Thiotepa for Injection USP Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed. RECENT MAJOR LABEL CHANGES ............................................................................................ 2

TABLE OF CONTENTS .............................................................................................................. 2

PART I: HEALTH PROFESSIONAL INFORMATION ...................................................................... 5

1. 1 INDICATIONS ............................................................................................................... 5

   1. 1.1 Pediatrics ................................................................................................................ 5
   2. 1.2 Geriatrics ................................................................................................................ 5
2. 2 CONTRAINDICATIONS ................................................................................................. 5
3. 3 SERIOUS WARNINGS AND PRECAUTIONS BOX ............................................................ 6

4. 4 DOSAGE AND ADMINISTRATION ................................................................................. 7

   1. 4.1 Dosing Considerations ............................................................................................ 7
   2. 4.2 Recommended Dose and Dosage Adjustment ....................................................... 7
   3. 4.3 Reconstitution ........................................................................................................ 8

What is a Notice of Compliance with Conditions (NOC/c)?

An NOC/c is a form of market approval granted to a product on the basis of promising evidence of clinical effectiveness following review of the submission by Health Canada.

Products authorized under Health Canada’s NOC/c policy are intended for the treatment, prevention or diagnosis of a serious, life-threatening or severely debilitating illness. They have demonstrated promising benefit, are of high quality and possess an acceptable safety profile based on a benefit/risk assessment. In addition, they either respond to a serious unmet medical need in Canada or have demonstrated a significant improvement in the benefit/risk profile over existing therapies. Health Canada has provided access to this product subject to conditions. Note that the manufacturer of the Canadian Reference Product will carry out additional clinical trials to verify the anticipated benefit of the medicinal ingredient in this product (thiotepa) within an agreed upon time frame.

1. 4.4 Administration ...................................................................................................... 9
2. 5 OVERDOSAGE .............................................................................................................. 9
3. 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ............................... 10
4. 7 WARNINGS AND PRECAUTIONS ................................................................................ 10
5. 7.1 Special Populations ........................................................................................ 15
6. 7.1.1 Pregnant Women ........................................................................................... 15
7. 7.1.2 Breast-feeding ................................................................................................ 15
8. 7.1.3 Pediatrics ........................................................................................................ 15
9. 7.1.4 Geriatrics ........................................................................................................ 16
10. 8 ADVERSE REACTIONS ................................................................................................ 16
11. 8.1 Adverse Reaction Overview .................................................................................. 16
12. 8.2 Clinical Trial Adverse Reactions ............................................................................ 16
13. 9 DRUG INTERACTIONS ................................................................................................ 19
14. 9.1 Serious Drug Interactions ..................................................................................... 19
15. 9.2 Drug Interactions Overview .................................................................................. 20
16. 9.4 Drug-Drug Interactions ......................................................................................... 20
17. 9.5 Drug-Food Interactions ......................................................................................... 22
18. 9.6 Drug-Herb Interactions ......................................................................................... 22
19. 9.7 Drug-Laboratory Test Interactions ........................................................................ 22
20. 10 CLINICAL PHARMACOLOGY ....................................................................................... 22
21. 10.1 Mechanism of Action ...................................................................................... 22
22. 10.2 Pharmacodynamics ........................................................................................ 22
23. 10.3 Pharmacokinetics ........................................................................................... 22
24. 11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 24
25. 12 SPECIAL HANDLING INSTRUCTIONS ........................................................................... 24

PART II: SCIENTIFIC INFORMATION ....................................................................................... 26

1. 13 PHARMACEUTICAL INFORMATION ............................................................................ 26

2. 14 CLINICAL TRIALS ........................................................................................................ 26

   1. 14.1 Trial Design and Study Demographics ............................................................ 26
   2. 14.2 Study Results .................................................................................................. 29
3. 15 MICROBIOLOGY ........................................................................................................ 32
4. 16 NON-CLINICAL TOXICOLOGY ..................................................................................... 32
5. 17 SUPPORTING PRODUCT MONOGRAPHS……………………………………………………………………32

PATIENT MEDICATION INFORMATION .................................................................................. 37

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

Thiotepa for Injection USP (thiotepa for injection) is indicated:

• in combination with other chemotherapeutic products as part of a high-dose chemotherapy (HDCT) consolidation regimen followed by autologous stem cell transplantation (ASCT) for adult patients with central nervous system (CNS) lymphoma

and has been issued marketing authorization with conditions. Patients should be advised of the nature of the authorization. For further information for Thiotepa for Injection USP please refer to Health Canada’s Notice of Compliance with conditions - drug products web site: https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/notice-compliance/conditions.html. Note that trials to verify the clinical benefit of the medicinal ingredient in Thiotepa for Injection USP are being carried out by the manufacturer of the Canadian Reference Product.

