NDC 0143-9565 Thiotepa

Thiotepa

NDC Product Code 0143-9565

NDC 0143-9565-01

Package Description: 1 VIAL in 1 BOX, UNIT-DOSE > 1.5 mL in 1 VIAL

NDC Product Information

Thiotepa with NDC 0143-9565 is a a human prescription drug product labeled by Hikma Pharmaceuticals Usa Inc.. The generic name of Thiotepa is thiotepa. The product's dosage form is injection, powder, lyophilized, for solution and is administered via intracavitary; intravenous; intravesical form.

Labeler Name: Hikma Pharmaceuticals Usa Inc.

Dosage Form: Injection, Powder, Lyophilized, For Solution - A dosage form intended for the solution prepared by lyophilization ("freeze drying"), a process which involves the removal of water from products in the frozen state at extremely low pressures; this is intended for subsequent addition of liquid to create a solution that conforms in all respects to the requirements for Injections.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Thiotepa Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • THIOTEPA 15 mg/1.5mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • WATER (UNII: 059QF0KO0R)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intracavitary - Administration within a non-pathologic cavity, such as that of the cervix, uterus, or penis, or such as that which is formed as the result of a wound.
  • Intravenous - Administration within or into a vein or veins.
  • Intravesical - Administration within the bladder.
  • Intracavitary - Administration within a non-pathologic cavity, such as that of the cervix, uterus, or penis, or such as that which is formed as the result of a wound.
  • Intravenous - Administration within or into a vein or veins.
  • Intravesical - Administration within the bladder.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Alkylating Activity - [MoA] (Mechanism of Action)
  • Alkylating Drug - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Hikma Pharmaceuticals Usa Inc.
Labeler Code: 0143
FDA Application Number: ANDA075547 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 06-01-2001 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

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Information for Patients

Thiotepa Injection

Thiotepa Injection is pronounced as (thye'' oh tep' a)

Why is thiotepa injection medication prescribed?
Thiotepa is used to treat certain types of ovarian cancer (cancer that begins in the female reproductive organs where eggs are formed), breast, and bladder cancer. It is ...
[Read More]

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Thiotepa Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Description

Thiotepa for Injection, USP is an ethylenimine-type compound. It is supplied as a non-pyrogenic, sterile Iyophilized powder for intravenous, intracavitary or intravesical administration, containing 15 mg of thiotepa. Thiotepa is a synthetic product with antitumor activity. The chemical name for thiotepa is Tris(1-aziridinyl)phosphine sulfide. Thiotepa has the following structural formula:Thiotepa has the molecular formula C6H12N3PS, and a molecular weight of 189.22. When reconstituted with sterile water for injection, the resulting solution has a pH of approximately 5.5 to 7.5. Thiotepa is stable in alkaline medium and unstable in acid medium.

Clinical Pharmacology

Thiotepa is a cytotoxic agent of the polyfunctional type, related chemically and pharmacologically to nitrogen mustard. The radiomimetic action of thiotepa is believed to occur through the release of ethylenimine radicals which, like irradiation, disrupt the bonds of DNA. One of the principal bond disruptions is initiated by alkylation of guanine at the N-7 position, which severs the linkage between the purine base and the sugar and liberates alkylated guanines.The pharmacokinetics of thiotepa and TEPA in thirteen female patients (45 to 84 years) with advanced stage ovarian cancer receiving 60 mg and 80 mg thiotepa by intravenous infusion on subsequent courses given at 4-week intervals are presented in the following table:  Mean ± SEM Pharmacokinetic Parameters Thiotepa TEPA  (units) 60 mg 80 mg 60 mg 80 mg Peak Serum concentration (ng/mL) 1331 ± 119 1828 ± 135 273 ± 46 353 ± 46 Elimination half-life (h) 2.4 ± 0.3 2.3 ± 0.3 17.6 ± 3.6 15.7 ± 2.7 Area under the curve (ng/h/mL) 2832 ± 412 4127 ± 668 4789 ± 1022 7452 ± 1667 Total body clearance (mL/min) 446 ± 63 419 ± 56  TEPA, which possesses cytotoxic activity, appears to be the major metabolite of thiotepa found in human serum and urine. Urinary excretion of 14C-labeled thiotepa and metabolites in a 34 year old patient with metastatic carcinoma of the cecum who received a dose of 0.3 mg/kg intravenously was 63%. Thiotepa and TEPA in urine each accounts for less than 2% of the administered dose.The pharmacokinetics of thiotepa in renal and hepatic dysfunction patients have not been evaluated. Possible pharmacokinetic interactions of thiotepa with any concomitantly administered medications have not been formally investigated.

