Thiotepa

1 INDICATIONS AND USAGE Thiotepa for injection is an alkylating drug indicated: To reduce the risk of graft rejection when used in conjunction with high-dose busulfan and cyclophosphamide as a preparative regimen for allogeneic hematopoietic progenitor (stem) cell transplantation (HSCT) for pediatric patients with class 3 beta-thalassemia. ( 1.1 , 14 ) 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 ) 1.1 Class 3 Beta-Thalassemia Thiotepa for injection is indicated to reduce the risk of graft rejection when used in conjunction with high-dose busulfan and cyclophosphamide as a preparative regimen for allogeneic hematopoietic progenitor (stem) cell transplantation (HSCT) for pediatric patients with class 3 beta-thalassemia [see Clinical Studies (14 )]. 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.

2 DOSAGE AND ADMINISTRATION The recommended dose of thiotepa for injection for class 3 beta-thalassemia is two administrations of 5 mg/kg given intravenously approximately 12 hours apart on Day -6 before allogeneic HSCT in conjunction with high-dose busulfan and cyclophosphamide. ( 2.1 ) 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 Class 3 Beta-Thalassemia The recommended dose of thiotepa for injection in pediatric patients is two administrations of 5 mg/kg given intravenously approximately 12 hours apart on Day -6 before allogeneic HSCT in conjunction with high-dose busulfan and cyclophosphamide as outlined in Table 1. See Prescribing Information for cyclophosphamide and busulfan for information on these drugs. Table 1: Dosage Regimen For Allogeneic HSCT In Pediatric Patients With Class 3 Beta-Thalassemia Day prior to transplantation Treatment Day -10 Day -9 Day -8 Day -7 Day -6 Day -5 Day -4 Day -3 Day -2 Day -1 Day 0 Busulfan IV weight-based dose * ▲ ▲ ▲ ▲ Thiotepa for injection IV 5 mg/kg twice ▲ Cyclophosphamide IV 40 mg/kg/day ▲ ▲ ▲ ▲ Stem cell Infusion ▲ *Busulfan IV weight-based dose: 1.0 mg/kg every 6 hours for patients less than 9 kg; 1.2 mg/kg every 6 hours for patients 9 to 16 kg; 1.1 mg/kg every 6 hours for patients 16.1 to 23 kg; 0.95 mg/kg every 6 hours for patients 23.1 to 34 kg; 0.8 mg/kg every 6 hours for patients more than 34 kg. Infuse thiotepa for injection via a central venous catheter over 3 hours using an infusion set equipped with a 0.2 micron in-line filter. Prior to and following each infusion, flush the catheter with approximately 5 ml sodium chloride 0.9% solution for injection. Thiotepa for injection is excreted through the skin of patients receiving high-dose therapy. Take precautions to prevent skin toxicity [see Warnings and Precautions (5.3 )]. 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. 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°C 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/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 concentration of 0.5 to 1 mg/mL Greater than 500 mg 1000 mL or appropriate volume to obtain a final concentration of 0.5 to 1 mg/mL After dilution the product is stable for 24 hours when stored at 2°C to 8°C (36° to 46°F) and for 4 hours when stored at 25°C (77°F). From a microbiological point of view, the product should be used immediately. Inspect the diluted solution visually for particulate matter and discoloration prior to administration. Use thiotepa for injection diluted solutions only if free of visible particulate matter. Filter using a 0.2 micron filter prior to administration. Filtering does not alter solution potency

