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WARNINGIT IS RECOMMENDED THAT MITHRACIN (plicamycin) BE ADMINISTERED ONLY TO HOSPITALIZED PATIENTS BY OR UNDER THE SUPERVISION OF A QUALIFIED PHYSICIAN WHO IS EXPERIENCED IN THE USE OF CANCER CHEMOTHERAPEUTIC AGENTS, BECAUSE OF THE POSSIBILITY OF SEVERE REACTIONS. FACILITIES FOR THE DETERMINATION OF NECESSARY LABORATORY STUDIES MUST BE AVAILABLE.SEVERE THROMBOCYTOPENIA, A HEMORRHAGIC TENDENCY AND EVEN DEATH MAY RESULT FROM THE USE OF MITHRACIN (plicamycin) . ALTHOUGH SEVERE TOXICITY IS MORE APT TO OCCUR IN PATIENTS WHO HAVE FAR-ADVANCED DISEASE OR ARE OTHERWISE CONSIDERED POOR RISKS FOR THERAPY, SERIOUS TOXICITY MAY ALSO OCCASIONALLY OCCUR EVEN IN PATIENTS WHO ARE IN RELATIVELY GOOD CONDITION. IN THE TREATMENT OF EACH PATIENT, THE PHYSICIAN MUST WEIGH CAREFULLY THE POSSIBILITY OF ACHIEVING THERAPEUTIC BENEFIT VERSUS THE RISK OF TOXICITY WHICH MAY OCCUR WITH MITHRACIN (plicamycin) THERAPY. THE FOLLOWING DATA CONCERNING THE USE OF MITHRACIN (plicamycin) IN THE TREATMENT OF TESTICULAR TUMORS, HYPERCALCEMIC AND/OR HYPERCALCIURIC CONDITIONS ASSOCIATED WITH VARIOUS ADVANCED MALIGNANCIES, SHOULD BE THOROUGHLY REVIEWED BEFORE ADMINISTERING THIS COMPOUND. |
Mithracin (plicamycin) is a yellow crystalline compound which is produced by a microorganism, Streptomyces plicatus. Mithracin (plicamycin) is available in vials as a freeze-dried, sterile preparation for intravenous administration. Each vial contains 2500 mcg (2.5 mg) of Mithracin (plicamycin) with 100 mg of mannitol and sufficient disodium phosphate to adjust to pH 7. After reconstitution with sterile water for injection, the solution has a pH of 7. The drug is unstable in acid solutions with a pH below 4.
Mithracin (plicamycin) is an antineoplastic agent. It has an empirical formula of C 52 H 76 O 24 .
Mithracin (plicamycin) is a potent antineoplastic agent which has been shown to be useful in the treatment of carefully selected hospitalized patients with malignant tumors of the testis in whom successful treatment by surgery and/or radiation is impossible. Also, on the basis of limited clinical experience to date, it may be considered in the treatment of certain symptomatic patients with hypercalcemia and hypercalciuria associated with a variety of advanced neoplasms.
The use of Mithracin (plicamycin) in other types of neoplastic disease is not recommended at the present time.
The daily dose of Mithracin (plicamycin) is based on the patient's body weight. If a patient has abnormal fluid retention such as edema, hydrothorax or ascites, the patient's ideal weight rather than actual body weight should be used to calculate the dose.
Treatment of Testicular Tumors: In the treatment of patients with testicular tumors the recommended daily dose of Mithracin (plicamycin) is 25 to 30 mcg (0.025-0.030 mg) per kilogram of body weight. Therapy should be continued for a period of 8 to 10 days unless significant side effects or toxicity occur during therapy. A course of therapy consisting of more than 10 daily doses is not recommended. Individual daily doses should not exceed 30 mcg (0.030 mg) per kilogram of body weight.
In those patients with responsive tumors, some degree of tumor regression is usually evident within 3 or 4 weeks following the initial course of therapy. If tumor masses remain unchanged following an initial course of therapy, additional courses of therapy at monthly intervals are warranted.
