PRESERVATIVE FREE SOLUTION

Rx Only

DESCRIPTION

Vincristine Sulfate Injection, USP is the salt ofan alkaloid obtained from a common flowering herb, the periwinkleplant (Vinca rosea Linn). Originallyknown as leurocristine, it has also been referred to as LCR and VCR.

The molecular formula for Vincristine Sulfate, USP isC46H56N4010•H2SO4. It has a molecular weight of 923.04.

The structural formula is as follows:

Vincristine Sulfate, USP is a white to off–whitepowder. It is soluble in methanol, freely soluble in water, but onlyslightly soluble in 95% ethanol. In 98% ethanol, Vincristine Sulfate,USP has an ultraviolet spectrum with maxima at 221 nm (∈+47,100).

Vincristine Sulfate Injection, USP is a sterile, preservative–free,single use only solution available for intravenous use in 2 mL (1mg and 2 mg) vials. Each mL contains 1 mg Vincristine Sulfate, USP,100 mg mannitol and Water for Injection, USP q.s. Sulfuric acid orsodium hydroxide have been added for pH control. The pH of VincristineSulfate Injection, USP ranges from 4.0 to 5.0. At the time of manufacture,the air in the containers is replaced by nitrogen.

CLINICAL PHARMACOLOGY

The mechanisms of action of vincristine sulfate remainunder investigation. The mechanism of action of vincristine sulfatehas been related to the inhibition of microtubule formation in mitoticspindle, resulting in an arrest of dividing cells at the metaphasestage.

Central nervous system leukemia has beenreported in patients undergoing otherwise successful therapy withvincristine sulfate. This suggests that vincristine does not penetratewell into the cerebrospinal fluid.

Pharmacokineticstudies in patients with cancer have shown a triphasic serum decaypattern following rapid intravenous injection. The initial, middleand terminal half–lives are 5 minutes, 2.3 hours, and 85 hoursrespectively; however, the range of the terminal half–lifein humans is from 19 to 155 hours. The liver is the major excretoryorgan in humans and animals. The metabolism of vinca alkaloids hasbeen shown to be mediated by hepatic cytochrome P450 isoenzymes inthe CYP 3A subfamily. This metabolic pathway may be impaired in patientswith hepatic dysfunction or who are taking concomitant potent inhibitorsof these isoenzymes (see Precautions). About 80% of an injected dose of vincristine sulfate appears inthe feces and 10% to 20% can be found in the urine. Within 15 to 30minutes after injection, over 90% of the drug is distributed fromthe blood into tissue, where it remains tightly, but not irreversibly,bound.

Current principles of cancer chemotherapyinvolve the simultaneous use of several agents. Generally, each agentused has a unique toxicity and mechanism of action so that therapeuticenhancement occurs without additive toxicity. It is rarely possibleto achieve equally good results with single–agent methods oftreatment. Thus, vincristine sulfate is often chosen as part of polychemotherapybecause of lack of significant bone–marrow suppression (atrecommended doses) and of unique clinical toxicity (neuropathy). See Dosage and Administration section for possibleincreased toxicity when used in combination therapy.

INDICATIONS AND USAGE

Vincristine sulfate injection is indicated in acuteleukemia.

Vincristine sulfate injection hasalso been shown to be useful in combination with other oncolytic agentsin Hodgkin’s disease, non–Hodgkin’s malignantlymphomas (lymphocytic, mixed cell, histiocytic, undifferentiated,nodular and diffuse types), rhabdomyosarcoma, neuroblastoma, and Wilms’tumor.

CONTRAINDICATIONS

Patients with the demyelinating form of Charcot–Marie–Toothsyndrome should not be given vincristine sulfate injection. Carefulattention should be given to those conditions listed under Warning and Precautions.

Pregnancy Category D

Vincristine sulfate can cause fetal harm when administeredto a pregnant woman. When pregnant mice and hamsters were given dosesof vincristine sulfate that caused resorption of 23% to 85% of fetuses,fetal malformations were produced in those that survived. Five monkeyswere given single doses of vincristine sulfate between days 27 and34 of their pregnancies; 3 of the fetuses were normal at term, and2 viable fetuses had grossly evident malformations at term. In severalanimal species, vincristine sulfate can induce teratogenesis as wellas embryo death at doses that are nontoxic to the pregnant animal.There are no adequate and well–controlled studies in pregnantwomen. If this drug is used during pregnancy or if the patient becomespregnant while receiving this drug, she should be apprised of thepotential hazard to the fetus. Women of child–bearing potentialshould be advised to avoid becoming pregnant.

