GENERIC NAME: VINCRISTINE SULPHATE

Each Vial Contains:

Vincristine Sulphate IP equivalent to Vincristin…………..1mg

The mechanisms of action of vincristine sulfate remain under investigation. The mechanism of action of vincristine 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 vincristine sulfate. This suggests that vincristine 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 About 80% of an injected dose of vincristine 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, vincristine 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).

Vincristine sulfate injection is indicated in acute leukemia.

Vincristine sulfate injection has also been shown to be useful in combination with other oncolytic agents in Hodgkin’s disease, non–Hodgkin’s malignant lymphomas, rhabdomyosarcoma, neuroblastoma, and Wilms’ tumor.

This preparation is for intravenous use only.

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

The usual dose of Vincristine Sulfate Injection, USP for pediatric patients is 1.5–2 mg/m2 . 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 Vincristine Sulfate Injection, USP for adults is 1.4 mg/m2 . A 50% reduction in the dose of Vincristine Sulfate Injection, USP is recommended for patients having a direct serum bilirubin value above 3 mg/100 mL.

The drug is administered intravenously  at weekly intervals.

TO REDUCE THE POTENTIAL FOR FATAL MEDICATION ERRORS DUE TO INCORRECT ROUTE OF ADMINISTRATION, VINCRISTINE SULFATE INJECTION SHOULD BE DILUTED IN A FLEXIBLE PLASTIC CONTAINER AND PROMINENTLY LABELED 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. Withdraw the solution of Vincristine 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.

Preparation for flexible plastic container

Vincristine Sulfate Injection, USP when diluted with 0.9% Sodium Chloride Injection in concentrations from 0.0015 mg/mL to 0.08 mg/mL is stable for up to 24 hours when protected from light or 8 hours under normal light at 25°C.

Preparation for syringe :

Special Dispensing Information: when dispensing Vincristine Sulfate Injection, USP in a syringe, it is imperative that it be packaged in the provided overwrap which bears the following statement:  “DO NOT REMOVE COVERING UNTIL MOMENT OF INJECTION. FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES” A syringe containing a specific dose must be labeled, using the auxiliary sticker provided, to state:  “FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN  BY OTHER ROUTES.”

Caution: It is extremely important that the intravenous needle or catheter be properly positioned before any vincristine is injected. Leakage into surrounding tissue during intravenous administration of Vincristine Sulfate Injection, USP may cause considerable irritation.   If extravasation occurs, the injection should be discontinued immediately and any remaining portion of the dose should then be introduced into another vein. Local injection of hyaluronidase and the application of moderate heat to the area of leakage will help disperse the drug and may minimize discomfort and the possibility of cellulitis.

Vincristine 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.

The solution may be injected either directly into a vein or into the tubing of a running intravenous infusion (see  Drug Interactions below). Injection of Vincristine Sulfate Injection, USP should be accomplished within 1 minute.

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

Handling and Disposal –Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

• This preparation is for intravenous use only. It should be administered by individuals experienced in the administration of vincristine sulfate injection. The intrathecal administration of vincristine sulfate injection usually results in death.To reduce the potential for fatal medication errors due to incorrect route of administration, Vincristine sulphate injection should be diluted in a flexible plastic container and prominently labeled as indicated for intravenous use only.Syringes containing this product must be labelled, using the auxiliary sticker provided, to state “FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES.”Extemporaneously prepared syringes containing this product must be packaged in an overwrap which is labeled “do not remove covering until moment of injection.  For intravenous use only – fatal if given by other routes.”

• This preparation should be administered by individuals experienced in the administration of Vincristine Sulfate Injection, USP. It is extremely important that the intravenous needle or catheter be properly positioned before any vincristine is injected. Leakage into surrounding tissue during intravenous administration of Vincristine Sulfate Injection, USP may cause considerable irritation. If extravasation occurs, the injection should be discontinued immediately, and any remaining portion of the dose should then be introduced into another vein. Local injection of hyaluronidase and the application of moderate heat to the area of leakage help disperse the drug and are thought to minimize discomfort and the possibility of cellulitis.

Prior to the use of this drug, patients  and/or their parents/guardian should be advised of the 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 troublesome  adverse reactions are neuromuscular in origin.