When a significant tumor regression is obtained, it is suggested that additional courses of therapy be given at monthly intervals until a complete regression of tumor masses is achieved or until definite tumor progression or new tumor masses occur in spite of continued courses of therapy.
Treatment of Hypercalcemia and Hypercalciuria: Reversal of hypercalcemia and hypercalciuria can usually be achieved with Mithracin (plicamycin) at doses considerably lower than those recommended for use in the treatment of testicular tumors.
In hypercalcemia and hypercalciuria associated with advanced malignancy the recommended course of treatment with Mithracin (plicamycin) is 25 mcg (0.025 mg) per kilogram of body weight per day for 3 or 4 days.
If the desired degree of reversal of hypercalcemia or hypercalciuria is not achieved with the initial course of therapy, additional courses of therapy may then be administered at intervals of one week or more to achieve the desired result or to maintain serum calcium and urinary calcium excretion at normal levels. It may be possible to maintain normal calcium balance with single, weekly doses or with a schedule of 2 or 3 doses per week.
By IV administration only. The appropriate daily dose of Mithracin (plicamycin) should be diluted in one liter of 5% Dextrose Injection, USP or Sodium Chloride Injection, USP and administered by slow intravenous infusion over a period of 4 to 6 hours. Rapid direct intravenous injection of Mithracin (plicamycin) should be avoided as it may be associated with a higher incidence and greater severity of gastrointestinal side effects. Extravasation of solutions of Mithracin (plicamycin) may cause local irritation and cellulitis at injection sites. Should thrombophlebitis or perivascular cellulitis occur, the infusion should be terminated and reinstituted at another site. The application of moderate heat to the site of extravasation may help to disperse the compound and minimize discomfort and local tissue irritation. The use of antiemetic compounds prior to and during treatment with Mithracin (plicamycin) may be helpful in relieving nausea and vomiting.
Procedures for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines on this subject have been published. 3 - 8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Mithracin (plicamycin) is available in vials as a freeze-dried preparation for intravenous administration. Each vial contains 2500 mcg (2.5 mg) of Mithracin (plicamycin) with 100 mg of mannitol and sufficient disodium phosphate to adjust to pH 7. These vials should be stored at refrigerator temperatures between 2°C to 8°C (36°F to 46°F).
To reconstitute, add aseptically 4.9 mL of Sterile Water for Injection to the contents of the vial and shake to dissolve. Each mL of the resulting solution will then contain 500 mcg (0.5 mg) of Mithracin (plicamycin) . NOTE: 1 mg (milligram)=1000 mcg (micrograms). AFTER REMOVAL OF THE APPROPRIATE DOSE, THE REMAINING UNUSED SOLUTION MUST BE DISCARDED, FRESH SOLUTIONS MUST BE PREPARED IN THE ABOVE MANNER EACH DAY OF THERAPY.
Manufactured for
Bayer Corporation
Pharmaceutical Division
400 Morgan Lane
West Haven, CT 06516
by Ben Venue Laboratories
Bedford, Ohio 44146
THE MOST IMPORTANT FORM OF TOXICITY ASSOCIATED WITH THE USE OF MITHRACIN (plicamycin) CONSISTS OF A BLEEDING SYNDROME WHICH USUALLY BEGINS WITH AN EPISODE OF EPISTAXIS. This bleeding tendency may only consist of a single or several episodes of epistaxis and progress no further. However, in some cases, this hemorrhagic syndrome can start with an episode of hematemesis which may progress to more widespread hemorrhage in the gastrointestinal tract or to a more generalized bleeding tendency. This hemorrhagic diathesis is most likely due to abnormalities in multiple clotting factors.
A detailed analysis of the clinical data in 1,160 patients treated with Mithracin (plicamycin) indicates that the hemorrhagic syndrome is dose related. With doses of 30 mcg/kg/day or less for 10 or fewer doses, the incidence of bleeding episodes has been 5.4% with an associated drug-related mortality rate of 1.6%. With doses greater than 30 mcg/kg/day and/or for more than 10 doses, a significantly larger number of bleeding episodes occurred (11.9%) and the associated drug-related mortality rate was also significantly higher (5.7%).