Thiotepa for Injection USP should be administered under the supervision of a physician who is experienced in the use of HDCT followed by SCT.

1.1 Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

There is limited clinical data on the use of high-dose thiotepa for injection as part of a HDCT regimen in geriatric patients (>65 years of age) with CNS lymphoma. Caution is needed in these patients.

2 CONTRAINDICATIONS

Thiotepa for Injection USP is contraindicated in:

• Patients who are hypersensitive to this drug or component of the container. For a complete listing, see the 6 DOSAGE FORMS, STRENGHTS, COMPOSITION AND PACKAGING section of the product monograph.
• Female patients who are pregnant or breastfeeding (see 7 WARNINGS AND PRECAUTIONS).
• Concomitant use with live virus or bacterial vaccines including yellow fever vaccine (see 7 WARNINGS AND PRECAUTIONS).

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

Thiotepa for Injection USP should only be administered under the supervision of a physician who is experienced in the use of high-dose chemotherapy (HDCT) and stem cell transplantation (SCT).

• Profound myelosuppression (anemia, neutropenia and thrombocytopenia) including refractory and fatal cases (see 7 WARNINGS AND PRECAUTIONS, Hematologic).
• Cardiotoxicity may occur. Cardiac function must be monitored regularly and caution is advised in patients with history of cardiac disease (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular).
• Hepatotoxicity: Liver function must be monitored regularly and caution is advised in patients with hepatic impairment (see 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic and Patients with Hepatic Impairment).
• Patients who have received prior radiation therapy, greater than or equal to three cycles of chemotherapy, or prior SCT may be at an increased risk of hepatic veno- occlusive disease (see 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, Patients with Hepatic Impairment, Patients with Renal Impairment and Special Populations).
• Pulmonary toxicity, including fatal cases, may occur and there may be additive effects produced by other cytotoxic agents (busulfan, fludarabine and cyclophosphamide) (see 7 WARNINGS AND PRECAUTIONS, Respiratory and 9 DRUG INTERACTIONS).
• Neurotoxicity may be greater in patients with prior brain or craniospinal irradiation (see 7 WARNINGS AND PRECAUTIONS, Neurologic).
• Renal toxicity (see 7 WARNINGS AND PRECAUTIONS, Renal).
• Thiotepa for Injection USP could cause fetal harm when administered to a pregnant female (see 7 WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women).
• Serious drug interactions (see 9 DRUG INTERACTIONS).

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

Thiotepa for Injection USP should be administered under the supervision of a physician who is experienced in the use of high-dose chemotherapy (HDCT) regimens followed by stem cell transplantation (SCT).

Dosing of obese patients based on total body weight may result in higher than expected thioTEPA/TEPA exposure. Consideration might be given to using adjusted body weight for calculating body surface area. Obese patients should be closely monitored for signs of toxicity.

4.2 Recommended Dose and Dosage Adjustment

The recommended dose for Thiotepa for Injection USP as part of HDCT regimens ranges from 185 mg/m²/day to 370 mg/m²/day, administered intravenously as one or two daily infusions over 2 to 3 consecutive days prior to ASCT. Do not exceed a total maximum cumulative dose of 750 mg/m² during the administration of the HDCT regimen.

Table 1 - Thiotepa for injection high-dose chemotherapy regimens used in CNS lymphoma patients

^aInfusion of autologous blood stem cells on Day 0; ^bThree patients additionally received rituximab; TT: thiotepa for injection; Bu: Busulfan; Cy: Cyclophosphamide: BCNU: Carmustine; VP-16: Etoposide; R: Rituximab; Mel: Melphalan

The recommended doses of Thiotepa for Injection USP are intended only as part of a HDCT regimen followed by SCT.