When single, weekly doses of the drug are employed, the adverse  reactions of leukopenia, neuritic pain, and constipation occur but are usually  of short duration (ie., less than 7 days). When the dosage is reduced, these  reactions may lessen or disappear. The severity of such reactions seems to  increase when the calculated amount of drug is given in divided doses. Other  adverse reactions, such as hair loss, sensory loss, paresthesia, difficulty in  walking, slapping gait, loss of deep–tendon reflexes, and muscle wasting, may  persist for at least as long as therapy is continued. Generalized sensorimotor  dysfunction may become progressively more severe with continued treatment.  Although most such symptoms usually disappear by about the sixth week after  discontinuance of treatment, some neuromuscular difficulties may persist for  prolonged periods in some patients. Regrowth of hair may occur while  maintenance therapy continues.

The following adverse reactions have been reported:

Hepatic veno-occlusive disease has been reported in patients  receiving vincristine, particularly in pediatric patients, as part of standard  combination chemotherapy regimens. Some of the patients had fatal outcomes;  some who survived had undergone liver transplantation.

Hypersensitivity –Rare cases of  allergic–type reactions, such as anaphylaxis, rash and edema, that are  temporally related to vincristine therapy have been reported in patients  receiving vincristine as a part 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–colon impaction, and, on physical  examination, the rectum may be empty. Colicky abdominal pain coupled with an  empty rectum may mislead the physician. A flat film of the abdomen is useful in  demonstrating this condition. All cases have responded to high enemas and  laxatives. A routine prophylactic regimen against constipation is recommended  for all patients receiving vincristine sulfate injection.

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

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

Cardiovascular –Hypertension and  hypotension have occurred. Chemotherapy combinations that have included  vincristine sulfate, when given to patients previously treated with mediastinal  radiation, have been associated with coronary artery disease and myocardial  infarction. Causality has not been established.

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

Loss of deep–tendon reflexes, foot drop, ataxia, and paralysis  have been reported with continued administration. Cranial nerve manifestations,  such as isolated paresis and/or paralysis of muscles controlled by cranial  motor nerves including potentially life–threatening bilateral vocal cord paralysis,  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 may be severe. Convulsions, frequently with  hypertension, have been reported in a few patients receiving vincristine  sulfate. Several instances of convulsions followed by coma have been reported  in pediatric patients. Transient cortical blindness and optic atrophy with  blindness have been reported. Treatment with vinca alkaloids has resulted in  both vestibular and auditory damage to the eighth cranial nerve. Manifestations  include partial or total deafness which may be temporary or permanent, and  difficulties with balance including dizziness, nystagmus, and vertigo.  Particular caution is warranted when vincristine is used in combination with  other agents known to be ototoxic such as the platinum–containing oncolytics.

Endocrine –Rare occurrences of a  syndrome attributable to inappropriate antidiuretic hormone secretion have been  observed in patients treated with vincristine sulfate. This syndrome is  characterized by high urinary sodium excretion in the presence of hyponatremia;  renal or adrenal disease, hypotension, dehydration, azotemia, and clinical  edema are absent. With fluid deprivation, improvement occurs in the  hyponatremia and in the renal loss of sodium.

Hematologic –Vincristine sulfate  injection does not appear to have any constant or significant effect on  platelets or red blood cells. Serious bone–marrow depression 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 –Alopecia and rash have  been reported.

Other –Fever and headache have  occurred.

Vincristine Sulfate Injection, USP should not be diluted in solutions that raise or lower the pH outside the range of 3.5 to 5.5. It should not be mixed with anything other than normal saline or glucose in water.

Whenever solution and container permit, parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Side effects following the use of vincristine sulfate  injection are dose related. In pediatric patients under 13 years of age,  death has occurred following doses of vincristine sulfate that were 10 times  those recommended for therapy. Severe symptoms may occur in this patient group  following dosages of 3 to 4 mg/m2. Adults can be  expected to experience severe symptoms after single doses of 3 mg/m2or more (see ADVERSE REACTIONS above). 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 vincristine sulfate (Cancer Res 1963;23:1390). Isolated case reports  suggest that folinic acid may be helpful in treating humans who have received  an overdose of vincristine 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 vincristine 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 vincristine is excreted  into the bile after rapid tissue binding ). 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  vincristine 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 vincristine. Should oral ingestion occur, the stomach should be  evacuated. Evacuation should be followed by oral administration of activated  charcoal and a cathartic.

Treatment of patients following intrathecal administration  of vincristine 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 initiated immediately after the intrathecal injection:

CONTRADICATIONS

Patients with the demyelinating form of Charcot–Marie–Tooth syndrome should not be given vincristine sulfate injection.

This product should be refrigerated between 2°–8°C (36°–46°F). Discard unused solution. Protect from light. Store Upright.

Vincristine Sulfate Injection, USP, preservative free solution.

1 mg/1 mL (single use)

2 mg/2 mL (single use)