The most common side effects reported with the use of Mithracin (plicamycin) consist of gastrointestinal symptoms: anorexia, nausea, vomiting, diarrhea, and stomatitis. Other less frequently reported side effects include fever, drowsiness, weakness, lethargy, malaise, headache, depression, phlebitis, facial flushing, and skin rash.
The following laboratory abnormalities have been reported during therapy with Mithracin (plicamycin) and in most instances were reversible following cessation of treatment:
Hematologic Abnormalities: Depression of platelet count, white count, hemoglobin and prothrombin content; elevation of clotting time and bleeding time; abnormal clot retraction.
Thrombocytopenia may be rapid in onset and may occur at any time during therapy or within several days following the last dose. With the occurrence of severe thrombocytopenia, the infusion of platelet concentrates of platelet-rich plasma may be helpful in elevating the platelet count.
The occurrence of leukopenia with the use of Mithracin (plicamycin) is relatively uncommon, occurring only in approximately 6% of patients.
It has been uncommon for abnormalities in clotting time or clot retraction to be demonstrated prior to the onset of an overt bleeding episode noted in some patients treated with Mithracin (plicamycin) . Nevertheless, the performance of these tests periodically is recommended because in a few instances, an abnormality in one of these studies may have served as a warning to terminate therapy because of impending serious toxicity.
Abnormal Liver Function Tests: Increased levels of serum glutamic oxalacetic transaminase, serum glutamic pyruvic transaminase, lactic dehydrogenase, alkaline phosphatase, serum bilirubin, ornithine carbamyl transferase, isocitric dehydrogenase, and increased retention of bromsulphalein.
Abnormal Renal Function Tests: Increased blood urea nitrogen and serum creatinine; proteinuria.
Abnormalities in Electrolyte Concentrations: Depression of serum calcium, phosphorus, and potassium.
No Information Provided.
IT IS RECOMMENDED THAT MITHRACIN (plicamycin) BE ADMINISTERED ONLY TO HOSPITALIZED PATIENTS BY OR UNDER THE SUPERVISION OF A QUALIFIED PHYSICIAN WHO IS EXPERIENCED IN THE USE OF CANCER CHEMOTHERAPEUTIC AGENTS, BECAUSE OF THE POSSIBILITY OF SEVERE REACTIONS. FACILITIES FOR THE DETERMINATION OF NECESSARY LABORATORY STUDIES MUST BE AVAILABLE.SEVERE THROMBOCYTOPENIA, A HEMORRHAGIC TENDENCY AND EVEN DEATH MAY RESULT FROM THE USE OF MITHRACIN (plicamycin) . ALTHOUGH SEVERE TOXICITY IS MORE APT TO OCCUR IN PATIENTS WHO HAVE FAR-ADVANCED DISEASE OR ARE OTHERWISE CONSIDERED POOR RISKS FOR THERAPY, SERIOUS TOXICITY MAY ALSO OCCASIONALLY OCCUR EVEN IN PATIENTS WHO ARE IN RELATIVELY GOOD CONDITION. IN THE TREATMENT OF EACH PATIENT, THE PHYSICIAN MUST WEIGH CAREFULLY THE POSSIBILITY OF ACHIEVING THERAPEUTIC BENEFIT VERSUS THE RISK OF TOXICITY WHICH MAY OCCUR WITH MITHRACIN (plicamycin) THERAPY. THE FOLLOWING DATA CONCERNING THE USE OF MITHRACIN (plicamycin) IN THE TREATMENT OF TESTICULAR TUMORS, HYPERCALCEMIC AND/OR HYPERCALCIURIC CONDITIONS ASSOCIATED WITH VARIOUS ADVANCED MALIGNANCIES, SHOULD BE THOROUGHLY REVIEWED BEFORE ADMINISTERING THIS COMPOUND. |
General: Mithracin (plicamycin) should be administered only to patients who are hospitalized and who can be observed carefully and frequently during and after therapy.
