TEPYLUTE

1 INDICATIONS AND USAGE TEPYLUTE is an alkylating drug indicated for treatment of adenocarcinoma of the breast or ovary. ( 1.1 ) 1.1 Adenocarcinoma of the Breast or Ovary TEPYLUTE is indicated for treatment of adenocarcinoma of the breast or ovary.

2 DOSAGE AND ADMINISTRATION The recommended dose of TEPYLUTE for treatment of adenocarcinoma of the breast or ovary is 0.3 mg/kg to 0.4 mg/kg intravenously. ( 2.1 ) See full prescribing information for preparation instructions. ( 2.2 ) 2.1 Recommended Dosage Adenocarcinoma of the Breast or Ovary The recommended dose of TEPYLUTE for treatment of adenocarcinoma of the breast or ovary is 0.3 mg/kg 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. 2.2 Preparation Instructions TEPYLUTE is a hazardous drug. Follow applicable special handling and disposal procedures 1 . Use aseptic technique to prepare TEPYLUTE. Dilution in the infusion bag Remove vial from refrigerated conditions 1 hour prior to dilution. Dilute the solution in an appropriate volume of 0.9% Sodium Chloride Injection to obtain a final TEPYLUTE concentration between 0.5 mg/mL and 1 mg/mL. Use a 16G needle with a Luer-lock syringe to dilute the solution. Use the diluted TEPYLUTE infusion solution immediately. If the solution is not used immediately, store refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours, or at room temperature 25°C (77°F) for up to 4 hours. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use TEPYLUTE 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. Storage of Undiluted TEPYLUTE: Single-dose vial: Each vial is intended for single-dose only. Discard any unused portion left in the vial. Multiple-dose vial: After first use, store the partially used vial in the original carton refrigerated at 2°C to 8°C (36°F to 46°F) for up to 28 days.

5 WARNINGS AND PRECAUTIONS Cutaneous Toxicity: Cleanse skin at least twice daily through 48 hours after the last dose of TEPYLUTE. ( 5.3 ) Polyethylene Glycol 400 Toxicity: Take into consideration the PEG 400 load from concomitant medications. ( 5.8 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.9 ) 5.1 Myelosuppression For patients receiving TEPYLUTE for treatment of adenocarcinoma of the breast or adenocarcinoma of the ovary, if the bone marrow has been compromised by prior irradiation or chemotherapy, or is recovering from chemotherapy, the risk of severe myelosuppression with TEPYLUTE may be increased. Perform periodic complete blood counts during the course of treatment with TEPYLUTE. 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 TEPYLUTE, initiate appropriate therapy, and monitor until signs and symptoms resolve [see Contraindications ( 4 ) and Adverse Reactions ( 6.1 )] . 5.3 Cutaneous Toxicity TEPYLUTE and/or its active metabolites may be excreted in part via skin in patients receiving high-dose therapy. Treatment with TEPYLUTE 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 TEPYLUTE. Change occlusive dressing and clean the covered skin at least twice daily through 48 hours after administration of TEPYLUTE. Change bed sheets daily during treatment. Skin reactions associated with accidental exposure to TEPYLUTE may occur. Wash the skin thoroughly with soap and water in case TEPYLUTE solution contacts the skin. Flush mucous membranes in case of TEPYLUTE 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 TEPYLUTE until the immunosuppressive effects have resolved. 5.5 Hepatic Veno-Occlusive Disease Monitor by physical examination, serum transaminases and bilirubin, 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 behavior and forgetfulness have been reported to occur in a dose-dependent manner during or shortly after administration of high-dose thiotepa. Do not exceed the recommended dose of TEPYLUTE. If severe or life-threatening central nervous system toxicity occurs, discontinue administration of TEPYLUTE 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 TEPYLUTE. 5.8 Polyethylene Glycol 400 Toxicity TEPYLUTE contains a high concentration of polyethylene glycol (PEG) 400. Based on findings in animals, administration of high amounts of PEG 400 may cause damage to the kidneys and liver at dosages higher than recommended. When prescribing TEPYLUTE, take into consideration the PEG 400 load from concomitant medications. 5.9 Embryo-Fetal Toxicity Based on the mechanism of action and fin…

4 CONTRAINDICATIONS TEPYLUTE 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 )

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 ( 12.3 )]. 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 TEPYLUTE 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 ( 12.3 )] . 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 ( 12.3 )] . The reduction in 4-hydroxycyclophosphamide levels may potentially reduce efficacy of cyclophosphamide treatment.

8.1 Pregnancy Risk Summary TEPYLUTE 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 TEPYLUTE for the mother and possible risks to the fetus when prescribing TEPYLUTE 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.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in other sections of the label: 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%) are 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 Shorla Oncology at 844-9-SHORLA 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 with 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 and adenocarcinoma of the ovary 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 The following adverse reactions have been identified during post approval use of thiotepa. 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. 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, sub…