Indications And Usage

  • Thiotepa for Injection, USP has been tried with varying results in the palliation of a wide variety of neoplastic diseases. However, the most consistent results have been seen in the following tumors:1.Adenocarcinoma of the breast.2.Adenocarcinoma of the ovary.3.For controlling intracavitary effusions secondary to diffuse or localized neoplastic diseases of various serosal cavities.4.For the treatment of superficial papillary carcinoma of the urinary bladder.While now largely superseded by other treatments, thiotepa has been effective against other lymphomas, such as lymphosarcoma and Hodgkin's disease.

Contraindications

Thiotepa is contraindicated in patients with a known hypersensitivity (allergy) to this preparation.Therapy is probably contraindicated in cases of existing hepatic, renal, or bone-marrow damage. However, if the need outweighs the risk in such patients, thiotepa may be used in low dosage, and accompanied by hepatic, renal and hemopoietic function tests.

Warnings

Death has occurred after intravesical administration, caused by bone-marrow depression from systematically absorbed drug.Death from septicemia and hemorrhage has occurred as a direct result of hematopoietic depression by thiotepa.Thiotepa is highly toxic to the hematopoietic system. A rapidly falling white blood cell or platelet count indicates the necessity for discontinuing or reducing the dosage of thiotepa. Weekly blood and platelet counts are recommended during therapy and for at least 3 weeks after therapy has been discontinued.Thiotepa can cause fetal harm when administered to a pregnant woman. Thiotepa given by the intraperitoneal (IP) route was teratogenic in mice at doses ≥ 1 mg/kg (3.2 mg/m2), approximately 8-fold less than the maximum recommended human therapeutic dose (0.8 mg/kg, 27 mg/m2), based on body-surface area. Thiotepa given by the IP route was teratogenic in rats at doses ≥ 3 mg/kg (21 mg/m2), approximately equal to the maximum recommended human therapeutic dose, based on body-surface area. Thiotepa was lethal to rabbit fetuses at a dose of 3 mg/kg (41 mg/m2), approximately two times the maximum recommended human therapeutic dose based on body-surface area.Effective contraception should be used during thiotepa therapy if either the patient or partner is of childbearing potential. There are no adequate and well-controlled studies in pregnant women. If thiotepa is used during pregnancy, or if pregnancy occurs during thiotepa therapy, the patient and partner should be apprised of the potential hazard to the fetus.Thiotepa is a polyfunctional alkylating agent, capable of cross-linking the DNA within a cell and changing its nature. The replication of the cell is, therefore, altered, and thiotepa may be described as mutagenic. An in vitro study has shown that it causes chromosomal aberrations of the chromatid type and that the frequency of induced aberrations increases with the age of the subject.Like many alkylating agents, thiotepa has been reported to be carcinogenic when administered to laboratory animals. Carcinogenicity is shown most clearly in studies using mice, but there is some evidence of carcinogenicity in man. In patients treated with thiotepa, cases of myelodysplastic syndromes and acute non-lymphocytic leukemia have been reported.

General

The serious complication of excessive thiotepa therapy, or sensitivity to the effects of thiotepa, is bone-marrow depression. If proper precautions are not observed thiotepa may cause leukopenia, thrombocytopenia, and anemia.

Fatigue, weakness. Febrile reaction and discharge from a subcutaneous lesion may occur as the result of breakdown of tumor tissue.