Special populations:

• Renal impairment: The safety and efficacy of high-dose thiotepa for injection has not been established in patients with renal impairment. Dedicated pharmacokinetic studies in patients with renal impairment have not been conducted. Patients with renal impairment should be treated with caution and monitored for signs of toxicity.
• Hepatic impairment: The safety and efficacy of high-dose thiotepa for injection has not been established in patients with hepatic impairment. Thiotepa for Injection is mainly metabolized by the liver and the risk of increased exposure in patients with hepatic impairment is unknown. Patients with hepatic impairment should be treated with caution and monitored for signs of toxicity.
• Obesity: Consideration might be given to using adjusted body weight for calculating BSA (see 10.3 Pharmacokinetics, Special Populations and Conditions).
• Geriatrics (>65 years of age): There is limited clinical data on the use of high-dose thiotepa for injection as part of a HDCT regimen in geriatric patients with CNS lymphoma. Caution is needed in these patients.
• Pediatrics (<18 years of age): Health Canada has not authorized an indication for pediatric use.

4.3 Reconstitution

Parenteral Products:

Reconstitution of vials

Reconstitute with Sterile Water for Injection as follows:

Table 2 - Reconstitution

Thiotepa for Injection USP must be reconstituted with sterile water for injection. Using a syringe fitted with a needle, aseptically withdraw sterile water for injection (see chart above). Inject the content of the syringe into the vial through the rubber stopper. Remove the syringe and the needle and mix manually by repeated inversions. Only clear colourless solutions, without any particulate matter, must be used. Reconstituted solutions may occasionally show opalescence; such solutions can still be administered.

For management of a suspected drug overdose contact your regional poison control centre.

Further dilution in the infusion bag

The reconstituted solution is hypotonic and must be further diluted prior to administration with 500 mL sodium chloride 9 mg/mL (0.9%) solution for injection (1000 mL if the dose is higher than 500 mg) or with an appropriate volume of sodium chloride 9 mg/mL (0.9%) solution for injection in order to obtain a final Thiotepa for Injection USP concentration between 0.5 and 1 mg/mL.

Prior to and following each infusion, the indwelling catheter line should be flushed with approximately 5 mL sodium chloride 9 mg/mL (0.9%) solution for injection. Infusion solutions should be administered using an infusion set equipped with a 0.2 μm in-line filter (polyethersulfone-fluid filter membrane B. Braun).

This medicinal product must not be mixed with other medicinal products except those mentioned in Reconstitution.

4.4 Administration

As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration.

Thiotepa for Injection USP must be administered by a qualified healthcare professional as a 2 to 4 hours intravenous infusion via a central venous catheter. Infusion solutions should be administered using an infusion set equipped with a 0.2 μm in-line filter.

Thiotepa for Injection USP is for single use only. Any unused product or waste material should be disposed of in accordance with local requirements.

5 OVERDOSAGE

The principal toxic effect of Thiotepa for Injection USP is profound myelosupression and pancytopenia but skin, gastrointestinal, hepatic, renal, cardiac, pulmonary and CNS toxicity can occur (see 7 WARNINGS AND PRECAUTIONS). There is no known specific antidote for Thiotepa for Injection USP overdose.

Management of overdosage would include appropriate treatment of any concurrent infection, myelosuppression or other toxicity, close monitoring of the hematologic status and institution of vigorous supportive measures as medically indicated to sustain the patient through any period of toxicity that might occur.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING Table 3 - Dosage Forms, Strengths, Composition and Packaging

Thiotepa for Injection USP

Type I clear glass vial with a stopper, containing either 15 mg or 100 mg Thiotepa for Injection USP. The stopper is not made with natural rubber latex. Pack size of 1 single use vial. Preservative free.

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

General

Prophylactic or empiric use of anti-infectives (bacterial, fungal, viral) should be considered for the prevention and management of infections during the neutropenic period.

Grade 3-4 mucositis occurs in the majority of patients treated with thiotepa for injection -containing HDCT. Management of mucositis often requires total parenteral nutrition.

