Thiotepa 100 mg Injection, Powder, Lyophilized, For Solution, 1 vial — NDC 72205-046-01 (Billing 72205-0046-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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.

12.2Pharmacokinetics Absorption Thiotepa reached maximal concentrations close to the end infusion following an intravenous infusion. Distribution The binding of thiotepa to plasma proteins is approximately 10% to 20%. The mean volume of distribution (% coefficient of variation) of thiotepa was 30 L/m2 (44%) or

1.2L/kg (47%) following a single intravenous infusion of thiotepa at a dose of 5 mg/kg over 3 hours in pediatric population. In adults administered intravenous thiotepa between 20 mg to 250 mg/m2 as an intravenous bolus or infusion up to 4 hours, the mean volume of distribution of thiotepa ranged from

1.0 L/kg (30%) to

1.9L/kg (17%). Elimination Following a single intravenous infusion over 3 hours of thiotepa at a dose of 5 mg/kg in pediatric population, the estimated mean (% coefficient of variation) clearance of thiotepa was

0.58 L/hr/kg (60%) or

13.8L/hr/m2 (52%). The mean terminal elimination half-life was 1.7 hours (64%) for thiotepa and 4 hours (29%) for its major active metabolite, N,N',N''-triethylenephosphoramide (TEPA) in pediatric population. In adults administered intravenous thiotepa between 20 mg to 250 mg/m2 as an intravenous bolus or infusion up to 4 hours, the mean thiotepa clearance ranged from

14.6 L/hr/m2 (23%) to

27.9L/hr/m2 (69%). In adult population, the mean terminal elimination half-life ranged from 1.4 hours (7%) to 3.7 hours (14%) for thiotepa and from 4.9 hours to 17.6 hours (20%) for TEPA. Metabolism Thiotepa undergoes hepatic metabolism.

In vitro data suggests that CYP3A4 and CYP2B6 may be responsible for the metabolism of thiotepa to TEPA, a major active metabolite. Ex cretion In adult and pediatric patients, urinary excretion of thiotepa accounted for less than 2% of the dose and TEPA accounted for 11% or less of the dose. Spec i fic Populations Hepatic Impairment The clearance of thiotepa following a single thiotepa dose of 5 mg/kg in pediatric population with mild hepatic impairment was similar to the clearance observed in patients with normal liver function administered thiotepa.

The exposure (as measured by area under the curve (AUC)) of thiotepa increased by 1.6-fold and 1.8-fold following administration of multiple thiotepa doses of 7 mg/kg administered every 2 days with cyclophosphamide in two adult patients who had liver metastases with moderate hepatic impairment compared to the exposure observed in one patient with normal hepatic function. The effect of severe hepatic impairment on thiotepa exposure is unknown. Renal Impairment The exposure (as measured by AUC) of thiotepa increased by 1.4-fold and TEPA increased by 2.6-fold following administration of multiple doses of 120 mg/m2/day in one patient with moderate renal impairment (CLcr = 38 mL/min) administered cyclophosphamide plus thiotepa plus carboplatin, compared to exposure of thiotepa in patients with normal renal function.

The effects of severe renal impairment or end-stage renal disease on thiotepa exposure are unknown. Drug Interactions The clinical relevance of in vitro inhibition of the cytochrome P450 enzymes described below is unknown, but it cannot be excluded that the systemic exposure of thiotepa or medicinal products that are substrates for these enzymes may be affected with concomitant administration with thiotepa. Effect of Cytochrome P450 Modulators on Thiotepa In vitro data demonstrates that CYP3A4 and CYP2B6 inhibitors decrease the metabolism of thiotepa [see Drug Interactions (7.1 )].

Effec… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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.