Information For Patients

The patient should notify the physician in the case of any sign of bleeding (epistaxis, easy bruising, change in color of urine, black stool) or infection (fever, chills) or for possible pregnancy to patient or partner.Effective contraception should be used during thiotepa therapy if either the patient or the partner is of childbearing potential.

Laboratory Tests

The most reliable guide to thiotepa toxicity is the white blood cell count. If this falls to 3000 or less, the dose should be discontinued. Another good index of thiotepa toxicity is the platelet count; if this falls to 150,000, therapy should be discontinued. Red blood cell count is a less accurate indicator of thiotepa toxicity. If the drug is used in patients with hepatic or renal damage (see CONTRAINDICATIONS section), regular assessment of hepatic and renal function tests are indicated.

Drug Interactions

It is not advisable to combine, simultaneously or sequentially, cancer chemotherapeutic agents or a cancer chemotherapeutic agent and a therapeutic modality having the same mechanism of action. Therefore, thiotepa combined with other alkylating agents such as nitrogen mustard or cyclophosphamide or thiotepa combined with irradiation would serve to intensify toxicity rather than to enhance therapeutic response. If these agents must follow each other, it is important that recovery from the first agent, as indicated by white blood cell count, be complete before therapy with the second agent is instituted.Other drugs which are known to produce bone-marrow depression should be avoided.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Also see WARNINGS section.

Carcinogenesis

In mice, repeated IP administration of thiotepa (1.15 or 2.3 mg/kg three times per week for 52 or 43 weeks, respectively) produced a significant increase in the combined incidence of squamous-cell carcinomas of the skin, preputial gland, and ear canal, and combined incidence of lymphoma and lymphocytic leukemia. In other studies in mice, repeated IP administration of thiotepa (4 or 8 mg/kg three times per week for 4 weeks followed by a 20 week observation period or 1.8 mg/kg three times per week for 4 weeks followed by a 35 week observation period) resulted in an increased incidence of lung tumors. In rats, repeated IP administration of thiotepa (0.7 or 1.4 mg/kg three times per week for 52 or 34 weeks, respectively) produced significant increases in the incidence of squamous-cell carcinomas of the skin or ear canal, combined hematopoietic neoplasms, and uterine adenocarcinomas. Thiotepa given intravenously (IV) to rats (1 mg/kg once per week for 52 weeks) produced an increased incidence of malignant tumors (abdominal cavity sarcoma, lymphosarcoma myelosis, seminoma, fibrosarcoma, salivary gland hemangioendothelioma, mammary sarcoma, pheochromocytoma) and benign tumors.The lowest reported carcinogenic dose in mice (1.15 mg/kg, 3.68 mg/m2) is approximately 7-fold less than the maximum recommended human therapeutic dose based on body-surface area. The lowest reported carcinogenic dose in rats (0.7 mg/kg, 4.9 mg/m2) is approximately 6-fold less than the maximum recommended human therapeutic dose based on body-surface area.

Mutagenesis

Thiotepa was mutagenic in in vitro assays in Salmonella typhimurium, E coli, Chinese hamster lung and human lymphocytes. Chromosomal aberrations and sister chromatid exchanges were observed in vitro with thiotepa in bean root tips, human lymphocytes, Chinese hamster lung, and monkey lymphocytes. Mutations were observed with oral thiotepa in mouse at doses > 2.5 mg/kg (8 mg/m2). The mouse micronucleus test was positive with IP administration of > 1 mg/kg (3.2 mg/m2). Other positive in vivo chromosomal aberration or mutation assays included Drosophila melanogaster, Chinese hamster marrow, murine marrow, monkey lymphocyte, and murine germ cell.

Impairment Of Fertility

Thiotepa impaired fertility in male mice at PO or IP doses ≥ 0.7 mg/kg (2.24 mg/m2), approximately 12-fold less than the maximum recommended human therapeutic dose based on body-surface area. Thiotepa (0.5 mg) inhibited implantation in female rats when instilled into the uterine cavity. Thiotepa interfered with spermatogenesis in mice at IP doses ≥ 0.5 mg/kg (1.6 mg/m2), approximately 17-fold less than the maximum recommended human therapeutic dose based on body-surface area. Thiotepa interfered with spermatogenesis in hamsters at an IP dose of 1 mg/kg (4.1 mg/m2), approximately 7-fold less than the maximum recommended human therapeutic dose based on body-surface area.

