Isoxan

Isoxan Uses, Dosage, Side Effects, Food Interaction and all others data.

Ifosfamide is converted to its active metabolites via hepatic microsomal enzymes. These active metabolites act as alkylating agents, disrupting DNA and protein synthesis of the target cells. It is routinely given with mesna to reduce urothelial toxicity.

Ifosfamide requires activation by microsomal liver enzymes to active metabolites in order to exert its cytotoxic effects. Activation occurs by hydroxylation at the ring carbon atom 4 to form the unstable intermediate 4-hydroxyifosfamide. This metabolite than rapidly degrades to the stable urinary metabolite 4-ketoifosfamide. The stable urinary metabolite, 4-carboxyifosfamide, is formed upon opening of the ring. These urinary metabolites have not been found to be cytotoxic. N, N-bis (2-chloroethyl)-phosphoric acid diamide (ifosphoramide) and acrolein are also found. The major urinary metabolites, dechloroethyl ifosfamide and dechloroethyl cyclophosphamide, are formed upon enzymatic oxidation of the chloroethyl side chains and subsequent dealkylation. It is the alkylated metabolites of ifosfamide that have been shown to interact with DNA. Ifosfamide is cycle-phase nonspecific.

Mesna is used to prevent urothelial toxicity associated with oxazaphosphorine, ifosfamide or cyclophosphamide. It acts in the kidney; reacting with thiol groups of urotoxic metabolites (e.g. acrolein) of ifosfamide and cyclophosphamide. It is used as a mucolytic in the management of some respiratory tract conditions e.g. cystic fibrosis where other mucolytics have failed. It acts by reducing the viscosity of pulmonary secretions; the drug's free sulfhydryl group is thought to reduce disulfide linkages of mucoproteins.

Isoxan
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Isoxan
Generic	Ifosfamide + Mesna
Type	Injection
Therapeutic Class
Manufacturer	Vhb Life Sciences Limited
Available Country	India
Last Updated:	September 19, 2023 at 7:00 am

Uses

Ifosfamide is used for use in combination with certain other approved antineoplastic agents for third-line chemotherapy of germ cell testicular cancer. It should be used in combination with Mesna for prophylaxis of hemorrhagic cystitis.

Mesna is a cytoprotective agent used as a prophylactic agent in reducing the incidence of ifosfamide-induced hemorrhagic cystitis.

Isoxan is also used to associated treatment for these conditions: Cancer, Bladder, Cervical Cancers, Ewing's Sarcoma, Head and Neck Carcinoma, Lymphoma, Hodgkins, Malignant Neoplasm of Pancreas, Non-Hodgkin's Lymphoma (NHL), Ovarian Cancer, Sarcoma, Osteogenic, Small Cell Lung Cancer (SCLC), Soft Tissue Sarcoma (STS), Testicular Germ Cell Cancer, Advanced thymic carcinoma

How Isoxan works

The exact mechanism of ifosfamide has not been determined, but appears to be similar to other alkylating agents. Ifosfamide requires biotransformation in the liver by mixed-function oxidases (cytochrome P450 system) before it becomes active. After metabolic activation, active metabolites of ifosfamide alkylate or bind with many intracellular molecular structures, including nucleic acids. The cytotoxic action is primarily through the alkylation of DNA, done by attaching the N-7 position of guanine to its reactive electrophilic groups. The formation of inter and intra strand cross-links in the DNA results in cell death.

Dosage

Isoxan dosage

Lymphoma, Sarcoma, Solid tumours: Different licensed dosage regimens are available.

Regimen 1: 8-12 gm/m2 divided over 3-5 days, repeat course every 2-4 wk.
Regimen 2: 6 gm/m2 divided over 5 days, repeat course every 3 wk.
Regimen 3: 5-6 gm/m2 (max: 10 gm), give as a single 24-hr infusion, repeat course every 3-4 wkly.

Germ cell testicular carcinoma: 1.2 gm/m2/day for 5 days via slow infusion over at least 30 minutes, repeat treatment every 3 wk or after recovery from haematological toxicity. To be given with mesna and adequate hydration of at least 2 L of oral or IV fluid per day.

Intravenous-Prophylaxis against urothelial toxicity:

Adult: Refer to individual and local protocol. Dose calculated according to cytotoxic dose. Normally given at a dose ≥cytotoxic dose. Duration of treatment should be as long as cytotoxic treatment; plus the time it takes for concentration of antineoplastic metabolites in urine to fall. Administered either by short (15-30 minutes) or continuous (24 hr) infusion.
Child: Refer to individual and local protocol. Has been used in children >4 mth.