PRECAUTIONS

General

Acute uric acid nephropathy, which may occur afterthe administration of oncolytic agents, has also been reported withvincristine sulfate. In the presence of leukopenia or a complicatinginfection, administration of the next dose of vincristine sulfateinjection warrants careful consideration.

Ifcentral nervous system leukemia is diagnosed, additional agents maybe required, because vincristine does not appear to cross the blood–brainbarrier in adequate amounts.

Particular attentionshould be given to dosage and neurologic side effects if vincristinesulfate injection is administered to patients with preexisting neuromusculardisease and when other drugs with neurotoxic potential are also beingused.

Acute shortness of breath and severe broncospasmhave been reported following the administration of vinca alkaloids.These reactions have been encountered most frequently when the vincaalkaloid was used in combination with mitomycin–C and may requireaggressive treatment, particularly when there is preexisting pulmonarydysfunction. The onset of these reactions may occur minutes to severalhours after the vinca alkaloid is injected and may occur up to 2 weeksfollowing the dose of mitomycin. Progressive dyspnea requiring chronictherapy may occur. Vincristine sulfate should not be readministered.

Care must be taken to avoid contamination of the eye withconcentration of vincristine sulfate injection used clinically. Ifaccidental contamination occurs severe irritation (or, if the drugwas delivered under pressure, even corneal ulceration) may result.The eye should be washed immediately and thoroughly.

Laboratory Tests

Because dose–limiting clinical toxicity ismanifested as neurotoxicity clinical eva luation (e.g., history, physicalexamination) is necessary to detect the need for dosage modification.Following administration of vincristine sulfate injection, some individualsmay have a fall in the white blood cell count or platelet count, particularlywhen previous therapy or the disease itself has reduced bone–marrowfunction. Therefore, a complete blood count should be done beforeadministration of each dose. Acute elevation of serum uric acid mayalso occur during induction of remission in acute leukemia; thus,such levels should be determined frequently during the first 3 to4 weeks of treatment or appropriate measures taken to prevent uricacid nephropathy. The laboratory performing these tests should beconsulted for its range of normal values.

Drug Interactions

The simultaneous oral or intravenous administrationof phenytoin and antineoplastic chemotherapy combinations that includedvincristine sulfate has been reported to reduce blood levels of theanticonvulsant and to increase seizure activity. Dosage adjustmentshould be based on serial blood level monitoring. The contributionof vincristine sulfate to this interaction is not certain. The interactionmay result from reduced absorption of phenytoin and an increase inthe rate of its metabolism and elimination.

Caution should be exercised in patients concurrently taking drugsknown to inhibit drug metabolism by hepatic cytochrome P450 isoenzymesin the CYP 3A subfamily, or in patients with hepatic dysfunction.Concurrent administration of vincristine sulfate with itraconazole(a known inhibitor of the metabolic pathway) has been reported tocause an earlier onset and/or an increased severity of neuromuscularside effects (see Adverse Reactions). This interaction is presumed to be related to inhibition of themetabolism of vincristine.

Carcinogenesis, Mutagenesis,Impairment of Fertility

Neither in vivo nor in vitro laboratory testshave conclusively demonstrated the mutagenicity of this product. Fertilityfollowing treatment with vincristine sulfate alone for malignant diseasehas not been studied in humans. Clinical reports of both male andfemale patients who received multiple–agent chemotherapy thatincluded vincristine sulfate indicate that azoospermia and amenorrheacan occur in postpubertal patients. Recovery occurred many monthsafter completion of chemotherapy in some but not all patients. Whenthe same treatment is administered to prepubertal patients, permanentazoospermia and amenorrhea are much less likely.

Patients who received chemotherapy with vincristine sulfate in combinationwith anti–cancer drugs known to be carcinogenic have developedsecond malignancies. The contributing role of vincristine sulfatein this development has not been determined. No evidence of carcinogenicitywas found following intraperitoneal administration of vincristinesulfate in rats and mice, although this study was limited.

Usage in Pregnancy

Pregnancy Category D. See Warnings.

Nursing Mothers

It is not known whether this drug is excreted inhuman milk. Because many drugs are excreted in human milk and becauseof the potential for serious adverse reactions due to vincristinesulfate in nursing infants, a decision should be made either to discontinuenursing or the drug, taking into account the importance of the drugto the mother.