Teratogenic Effects- Category D

See WARNINGS section.Thiotepa can cause fetal harm when administered to a pregnant woman. Thiotepa given by the IP route was teratogenic in mice at doses ≥ 1 mg/kg (3.2 mg/m2), approximately 8-fold less than the maximum recommended human therapeutic dose based on body-surface area. Thiotepa given by the IP route was teratogenic in rats at doses ≥3 mg/kg (21 mg/m2), approximately equal to the maximum recommended human therapeutic dose based on body-surface area. Thiotepa was lethal to rabbit fetuses at a dose of 3 mg/kg (41 mg/m2), approximately 2 times the maximum recommended human therapeutic dose based on body-surface area. Patients of childbearing potential should be advised to avoid pregnancy. There are no adequate and well-controlled studies in pregnant women. If thiotepa is used during pregnancy, or if pregnancy occurs during thiotepa therapy, the patient and partner should be apprised of the potential hazard to the fetus.

Nursing Mothers

It is not known whether thiotepa is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for thiotepa in animal studies, 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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of thiotepa did not include sufficient numbers of subjects aged 65 and over to determine whether elderly subjects respond differently from younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreasing hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Adverse Reactions

In addition to its effect on the blood-forming elements (see WARNINGS and PRECAUTIONS sections), thiotepa may cause other adverse reactions.

Hypersensitivity Reactions

Allergic reactions - rash, urticaria, laryngeal edema, asthma, anaphylactic shock, wheezing.

Local Reactions

Contact dermatitis, pain at the injection site.

Gastrointestinal

Nausea, vomiting, abdominal pain, anorexia.

Renal

Dysuria, urinary retention. There have been rare reports of chemical cystitis or hemorrhagic cystitis following intravesical, but not parenteral administration of thiotepa.

Respiratory

Prolonged apnea has been reported when succinylcholine was administered prior to surgery, following combined use of thiotepa and other anticancer agents. It was theorized that this was caused by decrease of pseudocholinesterase activity caused by the anticancer drugs.

Neurologic

Dizziness, headache, blurred vision.

Skin

Dermatitis, alopecia. Skin depigmentation has been reported following topical use.

Special Senses

Conjunctivitis.

Reproductive

Amenorrhea, interference with spermatogenesis.

Overdosage

Hematopoietic toxicity can occur following overdose, manifested by a decrease in the white cell count and/or platelets. Red blood cell count is a less accurate indicator of thiotepa toxicity. Bleeding manifestations may develop. The patient may become more vulnerable to infection, and less able to combat such infection.Dosages within and minimally above the recommended therapeutic doses have been associated with potentially life-threatening hematopoietic toxicity. Thiotepa has a toxic effect on the hematopoietic system that is dose related.Thiotepa is dialyzable.There is no known antidote for overdosage with thiotepa. Transfusions of whole blood or platelets have proven beneficial to the patient in combating hematopoietic toxicity.

Dosage And Administration

Since absorption from the gastrointestinal tract is variable, thiotepa should not be administered orally.Dosage must be carefully individualized. A slow response to thiotepa does not necessarily indicate a lack of effect. Therefore, increasing the frequency of dosing may only increase toxicity. After maximum benefit is obtained by initial therapy, it is necessary to continue the patient on maintenance therapy (1 to 4 week intervals). In order to continue optimal effect, maintenance doses should not be administered more frequently than weekly in order to preserve correlation between dose and blood counts.

Preparation And Administration Precautions

Thiotepa is a cytotoxic anticancer drug and as with other potentially toxic compounds, caution should be exercised in handling and preparation of thiotepa. Skin reactions associated with accidental exposure to thiotepa may occur. The use of gloves is recommended. If thiotepa solution contacts the skin, immediately wash the skin thoroughly with soap and water. If thiotepa contacts mucous membranes, the membranes should be flushed thoroughly with water.

