Thiotepa

1 INDICATIONS AND USAGE Thiotepa for Injection is an alkylating drug indicated: For treatment of adenocarcinoma of the breast or ovary. ( 1.2 ) For controlling intracavitary effusions secondary to diffuse or localized neoplastic diseases of various serosal cavities. ( 1.3 ) For treatment of superficial papillary carcinoma of the urinary bladder. ( 1.4 ) 1.2 Adenocarcinoma of the Breast or Ovary Thiotepa for Injection is indicated for treatment of adenocarcinoma of the breast or ovary. 1.3 Malignant Effusions Thiotepa for Injection is indicated for controlling intracavitary effusions secondary to diffuse or localized neoplastic diseases of various serosal cavities. 1.4 Superficial Papillary Carcinoma of the Urinary Bladder Thiotepa for Injection is indicated for treatment of superficial papillary carcinoma of the urinary bladder. Pediatric use information is approved for Adienne SA’s TEPADINA (thiotepa) for injection. However, due to Adienne SA’s marketing exclusivity rights, the drug product is not labeled with that information.

2 DOSAGE AND ADMINISTRATION The recommended dose of thiotepa for injection for treatment of adenocarcinoma of the breast or ovary is 0.3 to 0.4 mg/kg intravenously. ( 2.1 ) The recommended dose of thiotepa for injection for treatment of malignant effusions is 0.6 to 0.8 mg/kg intracavitary. ( 2.1 ) The recommended dose of thiotepa for injection for treatment of superficial papillary carcinoma of the urinary bladder is 60 mg in 30 to 60 mL of Sodium Chloride Injection into the bladder by catheter. ( 2.1 ) 2.1 Recommended Dosage Adenocarcinoma of the Breast or Ovary The recommended dose of thiotepa for injection for treatment of adenocarcinoma of the breast or ovary is 0.3 to 0.4 mg/kg intravenously. Doses should be given at 1 to 4 week intervals. 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. Maintenance doses should not be administered more frequently than weekly. Malignant Effusions The recommended dose of thiotepa for injection for treatment of malignant effusions is 0.6 to 0.8 mg/kg intracavitary. Administration is usually effected through the same tubing which is used to remove the fluid from the cavity involved. Doses should be given at 1 to 4 week intervals. 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. Maintenance doses should not be administered more frequently than weekly. Superficial Papillary Carcinoma of the Urinary Bladder The recommended dose of thiotepa for injection for treatment of superficial papillary carcinoma of the urinary bladder is 60 mg in 30 to 60 mL of Sodium Chloride Injection into the bladder by catheter. 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. The patient may be repositioned 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. Pediatric use information is approved for Adienne SA’s TEPADINA (thiotepa) for injection. However, due to Adienne SA’s marketing exclusivity rights, the drug product is not labeled with that information. 2.2 Preparation Instructions Thiotepa for injection is a cytotoxic drug. Follow applicable special handling and disposal procedures 1 . Reconstitution Reconstitute thiotepa for injection 15 mg with 1.5 mL of sterile water for injection. Using a syringe fitted with a needle, aseptically withdraw 1.5 mL of sterile water for injection. Inject the content of the syringe into the vial through the rubber stopper. Remove the syringe and needle, and mix manually by repeated inversions. Reconstitute thiotepa for injection 100 mg with 10 mL of sterile water for injection. Using a syringe fitted with a needle, aseptically withdraw 10 mL of sterile water for injection. Inject the content of the syringe into the vial through the rubber stopper. Remove the syringe and needle, and mix manually by repeated inversions. The reconstituted solution is hypotonic and must be diluted in saline prior to administration. Reconstituted solutions, free of visible particulate matter, may occasionally show opalescence; such solutions can still be used for further dilution. If not used immediately after reconstitution, the product is stable for 8 hours when stored at 2° to 8°C (36° to 46°F). Dilution in the Infusion Bag Prior to administration, dilute the reconstituted solution further with an appropriate volume of sodium chloride 0.9% solution for injection to obtain a final thiotepa for injection concentration between 0.5 and 1 mg per mL. Dilute thiotepa for injection as recommended in Table 2 . Table 2: Dilu …

3 DOSAGE FORMS AND STRENGTHS Thiotepa for Injection, USP, 15 mg, white lyophilized powder or lyophilized cake in single-dose vial for reconstitution Thiotepa for Injection, USP, 100 mg, white lyophilized powder or lyophilized cake in single-dose vial for reconstitution For injection: 15 mg, white lyophilized powder or lyophilized cake in single-dose vial for reconstitution. ( 3 ) For injection: 100 mg, white lyophilized powder or lyophilized cake in single-dose vial for reconstitution. ( 3 )