12.2Pharmacokinetics Absorption Thiotepa reached maximal concentrations close to the end infusion following an intravenous infusion. Distribution The binding of thiotepa to plasma proteins is approximately 10% to 20%. The mean volume of distribution (% coefficient of variation) of thiotepa was 30 L/m2 (44%) or

1.2L/kg (47%) following a single intravenous infusion of thiotepa at a dose of 5 mg/kg over 3 hours in pediatric population. In adults administered intravenous thiotepa between 20 mg to 250 mg/m2 as an intravenous bolus or infusion up to 4 hours, the mean volume of distribution of thiotepa ranged from

1.0 L/kg (30%) to

1.9L/kg (17%). Elimination Following a single intravenous infusion over 3 hours of thiotepa at a dose of 5 mg/kg in pediatric population, the estimated mean (% coefficient of variation) clearance of thiotepa was

0.58 L/hr/kg (60%) or

13.8L/hr/m2 (52%). The mean terminal elimination half-life was 1.7 hours (64%) for thiotepa and 4 hours (29%) for its major active metabolite, N,N',N''-triethylenephosphoramide (TEPA) in pediatric population. In adults administered intravenous thiotepa between 20 mg to 250 mg/m2 as an intravenous bolus or infusion up to 4 hours, the mean thiotepa clearance ranged from

14.6 L/hr/m2 (23%) to

27.9L/hr/m2 (69%). In adult population, the mean terminal elimination half-life ranged from 1.4 hours (7%) to 3.7 hours (14%) for thiotepa and from 4.9 hours to 17.6 hours (20%) for TEPA. Metabolism Thiotepa undergoes hepatic metabolism.

In vitro data suggests that CYP3A4 and CYP2B6 may be responsible for the metabolism of thiotepa to TEPA, a major active metabolite. Ex cretion In adult and pediatric patients, urinary excretion of thiotepa accounted for less than 2% of the dose and TEPA accounted for 11% or less of the dose. Spec i fic Populations Hepatic Impairment The clearance of thiotepa following a single thiotepa dose of 5 mg/kg in pediatric population with mild hepatic impairment was similar to the clearance observed in patients with normal liver function administered thiotepa.

The exposure (as measured by area under the curve (AUC)) of thiotepa increased by 1.6-fold and 1.8-fold following administration of multiple thiotepa doses of 7 mg/kg administered every 2 days with cyclophosphamide in two adult patients who had liver metastases with moderate hepatic impairment compared to the exposure observed in one patient with normal hepatic function. The effect of severe hepatic impairment on thiotepa exposure is unknown. Renal Impairment The exposure (as measured by AUC) of thiotepa increased by 1.4-fold and TEPA increased by 2.6-fold following administration of multiple doses of 120 mg/m2/day in one patient with moderate renal impairment (CLcr = 38 mL/min) administered cyclophosphamide plus thiotepa plus carboplatin, compared to exposure of thiotepa in patients with normal renal function.

The effects of severe renal impairment or end-stage renal disease on thiotepa exposure are unknown. Drug Interactions The clinical relevance of in vitro inhibition of the cytochrome P450 enzymes described below is unknown, but it cannot be excluded that the systemic exposure of thiotepa or medicinal products that are substrates for these enzymes may be affected with concomitant administration with thiotepa. Effect of Cytochrome P450 Modulators on Thiotepa In vitro data demonstrates that CYP3A4 and CYP2B6 inhibitors decrease the metabolism of thiotepa [see Drug Interactions (7.1 )].

Effect of Thiotepa on Cytochrome P450 2B6 In vitro data demonstrates that thiotepa inhibits CYP2B6. Effect of Thiotepa on Cyclophosphamide The administration of thiotepa 1.5 hours prior to intravenous cyclophosphamide in patients administered cyclophosphamide plus thiotepa plus carboplatin decreased the AUC of 4-hydroxycyclophosphamide by 26% and maximal concentrations of 4-­hydroxycyclophosphamide by 62%, compared to administration of cyclophosphamide prior to thiotepa.