Pediatric Use

See Dosage and Administration section.

ADVERSE REACTIONS

Prior to the use of thisdrug, patients and/or their parents/guardian should be advised ofthe possibility of untoward symptoms.

In general, adverse reactions are reversible and are related to dosage.The most common adverse reaction is hair loss; the most troublesomeadverse reactions are neuromuscular in origin.

When single, weekly doses of the drug are employed, the adverse reactionsof leukopenia, neuritic pain, and constipation occur but are usuallyof short duration (ie., less than 7 days). When the dosage is reduced,these reactions may lessen or disappear. The severity of such reactionsseems to increase when the calculated amount of drug is given in divideddoses. Other adverse reactions, such as hair loss, sensory loss, paresthesia, difficulty in walking, slapping gait, loss of deep–tendonreflexes, and muscle wasting, may persist for at least as long astherapy is continued. Generalized sensorimotor dysfunction may becomeprogressively more severe with continued treatment. Although mostsuch symptoms usually disappear by about the sixth week after discontinuanceof treatment, some neuromuscular difficulties may persist for prolongedperiods in some patients. Regrowth of hair may occur while maintenancetherapy continues.

The following adverse reactionshave been reported:

Hepatic veno-occlusive disease has been reported in patients receivingvincristine, particularly in pediatric patients, as part of standardcombination chemotherapy regimens. Some of the patients had fataloutcomes; some who survived had undergone liver transplantation.

Hypersensitivity – Rare cases of allergic–type reactions, such asanaphylaxis, rash and edema, that are temporally related to vincristinetherapy have been reported in patients receiving vincristine as apart of multidrug chemotherapy regimens.

Gastrointestinal – Constipation,abdominal cramps, weight loss, nausea, vomiting, oral ulceration,diarrhea, paralytic ileus, intestinal necrosis and/or perforation,and anorexia have occurred. Constipation may take the form of upper–colonimpaction, and, on physical examination, the rectum may be empty.Colicky abdominal pain coupled with an empty rectum may mislead thephysician. A flat film of the abdomen is useful in demonstrating thiscondition. All cases have responded to high enemas and laxatives.A routine prophylactic regimen against constipation is recommendedfor all patients receiving vincristine sulfate injection.

Paralytic ileus (which mimics the “surgical abdomen”)may occur, particularly in young pediatric patients. The ileus willreverse itself with temporary discontinuance of vincristine sulfateinjection and with symptomatic care.

Genitourinary – Polyuria, dysuria,and urinary retention due to bladder atony have occurred. Other drugsknown to cause urinary retention (particularly in the elderly) should,if possible, be discontinued for the first few days following administrationof vincristine sulfate injection.

Cardiovascular – Hypertension andhypotension have occurred. Chemotherapy combinations that have includedvincristine sulfate, when given to patients previously treated withmediastinal radiation, have been associated with coronary artery diseaseand myocardial infarction. Causality has not been established.

Neurologic – Frequently, there is a sequence to the development of neuromuscularside effects. Initially, only sensory impairment and paresthesia maybe encountered. With continued treatment, neuritic pain and, later,motor difficulties may occur. There have been no reports of any agentthat can reverse the neuromuscular manifestations that may accompanytherapy with vincristine sulfate.

Loss of deep–tendonreflexes, foot drop, ataxia, and paralysis have been reported withcontinued administration. Cranial nerve manifestations, such as isolatedparesis and/or paralysis of muscles controlled by cranial motor nervesincluding potentially life–threatening bilateral vocal cordparalysis, may occur in the absence of motor impairment elsewhere;extraocular and laryngeal muscles are those most commonly involved.Jaw pain, pharyngeal pain, parotid gland pain, bone pain, back pain,limb pain, and myalgias have been reported; pain in these areas maybe severe. Convulsions, frequently with hypertension, have been reportedin a few patients receiving vincristine sulfate. Several instancesof convulsions followed by coma have been reported in pediatric patients.Transient cortical blindness and optic atrophy with blindness havebeen reported. Treatment with vinca alkaloids has resulted in bothvestibular and auditory damage to the eighth cranial nerve. Manifestationsinclude partial or total deafness which may be temporary or permanent,and difficulties with balance including dizziness, nystagmus, andvertigo. Particular caution is warranted when vincristine is usedin combination with other agents known to be ototoxic such as theplatinum–containing oncolytics.

Pulmonary – See Precautions.