4 CONTRAINDICATIONS Thiotepa is contraindicated in: Patients with severe hypersensitivity to thiotepa [see Warnings and Precautions (5.2) ] Concomitant use with live or attenuated vaccines [see Warnings and Precautions (5.4) ] Hypersensitivity to the active substance. ( 4 ) Concomitant use with live or attenuated vaccines. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions ( 5.1 ) ] Infection [see Warnings and Precautions ( 5.1 ) ] Hypersensitivity [see Warnings and Precautions ( 5.2 )] Cutaneous Toxicity [see Warnings and Precautions ( 5.3 )] Hepatic Veno-Occlusive Disease [see Warnings and Precautions ( 5.5 )] Central Nervous System Toxicity [see Warnings and Precautions ( 5.6 )] Carcinogenicity [see Warnings and Precautions ( 5.7 )] The most common adverse reactions (incidence greater than 10%) were neutropenia, anemia, thrombocytopenia, elevated alanine aminotransferase, elevated aspartate aminotransferase, elevated bilirubin, mucositis, cytomegalovirus infection, hemorrhage, diarrhea, hematuria and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals, Inc. at 1-844-824-8426 or FDA at 1-800-FDA-1088 or www.fda.gov/ medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions with Treatment of adenocarcinoma of the breast, adenocarcinoma of the ovary, malignant effusions and superficial papillary carcinoma of the urinary bladder Gastrointestinal : Nausea, vomiting, abdominal pain, anorexia. General : Fatigue, weakness. Febrile reaction and discharge from a subcutaneous lesion may occur as the result of breakdown of tumor tissue. Hypersensitivity Reactions : Allergic reactions - rash, urticaria, laryngeal edema, asthma, anaphylactic shock, wheezing. Local Reactions : Contact dermatitis, pain at the injection site. Neurologic : Dizziness, headache, blurred vision. Renal : Dysuria, urinary retention, chemical cystitis or hemorrhagic cystitis. Reproductive : Amenorrhea, interference with spermatogenesis. 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. Skin : Dermatitis, alopecia. Skin depigmentation has been reported following topical use. Special Senses : Conjunctivitis. Pediatric use information is approved for Adienne SA’s TEPADINA (thiotepa) for injection. However, due to Adienne SA’s marketing exclusivity rights, the drug product is not labeled with that information. 6.2 Postmarketing Experience Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during post approval use of thiotepa in preparative regimens prior to allogeneic or autologous hematopoietic progenitor (stem) cell transplantation (HSCT) in patients. Blood and lymphatic system disorders : Febrile bone marrow aplasia. Cardiac disorders : Bradycardia, cardiac failure congestive, cardio-respiratory arrest, pericardial effusion, pericarditis, right ventricular hypertrophy. Congenital, familial and genetic disorders : Aplasia. Ear and labyrinth disorders : Deafness. Eye disorders : Blindness, eyelid ptosis, papilledema, strabismus. Gastrointestinal disorders : Ascites, dysphagia, enterocolitis, gastritis, palatal disorder. General disorders and administration site conditions : Device related infection, gait disturbance, malaise, multi-organ failure, pain. Hepatobiliary disorders : Hepatomegaly. Immune system disorders : Bone marrow transplant rejection, immunosuppression. Infections and infestations : Acute sinusitis, bronchopulmonary aspergillosis, candida sepsis, enterococcal infection, Epstein-Barr virus infection, Escherichia sepsis, Fusarium infection …

7 DRUG INTERACTIONS 7.1 Effect of Cytochrome CYP3A Inhibitors and Inducers In vitro studies suggest that thiotepa is metabolized by CYP3A4 and CYP2B6 to its active metabolite TEPA. Avoid coadministration of strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin, ritonavir) and strong CYP3A4 inducers (e.g., rifampin, phenytoin) with thiotepa due to the potential effects on efficacy and toxicity [see Clinical Pharmacology (12.2) ] . Consider alternative medications with no or minimal potential to inhibit or induce CYP3A4. If concomitant use of strong CYP3A4 modulators cannot be avoided, closely monitor for adverse drug reactions. 7.2 Effect of Thiotepa on Cytochrome CYP2B6 Substrates In vitro studies suggest that thiotepa inhibits CYP2B6. Thiotepa may increase the exposure of drugs that are substrates of CYP2B6 in patients; however, the clinical relevance of this in vitro interaction is unknown [see Clinical Pharmacology (12.2) ] . The administration of thiotepa with cyclophosphamide in patients reduces the conversion of cyclophosphamide to the active metabolite, 4-hydroxycyclophosphamide; the effect appears sequence dependent with a greater reduction in the conversion to 4-hydroxycyclophosphamide when thiotepa is administered 1.5 hours prior to the intravenous administration of cyclophosphamide compared to administration of thiotepa after intravenous cyclophosphamide [see Clinical Pharmacology (12.2) ] . The reduction in 4-hydroxycyclophosphamide levels may potentially reduce efficacy of cyclophosphamide treatment.