Severe thrombocytopenia, a hemorrhagic tendency and even death may result from the use of Mithracin (plicamycin) . Although severe toxicity is more apt to occur in patients who have far-advanced disease or are otherwise considered poor risks for therapy, serious toxicity may also occasionally occur even in patients who are in relatively good condition.
Electrolyte imbalance, especially hypocalcemia, hypokalemia, and hypophosphatemia, should be corrected with appropriate electrolyte therapy prior to treatment with Mithracin (plicamycin) .
Mithracin (plicamycin) should be used with extreme caution in patients with significant impairment of renal or hepatic function.
Mithracin (plicamycin) should not normally be administered to patients who are pregnant or to mothers who are breast feeding.
In the treatment of each patient, the physician must weigh carefully the possibility of achieving therapeutic benefit versus the risk of toxicity which may occur with Mithracin (plicamycin) therapy.
Laboratory Tests: The following laboratory studies should be obtained frequently during therapy and for several days following the last dose: platelet count, prothrombin time, bleeding time. The occurrence of thrombocytopenia or a significant prolongation of prothrombin time or bleeding time is an indication for the termination of therapy.
Carcinogenesis, mutagenesis, impairment of fertility: No long-term studies in animals have been performed to evaluate the carcinogenic potential of Mithracin (plicamycin) . Histologic evidence of inhibition of spermatogenesis was observed in a substantial number of male rats receiving doses of 0.6 mg/ kg/day and above.
Pregnancy Category X: See "Contraindications" section.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Mithracin (plicamycin) , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Generally, adverse effects following the use of Mithracin (plicamycin) , especially the hemorrhagic syndrome, are dose related. Therefore, following administration of an overdose, patients can be expected to experience an exaggeration of the usual adverse effects. Close monitoring of the hematologic picture, including factors involved in the clotting mechanism, hepatic and renal functions, and serum electrolytes, is necessary. No specific antidote for Mithracin (plicamycin) is known. Management of overdosage would include general supportive measures to sustain the patient through the period of toxicity.
Mithracin (plicamycin) is contraindicated in patients with thrombocytopenia, thrombocytopathy, coagulation disorder or an increased susceptibility to bleeding due to other causes. Mithracin (plicamycin) should not be administered to any patient with impairment of bone marrow function.
Mithracin (plicamycin) may cause fetal harm when administered to a pregnant woman. Mithracin (plicamycin) is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Although the exact mechanism by which Mithracin (plicamycin) causes tumor inhibition is not yet known, studies have indicated that this compound forms a complex with deoxyribonucleic acid (DNA) and inhibits cellular ribonucleic acid (RNA) and enzymic RNA synthesis. The binding of Mithracin (plicamycin) to DNA in the presence of Mg + + (or other divalent cations) is responsible for the inhibition of DNA-dependent or DNA-directed RNA synthesis. This action presumably accounts for the biological properties of Mithracin (plicamycin) .
Mithracin (plicamycin) shows potent cytotoxicity against malignant cells of human origin (Hela cells) growing in tissue culture. Mithracin (plicamycin) is lethal to Hela cells in 48 hours at concentrations as low as 0.5 micrograms per milliliter of tissue culture medium. Mithracin (plicamycin) has shown significant anti-tumor activity against experimental leukemia in mice when administered intraperitoneally.
Plicamycin may lower serum calcium levels; the exact mechanism (or mechanisms) by which the drug exerts this effect is unknown. It appears that plicamycin may block the hypercalcemic action of pharmacologic doses of vitamin D. It has also been suggested that plicamycin may lower calcium serum levels by inhibiting the effect of parathyroid hormone upon osteoclasts. Plicamycin's inhibition of DNA-dependent RNA synthesis appears to render osteoclasts unable to fully respond to parathyroid hormone with the biosynthesis necessary for osteolysis. Decreases in serum phosphate levels and urinary calcium excretion accompany the lowering of serum calcium concentrations.