Preparation Of Solution

Thiotepa for injection should be reconstituted with 1.5 mL of sterile water for injection resulting in a drug concentration of approximately 10 mg/mL. The actual withdrawable quantities and concentration achieved are illustrated in the following table: Label Claim(mg/vial) Actual Content(mg/vial) Amount ofDiluent to be Added(mL) ApproximateWithdrawableVolume(mL) ApproximateWithdrawableAmount(mg/vial) ApproximateReconstitutedConcentration(mg/mL) 15 15.6 1.5 1.4 14.7 10.4The reconstituted solution is hypotonic and should be further diluted with sodium chloride injection (0. 9% sodium chloride) before use.When reconstituted with sterile water for injection, solutions of thiotepa should be stored in a refrigerator and used within 8 hours. Reconstituted solutions further diluted with sodium chloride injection should be used immediately.In order to eliminate haze, filter solutions through a 0.22 micron filter* prior to administration. Filtering does not alter solution potency. Reconstituted solutions should be clear. Solutions that remain opaque or precipitate after filtration should not be used.*Polysulfone membrane (Gelman’s Sterile Aerodisc®, Single Use) or triton-free mixed ester of cellulose/PVC (Millipore’s MILLEX®-GS Filter Unit).

Initial And Maintenance Doses

Initially the higher dose in the given range is commonly administered. The maintenance dose should be adjusted weekly on the basis of pretreatment control blood counts and subsequent blood counts.

Intravenous Administration

Thiotepa may be given by rapid intravenous administration in doses of 0.3 to 0.4 mg/kg. Doses should be given at 1 to 4 week intervals.

Intracavitary Administration

The dosage recommended is 0.6 to 0.8 mg/kg. Administration is usually effected through the same tubing which is used to remove the fluid from the cavity involved.

Intravesical Administration

Patients with papillary carcinoma of the bladder are dehydrated for 8 to 12 hours prior to treatment. Then 60 mg of thiotepa in 30 to 60 mL of Sodium Chloride Injection is instilled into the bladder by catheter. For maximum effect, the solution should be retained for 2 hours. If the patient finds it impossible to retain 60 mL for 2 hours, the dose may be given in a volume of 30 mL. If desired, the patient may be positioned every 15 minutes for maximum area contact. The usual course of treatment is once a week for 4 weeks. The course may be repeated if necessary, but second and third courses must be given with caution since bone-marrow depression may be increased. Deaths have occurred after intravesical administration, caused by bone-marrow depression from systemically absorbed drug.

Handling And Disposal

Follow safe cytotoxic agent handling procedures. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

How Supplied

Thiotepa for Injection, USP, for single use only, is available in vials containing 15 mg of nonpyrogenic, sterile lyophilized powder, supplied as follows:NDC 0143-9565-01. Unit carton contains 1 x 15 mg single dose vial thiotepa.Store in a refrigerator between 2° to 8°C (36° to 46°F). PROTECT FROM LIGHT AT ALL TIMES.To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceutical Corp. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.For Product Inquiry call 1-877-845-0689.

References

  • 1.Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents, US Government Printing Office, Washington, DC 20402.2.AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA. 1985;253(11):1590-1592.3.National Study Commission on Cytotosic Exposure - Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, Sc D, Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.4.Clinical Oncological Society of Australia: Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia. 1983; 1:426-428.5.Jones RB, et al. Safe handling of chemotherapeutic agents: A report from the Mount Sinai Medical Center. Ca - A Cancer Journal for Clinicians. Sept/Oct 1983; 258-263.6.American Society of Hospital Pharmacists technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990; 47:1033-1049.7.Controlling Occupational Exposure to Hazardous Drugs. (OSHA WORK-PRACTICE GUIDELINES). AM J Health-Syst Pharm. 1996:53:1669-1685.

Vial Label

Vial Label

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