8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding is not recommended. ( 8.2 ) Moderate or severe renal impairment: Monitor patients more frequently for toxicity. ( 8.6 , 12.2 ) Moderate or severe hepatic impairment: Monitor patients more frequently for toxicity. ( 8.7 , 12.2 ) Pediatric use information is approved for Adienne SA’s TEPADINA (thiotepa) for injection. However, due to Adienne SA’s marketing exclusivity rights, the drug product is not labeled with that information. 8.1 Pregnancy Risk Summary Thiotepa can cause fetal harm when administered to a pregnant woman based on findings from animals and the drug’s mechanism of action [see Clinical Pharmacology (12.1) ] . Limited available data with thiotepa use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, administration of thiotepa to pregnant mice and rats during organogenesis produced teratogenic effects (neural tube defects and malformations of the skeletal system of the fetus) at doses approximately 0.125 and 1 times, respectively, the maximum recommended human daily dose on a mg/m 2 basis. Thiotepa was lethal to rabbit fetuses at approximately 2 times the maximum recommended human therapeutic dose based on body-surface area [see Data ] . Consider the benefits and risks of thiotepa for the mother and possible risks to the fetus when prescribing thiotepa to a pregnant woman. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Thiotepa given by the IP route in mice at doses ≥ 1 mg/kg (3.2 mg/m 2 ), approximately 8-fold less than the maximum recommended human therapeutic dose based on body-surface area, and in rats at doses ≥ 3 mg/kg (21 mg/m 2 ), approximately equal to the maximum recommended human therapeutic dose based on body-surface area, resulted in various malformations including neural tube defects, omphalocele, renal agenesis, atresia ani, limb and digit defects, cleft palate, micrognathia, other skeletal anomalies in the skull, vertebrae and ribs, and reduced skeletal ossification. Thiotepa was lethal to rabbit fetuses at a dose of 3 mg/kg (41 mg/m 2 ), approximately 2 times the maximum recommended human therapeutic dose based on body-surface area. 8.2 Lactation Risk Summary There is no information regarding the presence of thiotepa in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions, including the potential for tumorigenicity shown for thiotepa in animal studies, advise patients not to breastfeed during thiotepa treatment. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Thiotepa can cause fetal harm when administered to a pregnant female. Verify the pregnancy status of females of reproductive potential prior to initiating thiotepa therapy. Contraception Females Advise females of reproductive potential to avoid pregnancy during thiotepa treatment and for at least 6 months after the final dose of thiotepa. Advise females to immediately report pregnancy [see Use in Specific Populations (8.1) ] . Males Thiotepa may damage spermatozoa and testicular tissue, resulting in possible genetic abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during thiotepa treatment and for at least 1 year after the final dose of thiotepa [see Nonclinical Toxicology (13.1) ] . Infertility Based on nonclinical findings, male and female fertility may be compromised by treatment with thiotepa. Inform male patients about the possibility of sperm conservation before the start of therapy [see Nonclinical Toxicology (13.1 )] . 8.4 Pediatric Use Safety and effectiveness of thiotepa in neonates …

12.1 Mechanism of Action Thiotepa is a cytotoxic agent of the polyfunctional type, related chemically and pharmacologically to the nitrogen mustard. The radiomimetic action of thiotepa is believed to occur through the release of ethyleneimine radicals which, like irradiation, disrupt the bonds of DNA. One of the principle 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.

11 DESCRIPTION Thiotepa for Injection, USP is an alkylating agent. Thiotepa for Injection, USP is supplied as a nonpyrogenic, sterile, white lyophilized powder or lyophilized cake for intravenous, intracavitary, or intravesical use after reconstitution and dilution. Thiotepa for Injection, USP is available in a single-dose vial containing: 15 mg thiotepa. After reconstitution with 1.5 mL of water for injection, each mL contains 10 mg thiotepa. 100 mg thiotepa. After reconstitution with 10 mL of water for injection, each mL contains 10 mg 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 C 6 H 12 N 3 PS, and a molecular weight of 189.22, and it appears as fine, white crystalline flakes, with a melting range of 52° to 57°C. It is soluble in water and organic solvents. When reconstituted with sterile water for injection, the resulting solution has a pH of approximately 5.5 to 7.5. Thiotepa is unstable in acid medium. structural formula

10 OVERDOSE There is no experience with overdoses of thiotepa. The most important adverse reactions expected in case of overdose are myeloablation and pancytopenia [ see Nonclinical Toxicology (13.2) ] . There is no known antidote for thiotepa. Monitor the hematological status closely and provide vigorous supportive measures as medically indicated.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Thiotepa for Injection, USP, a white lyophilized powder or lyophilized cake, is supplied in a Type I clear glass vial with a chlorobutyl rubber stopper as follows: NDC Thiotepa for Injection, USP Package Factor 71288- 156 -05 71288- 157 -10 15 mg Single-Dose Vial 100 mg Single-Dose Vial 1 vial per carton 1 vial per carton 16.2 Storage and Handling Thiotepa for Injection, USP vials must be stored and transported refrigerated at 2° to 8°C (36° to 46°F). Do not freeze. Discard unused portion. Thiotepa for Injection, USP is a cytotoxic drug. Follow applicable special handling and disposal procedures 1 . Sterile, Nonpyrogenic, Preservative-free. The container closure is not made with natural rubber latex.