Administration of live attenuated vaccines (including yellow fever vaccines) should be avoided until the immunosuppressive effects have been resolved (see 2 CONTRAINDICATIONS).

Concomitant use with phenytoin and fosphenytoin should be avoided (see 9 DRUG INTERACTIONS).

Thiotepa must not be concurrently administered with cyclophosphamide when both medicinal products are present in the same high-dose chemotherapy (HDCT) regimen. Thiotepa for Injection USP must be delivered after the completion of any cyclophosphamide infusion (see 9 DRUG INTERACTIONS).

During the concomitant use of thiotepa and inhibitors or inducers of CYP2B6 or CYP3A4, patients should be carefully monitored (see 9 DRUG INTERACTIONS).

The safety assessment of high-dose thiotepa for injection as part of a high-dose chemotherapy (HDCT) regimen is derived from published literature where patients, including those with CNS lymphoma, were treated. As such, the safety information is limited by the information selected for inclusion into published reports. As high-dose thiotepa for injection is administered in combination with other chemotherapeutic agents, it is not always possible to assign, nor to exclude, causality to particular adverse events. The following sections describe adverse events reported with the use of HDCT regimens that include thiotepa for injection.

Carcinogenesis and Mutagenesis

Thiotepa for injection has been shown in pre-clinical studies to be mutagenic and carcinogenic. Treatment-related secondary malignancies, including myelodysplastic syndrome and acute non-lymphocytic leukemia, have been reported with the use of thiotepa (see 16 NON-CLINICAL TOXICOLOGY).

Cardiovascular

Cardiac-related adverse events such as arrhythmia (including tachycardia and atrial fibrillation) congestive cardiac failure, cardiomyopathy and myocarditis have been reported. Vascular disorders observed include hypertension, lymphedema and embolism. Cerebral aneurysm has also been reported.

Patients with organ dysfunction were generally excluded from clinical trials. Caution is advised in patients with a history of cardiac disease. Severe cardiotoxicity, including cases with a fatal outcome, have been reported in patients with reduced ejection fraction prior to stem cell transplantation. Regular monitoring of cardiac function is recommended in patients treated with Thiotepa for Injection USP.

Driving and Operating Machinery

Convulsion, hallucination, delirium, dizziness, headache and blurred vision have been reported in patients treated with thiotepa for injection. Patients experiencing these symptoms should use caution when driving or operating machines.

Ear/Nose/Throat

Ototoxicity (including hearing impairment and tinnitus) has been reported in patients treated with thiotepa for injection-containing HDCT regimens.

Endocrine and Metabolism

Anorexia, weight loss and dehydration have been reported in CNS lymphoma patients treated with thiotepa-containing HDCT regimens. Hyponatremia associated with syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been reported. Decreased appetite, hyperglycemia and hypopituitarism have been reported.

Gastrointestinal

Gastrointestinal toxicity occurs very commonly in patients receiving thiotepa for injection-containing HDCT regimens, including severe nausea, vomiting and diarrhea. Other gastrointestinal events reported include grade 3 stomatitis, colitis, pancreatitis, typhilitis, chronic enterocolitis (including Clostridium difficile colitis), as well as esophagitis, dyspepsia, abdominal pain, constipation, gastrointestinal perforation, and ileus.

Grade 3-4 mucositis occurs in the majority of patients treated with thiotepa for injection-containing HDCT. Management of mucositis often requires total parenteral nutrition.

Genitourinary

Hemorrhagic cystitis, dysuria, oliguria, cystitis and hematuria have been reported. Consideration should be given to administration of bladder protective agents. Patients must be adequately hydrated to reduce the risk of genitourinary toxicity.

Hematologic

High-dose thiotepa for injection causes profound myelosuppression in all patients. Reported median time for platelet recovery ranged from 8 to 18 days; median time for neutrophil recovery was between 7.5 to 11 days. Persistent grade 3-4 thrombocytopenia and severe febrile neutropenia have been reported. Refractory thrombocytopenia has been associated with fatal hemorrhage. Thrombotic micro-angiopathy involving the CNS has also been reported.

Frequent complete blood counts, including differential white blood cell counts, and platelet counts need to be performed during treatment and until recovery is achieved. Daily white blood cell counts and platelets are recommended during therapy with Thiotepa for Injection USP and after transplant for at least 30 days (see Monitoring and Laboratory Test).