14 CLINICAL STUDIES Thiotepa was evaluated in a retrospective study of pediatric patients with class 3 beta-thalassemia who underwent allogeneic hematopoietic progenitor (stem) cell transplantation (HSCT) from a human leukocyte antigen (HLA)-identical sibling donor. Twenty-five patients (10 male and 15 female) of median age 10 years (range, 5-16 years) were treated with intravenous busulfan at weight-based dosing from Day -10 to Day -7 pretransplant [see Table 1] ), intravenous thiotepa 5 mg/kg twice on Day -6, intravenous cyclophosphamide 40 mg/kg/day on Day -5 to Day -2, and marrow infusion on Day 0.

All patients had also received precytoreduction with hydroxyurea, azathioprine and fludarabine prior to start of the preparative regimen. Efficacy was based on the incidence of graft rejection (primary or late rejection). The incidence of graft rejection in these 25 patients using thiotepa was 0% (95% CI: [0, 0.12]).

Of the 51 patients who received the same preparative regimen, historically, without thiotepa, the incidence of graft rejection reported was 25.5% (95% CI: [0.13, 0.37]).

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility In mice, repeated intraperitoneal (IP) administration of thiotepa (1.15 or 2.3 mg/kg three times per week for 52 or 43 weeks, respectively) produced a significant increase in the combined incidence of squamous-cell carcinomas of the skin, preputial gland, and ear canal, and combined incidence of lymphoma and lymphocytic leukemia. In other studies in mice, repeated IP administration of thiotepa (4 or 8 mg/kg three times per week for 4 weeks followed by a 20 week observation period or 1.8 mg/kg three times per week for 4 weeks followed by a 35 week observation period) resulted in an increased incidence of lung tumors.

In rats, repeated IP administration of thiotepa (0.7 or 1.4 mg/kg three times per week for 52 or 34 weeks, respectively) produced significant increases in the incidence of squamous-cell carcinomas of the skin or ear canal, combined hematopoietic neoplasms, and uterine adenocarcinomas. Thiotepa given intravenously (IV) to rats (1 mg/kg once per week for 52 weeks) produced an increased incidence of malignant tumors (abdominal cavity sarcoma, lymphosarcoma myelosis, seminoma, fibrosarcoma, salivary gland hemangioendothelioma, mammary sarcoma, pheochromocytoma) and benign tumors.

The lowest reported carcinogenic dose in mice (1.15 mg/kg, 3.68 mg/m 2 ) is approximately 7-fold less than the maximum recommended human therapeutic dose based on body-surface area. The lowest reported carcinogenic dose in rats (0.7 mg/kg, 4.9 mg/m 2 ) is approximately 6-fold less than the maximum recommended human therapeutic dose based on body-surface area. Thiotepa was mutagenic in in vitro assays in Salmonella typhimurium , E coli , Chinese hamster lung and human lymphocytes.

Chromosomal aberrations and sister chromatid exchanges were observed in vitro with thiotepa in bean root tips, human lymphocytes, Chinese hamster lung, and monkey lymphocytes. Mutations were observed with oral thiotepa in mouse at doses >2.5 mg/kg (8 mg/m 2 ). The mouse micronucleus test was positive with intraperitoneal administration of >1 mg/kg (3.2 mg/m 2 ).

Other positive in vivo chromosomal aberration or mutation assays included Drosophila melanogaster , Chinese hamster marrow, murine marrow, monkey lymphocyte, and murine germ cell. Thiotepa impaired fertility in male mice at oral or intraperitoneal doses ≥0.7 mg/kg (2.24 mg/m 2 ), approximately 12-fold less than the maximum recommended human therapeutic dose based on body-surface area. Thiotepa (0.5 mg) inhibited implantation in female rats when instilled into the uterine cavity.

Thiotepa interfered with spermatogenesis in mice at IP doses ≥0.5 mg/kg (1.6 mg/m 2 ), approximately 17-fold less than the maximum recommended human therapeutic dose based on body-surface area. Thiotepa interfered with spermatogenesis in hamsters at an IP dose of 1 mg/kg (4.1 mg/m 2 ), approximately 7-fold less than the maximum recommended human therapeutic dose based on body-surface area.