4 CONTRAINDICATIONS Thiotepa for injection 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 )

5 WARNINGS AND PRECAUTIONS Cutaneous toxicity: Cleanse skin at least twice daily through 48 hours after the last dose of thiotepa for injection. ( 5.3 ) Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to avoid pregnancy. ( 5.8 ) 5.1 Myelosuppression The consequence of treatment with high doses of thiotepa together with other chemotherapy at the recommended dose and schedule in the preparative regimen for class 3 beta- thalassemia is profound myelosuppression occurring in all patients. Do not begin the preparative regimen if a stem cell donor is not available. Monitor complete blood counts, and provide supportive care for infections, anemia and thrombocytopenia until there is adequate hematopoietic recovery. For patients receiving thiotepa for treatment of adenocarcinoma of the breast, adenocarcinoma of the ovary, malignant effusions and superficial papillary carcinoma of the urinary bladder, if the bone marrow has been compromised by prior irradiation or chemotherapy, or is recovering from chemotherapy, the risk of severe myelosuppression with thiotepa may be increased. Perform periodic complete blood counts during the course of treatment with thiotepa. Provide supportive care for infections, bleeding, and symptomatic anemia [see Adverse Reactions (6.1)] . 5.2 Hypersensitivity Clinically significant hypersensitivity reactions, including anaphylaxis, have occurred following administration of thiotepa. If anaphylactic or other clinically significant allergic reaction occurs, discontinue treatment with thiotepa, initiate appropriate therapy, and monitor until signs and symptoms resolve [see Contraindications (4) , Adverse Reactions (6.1)] . 5.3 Cutaneous Toxicity Thiotepa and/or its active metabolites may be excreted in part via skin patients receiving high-dose therapy. Treatment with thiotepa may cause skin discoloration, pruritus, blistering, desquamation, and peeling that may be more severe in the groin, axillae, skin folds, in the neck area, and under dressings. Instruct patients to shower or bathe with water at least twice daily through 48 hours after administration of thiotepa. Change occlusive dressing and clean the covered skin at least twice daily through 48 hours after administration of thiotepa. Change bed sheets daily during treatment. Skin reactions associated with accidental exposure to thiotepa may also occur. Wash the skin thoroughly with soap and water in case thiotepa solution contacts the skin. Flush mucous membranes in case of thiotepa contact with mucous membranes. 5.4 Concomitant Use of Live and Attenuated Vaccines Do not administer live or attenuated viral or bacterial vaccines to a patient treated with thiotepa until the immunosuppressive effects have resolved. 5.5 Hepatic Veno-Occlusive Disease Hepatic veno-occlusive disease may occur in patients who have received high-dose thiotepa in conjunction with busulfan and cyclophosphamid e [see Adverse Reactions (6.1 )] . Monitor by physical examination, serum transaminases and bilirubin daily through BMT Day +28, and provide supportive care to patients who develop hepatic veno-occlusive disease. 5.6 Central Nervous System Toxicity Fatal encephalopathy has occurred in patients treated with high doses of thiotepa. Other central nervous system toxicities, such as headache, apathy, psychomotor retardation, disorientation, confusion, amnesia, hallucinations, drowsiness, somnolence, seizures, coma, inappropriate behaviour and forgetfulness have been reported to occur in a dose-dependent manner during or shortly after administration of high-dose thiotepa. In pediatric patients treated with thiotepa at the recommended dose in combination with busulfan and cyclophosphamide, 8% developed central nervous system toxicity (seizures and intracranial hemorrhage). Do not exceed the recommended dose of thiotepa. If severe or life-threatening central nervous system toxicity occurs, discontinue administration of thiotepa and provide supportive care. 5.7 Carcinogenicity Like many alkylating agents, thiotepa has been reported to be carcinogenic when administered to laboratory animals [see Nonclinical Toxicity (13.1) ] . Carcinogenicity is shown most clearly in studies using mice, but there is some evidence of carcinogenicity in man. There is an increased risk of a secondary malignancy with use of thiotepa. 5.8 Embryo-Fetal Toxicity Based on the mechanism of action and findings in animals, thiotepa can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of thiotepa in pregnant women. Thiotepa given by the intraperitoneal (IP) route was teratogenic in mice at doses ≥ 1 mg/kg (3.2 mg/m 2 ), approximately 8-fold less than the maximum recommended human therapeutic dose (0.8 mg/kg, 27 mg/m 2 ), based on body-surface area. Thiotepa given by the IP route was teratogenic 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. Thiotepa was lethal to rabbit fetuses at a dose of 3 mg/kg (41 mg/m 2 ), approximately two times the maximum recommended human therapeutic dose based on body-surface area. Advise pregnant women of the potential risk to the fetus [see Use in Specific Populations (8.1 , 8.3 )] . Advise females of reproductive potential to use highly effective contraception during and after treatment with thiotepa for at least 6 months after therapy. Advise males of reproductive potential to use effective contraception during and after treatment with thiotepa for at least 1 year after therapy [see Use in Specific Populations (8.1 , 8.3 )] .

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.

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 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 3-4 Any Grade Grade 3-4 Elevated alanine aminotransferase 22 (88%) 6 (24%) 49 (96%) 14 (27%) Elevated aspartate aminotransferase 20 (80%) 4 (16%) 45 (88%) 9 (18%) Elevated total bilirubin 20 (80%) 4 (16%) 39 (77%) 2 (4%) 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. 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 adult and pediatric 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, gastroenteritis, infection, lower respiratory tract infection fungal, lower respiratory tract infection viral, parainfluenza virus infection, Pneumonia legionella, relapsing fever, respiratory tract infection, sepsis, septic shock, Staphylococcal bacteremia, Staphylococcal infection, systemic candida, urinary tract infection. Injury, poisoning and procedural complications: Refractoriness to platelet transfusion, subdural hematoma. Investigations: Coagulation test abnormal, hemoglobin decreased, Klebsiella test positive, nuclear magnetic resonance imaging brain abnormal, transaminases increased, weight increased. Metabolism and nutrition disorders: Hyponatremia. Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Breast cancer metastatic, central nervous system lymphoma, leukemia recurrent, lymphoma, malignant neoplasm progression, metastatic neoplasm, post transplant lymphoproliferative disorder. Nervous system disorders: Aphasia, brain injury, bulbar palsy, central nervous system lesion, cerebral microangiopathy, cerebral ventricle dilatation, cerebrovascular accident, cognitive disorder, convulsion, coordination abnormal, encephalitis, encephalopathy, hemiplegia, hypotonia, leukoencephalopathy, memory impairment, motor dysfunction, neurotoxicity, quadriparesis, speech disorder, tremor, VIIth nerve paralysis, white matter lesion. Psychiatric disorders: Delirium, depression, disorientation, suicidal ideation. Renal and urinary disorders: Renal failure, nephropathy toxic. Respiratory, thoracic and mediastinal disorders: Acute respiratory distress, aspiration, dyspnea exertional, interstitial lung disease, lung disorder, pneumonitis, pulmonary arteriopathy, pulmonary sepsis, pulmonary veno-occlusive disease, respiratory distress, respiratory failure, pulmonary hypertension. Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome and toxic epidermal necrolysis. Vascular disorders: Capillary leak syndrome.

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.