Infections

Increased susceptibility to infection and sepsis have been reported very commonly. Serious infections, including sepsis, septic shock, fever and chills, may occur after ASCT. Prophylactic or empiric use of anti-infectives (bacterial, fungal, viral) is recommended for the prevention and management of infections during the neutropenic period.

Hemorrhage

Cases of epistaxis and cerebral hemorrhage (including fatalities) possibly secondary to thrombocytopenia have been reported.

Thrombosis

Pulmonary embolism, including fatal cases, has been reported.

Hepatic/Biliary/Pancreatic

Thiotepa for Injection USP is hepatotoxic. Increased transaminases, alkaline phosphatase, gamma-glutamyltransferase and bilirubin as well as elevated amylase have been reported in thiotepa for injection treated patients. Cases of veno-occlusive liver disease, hepatomegaly, jaundice and pancreatitis have also been reported. Patients who have received prior radiation therapy, greater than or equal to three cycles of chemotherapy, or prior SCT may be at an increased risk of hepatic veno-occlusive liver disease (see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX).

Immune

Depressed immunity caused by the profound myelosuppressive effects of high-dose Thiotepa for Injection USP occurs in patients treated with thiotepa for injection-containing HDCT regimens. Live vaccines (including yellow fever vaccines) should not be administered to immunocompromised patients.

Severe immunosuppression has led to serious, sometimes fatal, infections (see 7 WARNINGS AND PRECAUTIONS, Hematologic). Prophylactic or empiric use of anti-infectives (bacterial, fungal, viral) should be considered for the prevention and management of infections during the neutropenic period. Latent infections can be reactivated. Reactivation of cytomegalovirus (CMV) has occurred with thiotepa for injection-containing HDCT regimens administration. Monitoring and pre-emptive treatment of patients with positive CMV serology are advised. Acute and chronic graft-versus-host diseases have been reported, including some with fatal outcome.

Hypersensitivity reactions have been observed. Engraftment syndrome occurs frequently.

Monitoring and Laboratory Tests

Hematologic

Frequent complete blood counts, including differential white blood cell counts, and platelet counts need to be performed during the treatment and until recovery is achieved. Platelet and red blood cell support, as well as the use of growth factors such as Granulocyte-colony stimulating factor (G-CSF), should be employed as medically indicated. Daily white blood cell counts and platelet counts are recommended during therapy with Thiotepa for Injection USP and after transplant for at least 30 days.

Clinical Chemistry

Monitor hepatic function (including ALT, AST, alkaline phosphatase, total bilirubin and GGT) and amylase regularly following ASCT. Patients with any degree of hepatic impairment require close monitoring of liver function.

Renal function (creatinine and eGFR), electrolytes (e.g. sodium, potassium, phosphate), magnesium, and calcium should be assessed periodically.

Urinalysis should be performed at regular intervals to assess for hematuria.

Cardiac monitoring

Cardiac function should be monitored regularly in patients treated with Thiotepa for Injection USP.

Muscoskeletal

Back pain, myalgia and arthralgia have been reported.

Neurologic and Psychiatric

Thiotepa for Injection USP is a lipophilic alkylating agent that crosses the blood-brain barrier and achieves cerebrospinal fluid concentrations equivalent to plasma concentrations. Severe neurotoxicity can occur in Thiotepa for Injection USP treated patients. Neurotoxicity may be greater in patients with prior brain or craniospinal irradiation. Cases of leukoencephalopathy, including fatal cases, have been observed. Other neuropsychiatric events associated with the use of thiotepa for injection include: cognitive disorder, memory deficits, confusional state, delirium or change in mental status, agitation, hallucination, anxiety, extrapyramidal disorder, convulsion, dizziness, headache, blurred vision, encephalopathy and paraesthesias.

Ophthalmologic

Conjunctivitis and cataracts have been observed in patients treated with thiotepa for injection-containing HDCT regimens.

Patients with Renal Impairment

Patients with renal impairment should be treated with caution and monitored for signs of toxicity.

