Istin Information
Istin (Carbinoxamine maleate)
Istin (Carbinoxamine maleate) Description
VincrIstin (Carbinoxamine maleate) e Sulfate Injection, USP is the salt of an alkaloid obtained from a common flowering herb, the periwinkle plant ( Linn). Originally known as leurocrIstin (Carbinoxamine maleate) e, it has also been referred to as LCR and VCR.
The molecular formula for VincrIstin (Carbinoxamine maleate) e Sulfate, USP is CHN0•HSO. It has a molecular weight of 923.04.
The structural formula is as follows:
VincrIstin (Carbinoxamine maleate) e Sulfate, USP is a white to off–white powder. It is soluble in methanol, freely soluble in water, but only slightly soluble in 95% ethanol. In 98% ethanol, VincrIstin (Carbinoxamine maleate) e Sulfate, USP has an ultraviolet spectrum with maxima at 221 nm (∈+47,100).
VincrIstin (Carbinoxamine maleate) e Sulfate Injection, USP is a sterile, preservative–free, single use only solution available for intravenous use in 2 mL (1 mg and 2 mg) vials. Each mL contains 1 mg VincrIstin (Carbinoxamine maleate) e Sulfate, USP, 100 mg mannitol and Water for Injection, USP q.s. Sulfuric acid or sodium hydroxide have been added for pH control. The pH of VincrIstin (Carbinoxamine maleate) e Sulfate Injection, USP ranges from 4.0 to 5.0. At the time of manufacture, the air in the containers is replaced by nitrogen.
Istin (Carbinoxamine maleate) Clinical Pharmacology
The mechanisms of action of vincrIstin (Carbinoxamine maleate) e sulfate remain under investigation. The mechanism of action of vincrIstin (Carbinoxamine maleate) e sulfate has been related to the inhibition of microtubule formation in mitotic spindle, resulting in an arrest of dividing cells at the metaphase stage.
Central nervous system leukemia has been reported in patients undergoing otherwise successful therapy with vincrIstin (Carbinoxamine maleate) e sulfate. This suggests that vincrIstin (Carbinoxamine maleate) e does not penetrate well into the cerebrospinal fluid.
Pharmacokinetic studies in patients with cancer have shown a triphasic serum decay pattern following rapid intravenous injection. The initial, middle and terminal half–lives are 5 minutes, 2.3 hours, and 85 hours respectively; however, the range of the terminal half–life in humans is from 19 to 155 hours. The liver is the major excretory organ in humans and animals. The metabolism of vinca alkaloids has been shown to be mediated by hepatic cytochrome P450 isoenzymes in the CYP 3A subfamily. This metabolic pathway may be impaired in patients with hepatic dysfunction or who are taking concomitant potent inhibitors of these isoenzymes (see ). About 80% of an injected dose of vincrIstin (Carbinoxamine maleate) e sulfate appears in the feces and 10% to 20% can be found in the urine. Within 15 to 30 minutes after injection, over 90% of the drug is distributed from the blood into tissue, where it remains tightly, but not irreversibly, bound.
Current principles of cancer chemotherapy involve the simultaneous use of several agents. Generally, each agent used has a unique toxicity and mechanism of action so that therapeutic enhancement occurs without additive toxicity. It is rarely possible to achieve equally good results with single–agent methods of treatment. Thus, vincrIstin (Carbinoxamine maleate) e sulfate is often chosen as part of polychemotherapy because of lack of significant bone–marrow suppression (at recommended doses) and of unique clinical toxicity (neuropathy). See section for possible increased toxicity when used in combination therapy.
Istin (Carbinoxamine maleate) Indications And Usage
VincrIstin (Carbinoxamine maleate) e sulfate injection is indicated in acute leukemia.
VincrIstin (Carbinoxamine maleate) e sulfate injection has also been shown to be useful in combination with other oncolytic agents in Hodgkin’s disease, non–Hodgkin’s malignant lymphomas (lymphocytic, mixed cell, histiocytic, undifferentiated, nodular and diffuse types), rhabdomyosarcoma, neuroblastoma, and Wilms’ tumor.
