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.

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 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°C to 8°C (36° to 46°F). Discard unused portion. 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/mL. Dilute thiotepa for injection as recommended in Table 2. Table 2: Dilution of Thiotepa for Injection in the infusion bag Calculated Thiotepa for Injection Dose Dilution Volume (Sodium Chloride 0.9% solution for injection) Less than 250 mg Appropriate volume to obtain a final concentration of 0.5 to 1 mg/mL 250 mg to 500 mg 500 mL or appropriate volume to obtain a final concentrat …

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

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.

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 Novadoz Pharmaceuticals LLC at 1-855-668-2369 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 the Preparative Regimen for Class 3 Beta-Thalassemia The safety of thiotepa was evaluated by retrospective analysis of 76 pediatric patients with class 3 beta-thalassemia who underwent allogeneic hematopoietic progenitor (stem) cell transplantation (HSCT) using busulfan and cyclophosphamide with thiotepa (n=25) or without thiotepa (n=51) [see Clinical Studies (14)]. Adverse reactions were abstracted retrospectively from the medical records. Serious adverse events that occurred in the thiotepa-treated and control cohort were, respectively: gastrointestinal hemorrhage (4% vs 2%), pneumonia (4% vs 0), seizure (4% vs 2%), subarachnoid hemorrhage (4% vs 0) and veno­occlusive disease (4% vs 2%). By 90 days after HSCT, grades 2 to 4 acute graft-versus-host disease was observed in 7 (28%) patients in the thiotepa cohort and in 13 (26%) patients in the control cohort. By 1-year after transplantation, chronic graft-versus-host disease was observed in 8 (35%) of 23 evaluable patients in the thiotepa cohort, and 7 (14%) of 49 evaluable patients in the control cohort. Adverse reactions occurring in at least 5% of patients treated with thiotepa from start of the preparative regimen through 30 days after transplantation are shown in Table 3. Table 3: Common Adverse Reactions (>5%) Occurring Through 30 Days After Transplantation In Patients With Class 3 Beta-Thalassemia Using Busulfan And Cyclophosphamide With Or Without Thiotepa in the Preparative Regimen Preparative Regimen of Busulfan and Cyclophosphamide Adverse Reaction With Thiotepa Without Thiotepa N=25 patients (%) N=51 patients (%) Any Grade Grade 3-5 1 Any Grade Grade 3-5 1 Mucositis 2 16 (64%) 4 (16%) 22 (43%) 1 (2%) Cytomegalovirus Infection 12 (48%) 0 15 (29%) 0 Hemorrhage 3 7 (28%) 2 (8%) 12 (24%) 3 (6%) Diarrhea 6 (24%) 0 7 (14%) 2 (4%) Hematuria 4 5 (20%) 0 10 (20%) 3 (6%) Rash 5 3 (12%) 0 11 (22%) 0 Intracranial Hemorrhage 6 2 (8%) 1 (4%) 0 0 Pseudomonas Infection 2 (8%) 0 0 0 1 Severe, life-threatening or fatal 2 Mucositis includes mouth hemorrhage, mucosal inflammation and stomatitis 3 Hemorrhage includes all hemorrhage terms 4 Hematuria includes cystitis hemorrhagic and hematuria 5Rash includes dermatitis exfoliative, palmar erythema, rash, rash maculo-papular, rash pruritic and skin toxicity 6 Hemorrhage Intracranial includes hemorrhage intracranial and subarachnoid hemorrhage All patients in the thiotepa-treated and control cohorts developed profound cytopenias, including neutropenia, anemia, thrombocytopenia. Table 4 shows the selected chemistry abnormalities that occurred from start of the preparative regimen through 30 days after transplantation. Table 4: Selected Laboratory Abnormalities Occurring Through 30 Days After Tra …

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.

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 severerenal impairment: Monitorpatients 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 to 4% and 15 to 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 is an alkylating agent. Thiotepa for injection, USP is supplied as a non-pyrogenic, sterile lyophilized white powder 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°C to 57°C. It is soluble in alcohol, in chloroform and in ether; soluble in water and methanol. 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. strctre

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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Thiotepa for Injection, USP 100 mg is supplied as Unit carton with one single-dose Type I clear glass vial with a bromobutyl stopper. One vial contains 100 mg thiotepa ( NDC 0143-9292-01 ). 16.2 Storage and Handling Thiotepa for Injection, USP vials must be stored and transported refrigerated at 2°C to 8°C (36° to 46°F). Do not freeze. Protect from light. Thiotepa for Injection, USP is a cytotoxic drug. Follow applicable special handling and disposal procedures 1 . To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. 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.

16.1 How Supplied Thiotepa for Injection, USP 100 mg is supplied as Unit carton with one single-dose Type I clear glass vial with a bromobutyl stopper. One vial contains 100 mg thiotepa ( NDC 0143-9292-01 ).

16.2 Storage and Handling Thiotepa for Injection, USP vials must be stored and transported refrigerated at 2°C to 8°C (36° to 46°F). Do not freeze. Protect from light. Thiotepa for Injection, USP is a cytotoxic drug. Follow applicable special handling and disposal procedures 1 . To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. 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.