Oral-Prophylaxis against urothelial toxicity:

Adult: Refer to individual and local protocol. Dose calculated according to cytotoxic dose. Normally given at a dose ≥cytotoxic dose. Duration of treatment should be as long as cytotoxic treatment; plus the time it takes for concentration of antineoplastic metabolites in urine to fall.
Child: Refer to individual and local protocol.

Add 20 ml of sterile water for inj or sterile bacteriostatic water for inj containing benzyl alcohol or parabens for each 1 g of the drug to produce solutions of 50 mg/ml.

Dilute in 50-1000 ml normal saline, 5% dextrose or lactated Ringer's.

Side Effects

Confusion, alopoecia, nausea, vomiting, phloebitis, somnolence, depression, hallucinations. Wound healing may be impaired during ifosfamide use.

Potentially Fatal: Severe myelosuppression, haemorrhagic cystitis, nephrotoxicity, cardiotoxicity, coma.

Nausea, vomiting, colic, diarrhoea, anorexia, dyspepsia, unpleasant taste, constipation; headache, malaise, fatigue, depression, irritability, somnolence, hyperaesthesia, dizziness, confusion; rash, pruritus, generalised urticaria, alopecia, inj site reactions, flushing; leucopenia, thrombocytopenia, anaemia, granulocytopenia, chest pain, oedema (peripheral, facial and periorbital), hypotension, tachycardia, hypertension, increased heart rate, ST-segment elevation; dyspnoea, coughing, pneumonia, tachypnea; fever; hypocalcaemia; increased sweating; back pain, limb pain, myalgia; increased hepatic enzyme concentrations; pharyngitis; ulceration of mucous membranes. In patients receiving oral and/or IV mesna and were specifically not treated with concurrent cytotoxic therapy: flatulence; rhinitis; rigors; back pain; rash; conjunctivitis; arthralgia. Inhalation: bronchospasm.

Toxicity

LD₅₀ (mouse) = 390-1005 mg/kg, LD₅₀ (rat) = 150-190 mg/kg. Side effects include nausea, vomiting and myelosuppression. Toxic effects include central nervous system toxicity (confusion, hallucinations) and urotoxic effects (cystitis, blood in urine).

Precaution

Hepatic or renal dysfunction, compromised bone marrow reserve. Use with mesna and ensure high oral/IV fluid intake to reduce urotoxic effects.

Protective effect applies only to the urinary tract; pregnancy, lactation. Patients with auto-immune disorders. IV formulation may contain benzyl alcohol as a preservative; avoid in neonates or infants. Instruct patients to seek medical attention if discolouration of urine occurs. During treatment, monitor urine for erythrocytes and haematuria. Maintain adequate hydration in all patients. Patients who vomit within 2 hr of oral dose should repeat dose or receive IV dose.

Interaction

Causes enhanced toxicity with allopurinol, cisplatin. Ifosfamide enhances the anticoagulant effect of warfarin. CYP2A6 inducers (e.g. amobarbital, pentobarbital, phenobarbital, rifampin and secobarbital) may reduce serum levels of ifosfamide while the inhibitors (e.g. isoniazid, methoxsalen and miconazole) may increase its serum levels. CYP3A4 inducers (e.g. aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins) may reduce serum levels of ifosfamide while the inhibitors (e.g. azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid) may increase its serum levels.

Volume of Distribution

Ifosfamide volume of distribution (Vd) approximates the total body water volume, suggesting that distribution takes place with minimal tissue binding. Following intravenous administration of 1.5 g/m2 over 0.5 hour once daily for 5 days to 15 patients with neoplastic disease, the median Vd of ifosfamide was 0.64 L/kg on Day 1 and 0.72 L/kg on Day 5. When given to pediatric patients, the volume of distribution was 21±1.6 L/m^2.

Half Life

7-15 hours. The elimination half-life increase appeared to be related to the increase in ifosfamide volume of distribution with age.

Clearance

2.4±0.33 L/h/m^2 [pediatric patients]

Elimination Route

Ifosfamide is extensively metabolized in humans and the metabolic pathways appear to be saturated at high doses. After administration of doses of 5 g/m2 of 14C-labeled ifosfamide, from 70% to 86% of the dosed radioactivity was recovered in the urine, with about 61% of the dose excreted as parent compound. At doses of 1.6–2.4 g/m2 only 12% to 18% of the dose was excreted in the urine as unchanged drug within 72 hours.

Pregnancy & Breastfeeding use

Category D: There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Pregnancy Category B. Either animal-reproduction studies have not demonstrated a foetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the 1st trimester (and there is no evidence of a risk in later trimesters).