Radioautography studies 1 with 3 H-labeled plicamycin in C3H mice show that the greatest concentrations of the isotope are in the Kupffer cells of the liver and cells of the renal tubules. Plicamycin is rapidly cleared from the blood within the first 2 hours and excretion is also rapid. Sixty-seven percent of measured excretion occurs within 4 hours, 75% within 8 hours, and 90% is recovered in the first 24 hours after injection. There is no evidence of protein binding, nor is there any evidence of metabolism of the carbohydrate moiety of the drug to carbon dioxide and water with loss through respiration. Plicamycin crosses the blood-brain barrier; the concentration found in brain tissue is low but it persists longer than in other tissues. The experimental results in animals correlate closely with results achieved in man. 2
In mice the average intravenous LD 50 of Mithracin (plicamycin) is 2,000 mcg/kg of body weight. When administered orally, it is not toxic to mice even at doses 100 times greater than the intravenous LD 50 . In rats the average intravenous LD 50 of Mithracin (plicamycin) is 1,700 mcg/kg of body weight. It is not toxic to rats when administered orally at doses 17 times greater than the intravenous LD 50 . In dogs and monkeys Mithracin (plicamycin) is essentially non-toxic when administered intravenously for 24 days at daily doses as high as 50 and 24 mcg/kg of body weight, respectively. However, at higher doses of 100 mcg/kg/day intravenously it is lethal to dogs and monkeys. Signs of toxicity in dogs and monkeys included anorexia, vomiting, listlessness, melena, anemia, lymphopenia, elevated alkaline phosphatase, serum glutamic oxalacetic transaminase, serum glutamic pyruvic transaminase values, hypochloremia, and azotemia. Dogs also showed marked thrombocytopenia, hyponatremia, hypokalemia, hypocalcemia, and decreased prothrombin consumption. Necropsy findings consisted of necrosis of lymphoid tissue and multiple generalized hemorrhages. Mithracin (plicamycin) was only mildly irritating when injected intramuscularly in rabbits and subcutaneously in guinea pigs. Histologic evidence of inhibition of spermatogenesis was observed in a substantial number of male rats receiving doses of 0.6 mg/kg/day and above. This preclinical finding of selective drug effect constituted the scientific rationale for clinical trials in testicular tumors.
CLINICAL REPORTS
Treatment of Patients with Inoperable Testicular Tumors: In a combined series of 305 patients with inoperable testicular tumors treated with Mithracin (plicamycin) , 33 patients (10.8%) showed a complete disappearance of tumor masses and an additional 80 patients (26.2%) responded with significant partial regression of tumor masses. The longest duration of a continuing complete response is now over 8 1 / 2 years. The therapeutic responses in this series of patients have been summarized by type of testicular tumor in the accompanying table.
| MITHRACIN | ||||
RESULTS IN 305 TESTICULAR TUMOR CASES BY TUMOR TYPE |
||||
| TYPE OF TESTICULAR TUMOR |
TOTAL | COMPLETE RESPONSE |
PARTIAL RESPONSE |
NO RESPONSE |
EMBRYONAL CELL |
173 | 26 | 42 | 105 |
TERATOMA |
5 | 0 | 1 | 4 |
TERATOCARCINOMA |
23 | 0 | 5 | 18 |
SEMINOMA |
18 | 0 | 7 | 11 |
CHORIOCARCINOMA |
13 | 1 | 6 | 6 |
MIXED TUMOR |
73 | 6 | 19 | 48 |
TOTALS |
305 | 33 | 80 | 192 |
Mithracin (plicamycin) may be useful in the treatment of patients with testicular tumors which are resistant to other chemotherapeutic agents. Prior radiation therapy or prior chemotherapy did not alter the response rate with Mithracin (plicamycin) . This suggests that there is no significant cross resistance between Mithracin (plicamycin) and other chemotherapeutic agents.
Treatment of Patients with Hypercalcemia and Hypercalciuria: A limited number of patients with hypercalcemia (range: 12.0-25.8 mg%) and patients with hypercalciuria (range 215-492 mg/day) associated with malignant disease were treated with Mithracin (plicamycin) . Hypercalcemia and hypercalciuria were promptly reversed in all patients. In some patients, the primary malignancy was of non-testicular origin.
No Information Provided.