Patients with Hepatic Impairment

Patients with hepatic impairment should be treated with caution and regular monitoring of serum transaminase, alkaline phosphatase and bilirubin is recommended for prompt detection of signs of toxicity.

Renal

Renal failure, increased creatinine levels and increased urea levels have been reported.

Reproductive Health: Female and Male Potential

• Fertility

Pre-clinical toxicity studies show that thiotepa for injection impairs spermatogenesis and ovarian function in mice (see 16 TOXICOLOGY). Azoospermia and amenorrhea occur with thiotepa for injection use and thiotepa for injection commonly causes infertility in male and female patients. Fertility preservation strategies should be discussed with male patients and female patients of childbearing potential.

• Teratogenic Risk

Thiotepa for injection was shown pre-clinically to be teratogenic and to cause fetal death (see 16 TOXICOLOGY). Thiotepa for Injection USP must not be used during pregnancy (see 2 CONTRAINDICATIONS). Effective methods of contraception should be used during therapy if either the patient or the partner is of childbearing potential.

Vaginal haemorrhage and menopausal symptoms have been reported.

Respiratory

Pulmonary toxicity occurs in patients treated with thiotepa for injection-containing HDCT. Idiopathic pneumonia syndrome, pulmonary oedema, cough and pneumonitis have been reported. Fatal acute respiratory distress has also been reported.

Skin

Thiotepa for Injection USP is excreted through the skin. Skin toxicity reported with thiotepa for injection use includes rash (predominantly involving axillae, groin and elbows), pruritus, urticaria, erythrodermic psoriasis, alopecia, pigmentation disorders, Stevens-Johnson syndrome (including fatal cases) and toxic epidermal necrolysis.

7.1 Special Populations

7.1.1 Pregnant Women

Thiotepa for Injection USP is contraindicated in pregnancy. There are no studies in pregnant women using thiotepa for injection. Based on its mechanism of action, Thiotepa for Injection USP has the potential to cause fetal harm; including teratogenicity and fetal death (see 16 TOXICOLOGY). Women of childbearing potential should use effective contraception during treatment. A pregnancy test should be performed and confirmed negative before treatment is initiated. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Thiotepa for Injection USP. If the patient becomes pregnant while receiving Thiotepa for Injection USP, the patient should be informed of the potential hazard to the fetus.

7.1.2 Breast-feeding

It is not known whether thiotepa for injection is excreted in human milk. Due to its pharmacological properties and its potential toxicity for nursing infant, breastfeeding is contraindicated during treatment with Thiotepa for Injection USP.

7.1.3 Pediatrics

Pediatrics (< 18 years of age): CNS lymphoma does not typically occur in pediatric patients. The safety and efficacy of high-dose thiotepa for injection as part of a HDCT regimen have not been established in pediatric CNS lymphoma patients.

Cases of leukoencephalopathy have been observed following treatment with thiotepa for injection in adult and pediatric patients with multiple previous chemotherapies, including methotrexate and radiotherapy. Some cases have been fatal.

Cases of pulmonary arterial hypertension have been observed following treatment with thiotepa for injection in pediatric patients. All cases had a fatal outcome.

Cases of hypothyroidism, paresis, cardiac arrest, pulmonary hemorrhage, respiratory arrest and growth retardation have also been observed in pediatric patients administered with high- dose thiotepa for injection.

7.1.4 Geriatrics

Geriatrics (> 65 years of age): There is limited clinical data on the use of high-dose thiotepa for injection as part of a HDCT regimen in geriatric patients with CNS lymphoma. Caution is needed in these patients.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The most commonly reported adverse events in the clinical studies of CNS lymphoma patients treated with thiotepa for injection-containing high-dose chemotherapy (HDCT) were myelosupression, infections, diarrhea, nausea, vomiting, stomatitis, edema, mucositis, neurotoxicity, skin rash and alopecia.

Serious adverse events included thrombocytopenia, neutropenia, pancytopenia, febrile neutropenia, refractory thrombocytopenia, hemorrhage, pulmonary embolism, pneumonia, sepsis, leukoencephalopathy, micro-angiopathy, convulsion, extrapyramidal symptoms, delirium, mucositis, veno-occlusive disease, gastrointestinal graft-versus-host disease, typhilitis, pancreatitis, hemorrhagic cystitis, acute renal insufficiency and Stevens-Johnson syndrome.