Istin (Carbinoxamine maleate) Contraindications
Patients with the demyelinating form of Charcot–Marie–Tooth syndrome should not be given vincrIstin (Carbinoxamine maleate) e sulfate injection. Careful attention should be given to those conditions listed under and .
Istin (Carbinoxamine maleate) Warnings
Extemporaneously prepared syringes containing this product must be packaged in an overwrap which is labeled
Treatment of patients following intrathecal administration of vincrIstin (Carbinoxamine maleate) e sulfate injection has included immediate removal of spinal fluid and flushing with Lactated Ringer’s, as well as other solutions and has not prevented ascending paralysis and death. In one case, progressive paralysis in an adult was arrested by the following treatment
Istin (Carbinoxamine maleate)
Istin (Carbinoxamine maleate) Precautions
If central nervous system leukemia is diagnosed, additional agents may be required, because vincrIstin (Carbinoxamine maleate) e does not appear to cross the blood–brain barrier in adequate amounts.
Particular attention should be given to dosage and neurologic side effects if vincrIstin (Carbinoxamine maleate) e sulfate injection is administered to patients with preexIstin (Carbinoxamine maleate) g neuromuscular disease and when other drugs with neurotoxic potential are also being used.
Acute shortness of breath and severe broncospasm have been reported following the administration of vinca alkaloids. These reactions have been encountered most frequently when the vinca alkaloid was used in combination with mitomycin–C and may require aggressive treatment, particularly when there is preexIstin (Carbinoxamine maleate) g pulmonary dysfunction. The onset of these reactions may occur minutes to several hours after the vinca alkaloid is injected and may occur up to 2 weeks following the dose of mitomycin. Progressive dyspnea requiring chronic therapy may occur. VincrIstin (Carbinoxamine maleate) e sulfate should not be readministered.
Care must be taken to avoid contamination of the eye with concentration of vincrIstin (Carbinoxamine maleate) e sulfate injection used clinically. If accidental contamination occurs severe irritation (or, if the drug was delivered under pressure, even corneal ulceration) may result. The eye should be washed immediately and thoroughly.
Caution should be exercised in patients concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP 3A subfamily, or in patients with hepatic dysfunction. Concurrent administration of vincrIstin (Carbinoxamine maleate) e sulfate with itraconazole (a known inhibitor of the metabolic pathway) has been reported to cause an earlier onset and/or an increased severity of neuromuscular side effects (see ). This interaction is presumed to be related to inhibition of the metabolism of vincrIstin (Carbinoxamine maleate) e.
Patients who received chemotherapy with vincrIstin (Carbinoxamine maleate) e sulfate in combination with anti–cancer drugs known to be carcinogenic have developed second malignancies. The contributing role of vincrIstin (Carbinoxamine maleate) e sulfate in this development has not been determined. No evidence of carcinogenicity was found following intraperitoneal administration of vincrIstin (Carbinoxamine maleate) e sulfate in rats and mice, although this study was limited.
Istin (Carbinoxamine maleate)
Istin (Carbinoxamine maleate) Overdosage
Side effects following the use of vincrIstin (Carbinoxamine maleate) e sulfate injection are dose related. In pediatric patients under 13 years of age, death has occurred following doses of vincrIstin (Carbinoxamine maleate) e sulfate that were 10 times those recommended for therapy. Severe symptoms may occur in this patient group following dosages of 3 to 4 mg/m. Adults can be expected to experience severe symptoms after single doses of 3 mg/m or more (see ). Therefore, following administration of doses higher than those recommended, patients can be expected to experience exaggerated side effects. Supportive care should include the following: (1) prevention of side effects resulting from the syndrome of inappropriate antidiuretic hormone secretion (preventive treatment would include restriction of fluid intake and perhaps the administration of a diuretic affecting the function of Henle’s loop and the distal tubule); (2) administration of anticonvulsants; (3) use of enemas or cathartics to prevent ileus (in some instances, decompression of the gastrointestinal tract may be necessary); (4) monitoring the cardiovascular system; (5) determining daily blood counts for guidance in transfusion requirements.