Endocrine – Rare occurrences ofa syndrome attributable to inappropriate antidiuretic hormone secretionhave been observed in patients treated with vincristine sulfate. Thissyndrome is characterized by high urinary sodium excretion in thepresence of hyponatremia; renal or adrenal disease, hypotension, dehydration,azotemia, and clinical edema are absent. With fluid deprivation, improvementoccurs in the hyponatremia and in the renal loss of sodium.

Hematologic – Vincristine sulfate injection does not appear to have any constantor significant effect on platelets or red blood cells. Serious bone–marrowdepression is usually not a major dose–limiting event. However,anemia, leukopenia, and thrombocytopenia have been reported. Thrombocytopenia,if present when therapy with vincristine sulfate injection is begun,may actually improve before the appearance of bone marrow remission.

Skin – Alopeciaand rash have been reported.

Other – Fever and headache haveoccurred.

OVERDOSAGE

Side effects following the use of vincristine sulfateinjection are dose related. In pediatric patients under 13 years ofage, death has occurred following doses of vincristine sulfate thatwere 10 times those recommended for therapy. Severe symptoms may occurin this patient group following dosages of 3 to 4 mg/m2. Adults can be expected to experience severe symptoms after singledoses of 3 mg/m2 or more (see Adverse Reactions). Therefore, following administrationof doses higher than those recommended, patients can be expected toexperience exaggerated side effects. Supportive care should includethe following: (1) prevention of side effects resulting from the syndromeof inappropriate antidiuretic hormone secretion (preventive treatmentwould include restriction of fluid intake and perhaps the administrationof a diuretic affecting the function of Henle’s loop and thedistal tubule); (2) administration of anticonvulsants; (3) use ofenemas or cathartics to prevent ileus (in some instances, decompressionof the gastrointestinal tract may be necessary); (4) monitoring thecardiovascular system; (5) determining daily blood counts for guidancein transfusion requirements.

Folinic acid hasbeen observed to have a protective effect in normal mice that wereadministered lethal doses of vincristine sulfate (Cancer Res 1963;23:1390). Isolated casereports suggest that folinic acid may be helpful in treating humanswho have received an overdose of vincristine sulfate. It is suggestedthat 100 mg of folinic acid be administered intravenously every 3hours for 24 hours and then every 6 hours for at least 48 hours. Theoretically(based on pharmacokinetic data), tissue levels of vincristine sulfatecan be expected to remain significantly elevated for at least 72 hours.Treatment with folinic acid does not eliminate the need for the abovementioned supportive measures.

Most of an intravenousdose of vincristine is excreted into the bile after rapid tissue binding(see Clinical Pharmacology). Becauseonly very small amounts of the drug appear in dialysate, hemodialysisis not likely to be helpful in cases of overdosage. An increase inthe severity of side effects may be experienced by patients with liverdisease that is severe enough to decrease biliary excretion.

Enhanced fecal excretion of parenterally administeredvincristine has been demonstrated in dogs pretreated with cholestyramine.There are no published clinical data on the use of cholestyramineas an antidote in humans.

There are no publishedclinical data on the consequences of oral ingestion of vincristine.Should oral ingestion occur, the stomach should be evacuated. Evacuationshould be followed by oral administration of activated charcoal anda cathartic.

DOSAGE AND ADMINISTRATION

This preparation isfor intravenous use only (see Warnings).

Neurotoxicity appears to be dose related. Extreme care must be usedin calculating and administering the dose of Vincristine Sulfate Injection, USP since overdosage mayhave a very serious or fatal outcome.

Special Dispensing Information:WHEN DISPENSINGVINCRISTINE SULFATE INJECTION, USP IN OTHER THAN THE ORIGINAL CONTAINER,IT IS IMPERATIVE THAT IT BE PACKAGED IN THE PROVIDED OVERWRAP WHICHBEARS THE FOLLOWING STATEMENT: “DO NOT REMOVE COVERING UNTILMOMENT OF INJECTION. FATAL IF GIVEN INTRATHECALLY. FOR INTRAVENOUSUSE ONLY” (see Warnings). A syringe containinga specific dose must be labeled, using the auxiliary sticker provided,to state: “FATAL IF GIVEN INTRATHECALLY.FOR INTRAVENOUS USE ONLY.”

The concentration of Vincristine Sulfate Injection, USP is 1 mg/mL.Do not add extra fluid to the vial prior to removal of the dose. Withdrawthe solution of Vincristine Sulfate Injection, USP into an accuratedry syringe, measuring the dose carefully. Do not add extra fluidto the vial in an attempt to empty it completely.