8.2 Clinical Trial Adverse Reactions

Treatment emergent adverse events reported with the use of high-dose thiotepa for injection as part of a high-dose chemotherapy (HDCT) regimen followed by autologous stem cell transplantation (ASCT) are derived from published literature where CNS lymphoma patients were treated. As such, the safety information is limited by the information selected for inclusion into published reports. Adverse events in the tables below are not pooled nor listed by MedDRA organ classes as there are major reporting differences across publications.

Table 4 - Treatment emergent adverse events reported in newly diagnosed PCNSL patients administered with a thiotepa for injection-containing HDCT regimen

^a: Number of enrolled patients that were treated with a thiotepa for injection-containing HDCT regimen

N.R.: not reported

Table 5 - Treatment emergent adverse events reported in refractory or relapsed PCNSL patients administered with a thiotepa for injection -containing HDCT regimen

^a: Number of enrolled patients that were treated with a thiotepa for injection -containing HDCT regimen.

^b: Retrospective studies over 79 patients, of which 47 were from Soussain 2001 and Soussain 2008. Here presented data relate to the remaining 32 patients only.

N.R.: not reported

Table 6 - Treatment emergent adverse events reported in SCNSL patients administered with a thiotepa for injection-containing HDCT regimen

^a: Number of enrolled patients that were treated with a thiotepa for injection-containing HDCT regimen

N.R.: not reported

Table 7 - Treatment emergent adverse events reported in newly diagnosed or relapsed PCNSL patients administered with a thiotepa for injection-containing HDCT regimen

^a: Number of enrolled patients that were treated with a thiotepa for injection -containing HDCT regimen.

*: 1 relapsed PCNSL patient and 6 newly diagnosed PCNSL

Table 8 - Treatment emergent adverse events reported in PCNSL and SCNSL patients administered with a thiotepa for injection-containing HDCT regimen

^a: Number of patients treated with a thiotepa for injection-containing HDCT regimen.

^b: 7 relapsed PCNSL patients and 8 relapsed SCNSL patients

^c: 18 PCNSL patients and 11 SCNSL patients

^d: 16 PCNSL patients and 16 SCNSL patients N.R.: Not reported

9 DRUG INTERACTIONS

9.1 Serious Drug Interactions

Serious Drug Interactions

• Live attenuated virus or bacterial vaccines, including yellow fever vaccine (see Drug- Drug Interactions)
• Phenytoin (see Drug-Drug Interactions)
• Cyclophosphamide and other myelosuppressive or myelotoxic agents, for example (e.g.), melphalan, busulfan, fludarabine, treosulfan etc. (see Drug-Drug Interactions)

9.2 Drug Interactions Overview

Thiotepa appears to be metabolised to tepa via CYP3A4 and CYP2B6 in vitro.

Thiotepa is a major inhibitor for CYP2B6 in vitro, and may thereby potentially increase plasma concentrations of co-administered CYP2B6 substrates. CYP2B6 catalyzes the metabolic conversion of cyclophosphamide to its active form 4-hydroxycyclophosphamide (4-OHCP).

The related findings and effects are discussed further below in Table 9.

9.4 Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 9 - Established or Potential Drug-Drug Interactions

Legend: C = Case Study, CT = Clinical Trial, T = Theoretical

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Thiotepa is a polyfunctional cytotoxic agent chemically and pharmacologically related to nitrogen mustard. The radiomimetic action of thiotepa is believed to occur through the release of ethylene imine radicals that disrupts the DNA bonds, e.g. by alkylation of guanine at the N-7, breaking the linkage between the purine base and the sugar and liberating alkylated guanine.

10.2 Pharmacodynamics

The primary pharmacodynamic action of thiotepa for injection consists of damaging the DNA and cellular structure of malignant cells. When used in the conventional dose range, thiotepa’s dose-limiting toxicity is bone marrow suppression. Autologous stem cell transplantation (ASCT) permits the use of thiotepa at doses higher than the conventional dose range and when combined with non-cross resistant cytotoxic agents, it is expected to provide improved cytoreduction and ideally disease eradication. Active metabolites of thiotepa have alkylating effects; however their clinical role is unclear.