Folinic acid has been observed to have a protective effect in normal mice that were administered lethal doses of vincrIstin (Carbinoxamine maleate) e sulfate ( 1963;23:1390). Isolated case reports suggest that folinic acid may be helpful in treating humans who have received an overdose of vincrIstin (Carbinoxamine maleate) e sulfate. It is suggested that 100 mg of folinic acid be administered intravenously every 3 hours for 24 hours and then every 6 hours for at least 48 hours. Theoretically (based on pharmacokinetic data), tissue levels of vincrIstin (Carbinoxamine maleate) e sulfate can be expected to remain significantly elevated for at least 72 hours. Treatment with folinic acid does not eliminate the need for the above mentioned supportive measures.
Most of an intravenous dose of vincrIstin (Carbinoxamine maleate) e is excreted into the bile after rapid tissue binding (see ). Because only very small amounts of the drug appear in dialysate, hemodialysis is not likely to be helpful in cases of overdosage. An increase in the severity of side effects may be experienced by patients with liver disease that is severe enough to decrease biliary excretion.
Enhanced fecal excretion of parenterally administered vincrIstin (Carbinoxamine maleate) e has been demonstrated in dogs pretreated with cholestyramine. There are no published clinical data on the use of cholestyramine as an antidote in humans.
There are no published clinical data on the consequences of oral ingestion of vincrIstin (Carbinoxamine maleate) e. Should oral ingestion occur, the stomach should be evacuated. Evacuation should be followed by oral administration of activated charcoal and a cathartic.
Istin (Carbinoxamine maleate) Dosage And Administration
The concentration of VincrIstin (Carbinoxamine maleate) e Sulfate Injection, USP is 1 mg/mL. Do not add extra fluid to the vial prior to removal of the dose. Withdraw the solution of VincrIstin (Carbinoxamine maleate) e Sulfate Injection, USP into an accurate dry syringe, measuring the dose carefully. Do not add extra fluid to the vial in an attempt to empty it completely.
VincrIstin (Carbinoxamine maleate) e Sulfate Injection, USP must be administered via an intact, free–flowing intravenous needle or catheter. Care should be taken that there is no leakage or swelling occurring during administration (see boxed ).
The solution may be injected either directly into a vein or into the tubing of a running intravenous infusion (see below). Injection of VincrIstin (Carbinoxamine maleate) e Sulfate Injection, USP should be accomplished within 1 minute.
The drug is administered intravenously .
The usual dose of VincrIstin (Carbinoxamine maleate) e Sulfate Injection, USP for pediatric patients is 1.5–2 mg/m. For pediatric patients weighing 10 kg or less, the starting dose should be 0.05 mg/kg, administered once a week. The usual dose of VincrIstin (Carbinoxamine maleate) e Sulfate Injection, USP for adults is 1.4 mg/m. A 50% reduction in the dose of VincrIstin (Carbinoxamine maleate) e Sulfate Injection, USP is recommended for patients having a direct serum bilirubin value above 3 mg/100 mL.
Whenever solution and container permit, parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
Istin (Carbinoxamine maleate) How Supplied
VincrIstin (Carbinoxamine maleate) e Sulfate Injection, USP, preservative free solution.
NDC 61703–309–06 1 mg, 1 mg/1 mL (single use), flip–top vial (blue cap) NDC 61703–309–16 2 mg, 2 mg/2 mL (single use), flip–top vial (blue cap)
This product should be refrigerated between 2°–8°C (36°–46°F). Discard unused solution. Protect from light. Store Upright.
Istin (Carbinoxamine maleate) References
Lake Forest, IL 60045
Product of Australia 432933
Revised: August, 2011
Istin (Carbinoxamine maleate)
