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: Dilution of Thiotepa in the Infusion Bag Calculated Thiotepa 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 per mL 250 mg to 500 mg 500 mL or appropriate volume to obtain a final concentration of 0.5 to 1 mg per mL Greater than 500 mg 1,000 mL or appropriate volume to obtain a final concentration of 0.5 to 1 mg per mL After dilution the product is stable for 24 hours when stored at 2° 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. Discard unused portion. 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 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 )

Not available.

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, 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. 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.