.

The most common side effects of Ifosfamide include:

• Nausea
• Pale/wrinkled skin
• Temporary hair loss
• Vomiting
• Blood in urine
• Anemia (low number of red blood cells)
• Hair loss
• Dehydration
• Dry mouth/increased thirst
• Trouble breathing
• Decreased white blood cell count
• Infection
• CNS toxicity

•Pregnancy

Pregnancy Category D (FDA): Use in cases where no safer medication is available and life is in danger. Positive evidence of prenatal risk in humans.

If given to a pregnant woman, ifosfamide may harm the developing fetus. There have been cases of fetal development retardation and neonatal anaemia after pregnant women received chemotherapy regimens containing ifosfamide. In both male and female germ cells, ifosfamide is genotoxic and mutagenic. At dosages between 0.05 and 0.075 times that of humans, embryotoxic and teratogenic effects have been found in mice, rats, and rabbits.

During ifosfamide therapy, women should not become pregnant. Moreover, males shouldn't father a child for a maximum of six months following the conclusion of treatment. Patients who use this medication while pregnant, if they become pregnant while taking it, or after treatment, should be informed of the possible risk to the developing fetus.

•Fertility

Oogenesis and spermatogenesis are inhibited by ifosfamide. There have been reports of azoospermia, amenorrhea, and sterility in both sexes. The onset of sterility is influenced by the ifosfamide dosage, length of treatment, and gonadal function at the beginning of treatment. Some patients may never regain their sterility.

•Nursing Mothers

In breast milk, ifosfamide is excreted. It is essential to consider the value of the drug to the mother when deciding whether to stop nursing or to stop taking it altogether due to the possibility of significant side effects and the tumorigenicity of ifosfamide, as demonstrated in animal studies.

•Pediatric Use

As per the FDA, safety and effectiveness in the pediatric population have not been established.

•Geriatric Use

A geriatric patient's dose selection should generally be cautious due to the increased likelihood of reduced cardiac, renal, or liver function and concurrent diseases or other pharmacological therapies.

According to a study including patients between 40 and 71, the elimination half-life lengthens with age. Age-related changes in ifosfamide's volume of distribution are connected to this apparent half-life increase. Age-related variations in either renal or non-renal plasma clearance or total plasma clearance were not found to be significant.

Choosing doses carefully and monitoring renal function is essential because seniors are likelier to have reduced renal function. Since the kidneys are known to eliminate a significant amount of ifosfamide and its metabolites, patients with poor renal function may be more susceptible to adverse effects from this medication. Due to the increased likelihood of reduced renal function in senior patients, caution should be used when choosing dosages, and renal function monitoring may be helpful.

Dose Adjustment in Kidney Impairment Patients:

Dose Adjustment is based on the creatinine clearance

CrCl >60 mL/min: 100% of regular dose

CrCl 30-60 mL/min: 75% of regular dose

CrCl 10-30 mL/min: 50% of regular dose

CrCl <10 mL/min: Not recommended

Dose Adjustment in Hepatic Impairment Patients:

Bilirubin >3 mg/dL: 25% of regular dose

Signs and Symptoms

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Ifosfamide.

Overconsumption of Ifosfamide could lead to Myelosuppression, CNS toxicity, nephrotoxicity, and mucositis.

Management

If an Ifosfamide overdose is suspected, immediately seek medical attention. Provide supportive care, monitor vital signs, and implement symptomatic measures. There is no specific antidote; closely monitor the blood picture and consider general supportive measures, including hematopoietic growth factors and blood product transfusions if necessary. Administration of mesna for cystitis prophylaxis may help prevent urotoxic effects.

In severe cases, consulting a poison control centre or a medical toxicologist can be beneficial for appropriate guidance and intervention.

Pharmacodynamics:

For ifosfamide to have cytotoxic effects, it must be converted to active metabolites by microsomal liver enzymes. Activation occurs by hydroxylating at carbon atom 4 in the ring, resulting in the unstable intermediate 4-hydroxyifosfamide. The quick breakdown of this molecule then produces the stable urinary metabolite 4-ketoifosfamide. Opening the ring results in the formation of 4-carboxyifosfamide, a persistent urine metabolite. It has not been discovered that specific urine metabolites are cytotoxic. Acrolein and N, N-bis (2-chloroethyl)-phosphoric acid diamide, often known as phosphoramide, are also present. Enzymatic oxidation of the chloroethyl side chains and subsequent dealkylation result in the formation of the primary urinary metabolites, dechloroethyl cyclophosphamide and dechloroethyl ifosfamide. It has been demonstrated that ifosfamide interacts with DNA through its alkylated metabolites. It is not cycle-phase specific, isosfamide.

Pharmacokinetics:

• Absorption: Ifosfamide exhibits rapid absorption from the administration site, facilitating its swift entry into the bloodstream.
• Distribution: The drug quickly penetrates the blood-brain barrier, allowing distribution into the cerebrospinal fluid (CSF). Furthermore, ifosfamide can traverse into breast milk.
• Metabolism: Extensive metabolism occurs in the liver through two distinct pathways. Ring oxidation leads to the formation of the active metabolite, 4-hydroxy-ifosfamide. Simultaneously, side-chain oxidation generates inactive metabolites, such as 3-dichloro-ethyl ifosfamide or 2-dichloro-ethyl ifosfamide. This metabolic process liberates the toxic metabolite chloroacetaldehyde.
• Excretion: Mainly excreted via urine, ifosfamide and its metabolites are eliminated through renal pathways. This process plays a crucial role in removing the drug from the body.
• Elimination Half-life: The elimination half-life of ifosfamide varies with dosage. It is approximately 15 hours for high doses, while for lower doses, it is around 7 hours.

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