Caution: It is extremely important thatthe intravenous needle or catheter be properly positioned before anyvincristine is injected. Leakage into surrounding tissue during intravenousadministration of Vincristine Sulfate Injection, USP may cause considerableirritation. If extravasation occurs, the injection should be discontinuedimmediately and any remaining portion of the dose should then be introducedinto another vein. Local injection of hyaluronidase and the applicationof moderate heat to the area of leakage will help disperse the drugand may minimize discomfort and the possibility of cellulitis.

Vincristine Sulfate Injection, USP must beadministered via an intact, free–flowing intravenous needleor catheter. Care should be taken that there is no leakage or swellingoccurring during administration (see boxed Warnings).

The solution may be injectedeither directly into a vein or into the tubing of a running intravenousinfusion (see Drug Interactions below). Injection of Vincristine Sulfate Injection, USP should beaccomplished within 1 minute.

The drug is administeredintravenously at weekly intervals.

The usual dose of Vincristine Sulfate Injection,USP for pediatric patients is 1.5–2 mg/m2. For pediatricpatients weighing 10 kg or less, the starting dose should be 0.05mg/kg, administered once a week. The usual dose of Vincristine SulfateInjection, USP for adults is 1.4 mg/m2. A 50% reductionin the dose of Vincristine Sulfate Injection, USP is recommended forpatients having a direct serum bilirubin value above 3 mg/100 mL.

Vincristine Sulfate Injection,USP should not be given to patients while they are receiving radiationtherapy through ports that include the liver. When VincristineSulfate Injection, USP is used in combination with L–asparaginase,Vincristine Sulfate Injection, USP should be given 12 to 24 hoursbefore administration of the enzyme in order to minimize toxicity;administering L–asparaginase before Vincristine Sulfate Injection,USP may reduce hepatic clearance of vincristine.

Drug Interactions – VincristineSulfate Injection, USP should not be diluted in solutions that raiseor lower the pH outside the range of 3.5 to 5.5. It should not bemixed with anything other than normal saline or glucose in water.

Whenever solution and container permit, parenteral drugproducts should be inspected visually for particulate matter and discolorationprior to administration.

Handling and Disposal – Procedures for proper handlingand disposal of anticancer drugs should be considered. Several guidelineson this subject have been published.1-7 There is no generalagreement that all of the procedures recommended in the guidelinesare necessary or appropriate.

HOW SUPPLIED

Vincristine Sulfate Injection, USP, preservativefree solution.

NDC 61703–309–061 mg, 1 mg/1 mL (single use), flip–top vial (blue cap)
NDC61703–309–16 2 mg, 2 mg/2 mL (single use), flip–topvial (blue cap)

This product should be refrigeratedbetween 2°–8°C (36°– 46°F). Discardunused solution. Protect from light. Store Upright.

REFERENCES

1. Recommendations for the Safe Handling of Parenteral AntineoplasticDrugs, NIH Publication No. 83–2621. For sale by the Superintendentof Documents, U.S. Government Printing Office, Washington, D.C. 20402.
2. AMA Council Report, Guidelines for Handling Parenteral Antineoplastics,JAMA, 1985; 253 (11): 1590–1592.
3. National Study Commission on Cytotoxic Exposure – Recommendationsfor Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD.,Chairman, National Study Commission on Cytotoxic Exposure, MassachusettsCollege of Pharmacy and Allied Health Sciences, 179 Longwood Avenue,Boston, Massachusetts 02115.
4. Clinical Oncological Society of Australia, Guidelines and Recommendationsfor Safe Handling of Antineoplastic Agents. Med J Australia, 1983; 1:426–428.
5. Jones RB, et al: SafeHandling of Chemotherapeutic Agents: Report from the Mount Sinai Medical Center. CA – A Cancer Journal of Clinicians,1983; (Sept/Oct) 258–263.
6. American Society of Hospital Pharmacists Technical AssistanceBulletin on Handling Cytotoxic and Hazardous Drugs. Am J. Hosp. Pharm,1990; 47:1033–1049.
7. OSHA Work–Practice Guidelines for Personnel Dealing withCytotoxic (Antineoplastic) Drugs. Am J Hosp Pharm, 1986; 43: 1193–1204.

Hospira, Inc.

Lake Forest, IL 60045

Product of Australia

Revision December 2007

482805