10.3 Pharmacokinetics

Absorption:

Thiotepa is to be administered intravenously. Thiotepa is unreliably absorbed from the gastrointestinal tract: acid instability prevents thiotepa from being administered orally.

Distribution:

Thiotepa is a highly lipophilic compound. After intravenous administration, plasma concentrations of the active substance fit a two compartment model with a rapid distribution phase. The volume of distribution of thiotepa is large and it has been reported as ranging from

40.8 L/m² to 75 L/m². The apparent volume of distribution of thiotepa appears independent of the administered dose. The fraction unbound to proteins in plasma is 70-90%; insignificant binding of thiotepa to gamma globulin and minimal albumin binding (10-30%) has been reported.

After intravenous administration of thiotepa at non-myeloablative doses in children with refractory malignancies, cerebrospinal fluid (CSF) medicinal product exposure is nearly equivalent to that achieved in plasma; the mean ratio of AUC in CSF to plasma for thiotepa is

0.92 and 0.99 for triethylenephosphoramide (tepa), a major metabolite of thiotepa. CSF and plasma concentrations of tepa exceed the concentrations of the parent compound.

Metabolism:

Thiotepa undergoes rapid and extensive hepatic metabolism and metabolites could be detected in urine within 1 hour after infusion. Thiotepa undergoes oxidative desulfuration via the cytochrome P450 CYP2B and CYP3A isoenzyme families to form the major metabolite tepa and also likely conjugation with glutathione to form thiotepa-mercapturate. The total excreted amount of thiotepa and its identified metabolites accounts for 54-100% of the total alkylating activity, indicating the presence of other alkylating metabolites.

Elimination:

The total clearance of thiotepa ranged from 11.4 to 23.2 L/h/m². The elimination half-life of thiotepa varied from 1.4 to 3.7 hours, the elimination half-life of tepa varied from 4.9 to 17.6 hours. The identified metabolites tepa, monochlorotepa and thiotepa-mercapturate are all excreted in the urine. The mean urinary recovery of thiotepa and its metabolites is 0.5% for the unchanged medicinal product and monochlorotepa, and 11% for tepa and thiotepa- mercapturate. Thiotepa was also detected in skin and sweat of patients receiving high-dose regimens, although the percentage of skin excretion in the total dose of administration was unknown.

Special Populations and Conditions

• Pediatrics: Thiotepa for Injection USP is not indicated for pediatric patients, as CNS lymphoma is not typically seen in this population.
• Geriatrics: Thiotepa metabolism and elimination have not been assessed in elderly patients.

• Hepatic Insufficiency: No pharmacokinetic studies have been conducted in

  • patients with hepatic impairment. Since thiotepa is mainly metabolized through the liver, thiotepa exposure may be increased in patients with hepatic impairment.
• Renal Insufficiency: No pharmacokinetic studies have been conducted in patients with renal impairment. Urinary excretion is a major route of elimination of alkylating metabolites of thiotepa. Renal impairment may increase the exposure to these metabolites.
• Obesity: The pharmacokinetic profile of high-dose thiotepa for injection has not been established in obese patients. Increased thioTEPA/TEPA exposure has been reported in obese patients dosed on body surface area (BSA) calculated using total body weight. Consideration might be given to using adjusted body weight for calculating BSA.

11 STORAGE, STABILITY AND DISPOSAL

Unopened vial

Store and transport refrigerated (2 to 8 °C). Do not freeze. Keep out of reach and sight of children.

After reconstitution

Chemical and physical in-use stability after reconstitution has been demonstrated for 8 hours when stored at 2 to 8 °C.

After dilution

Chemical and physical in-use stability after dilution has been demonstrated for 24 hours when stored at 2 to 8 °C and for 4 hours when stored at 25°C. Thiotepa for Injection USP is for single use only. Any unused product or waste material should be disposed of in accordance with local requirements.

From a microbiological point of view, the product should be used immediately after dilution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than the above mentioned conditions when dilution has taken place in controlled and validated aseptic conditions.

12 SPECIAL HANDLING INSTRUCTIONS

Procedures for proper handling and disposal of anticancer medicinal products must be considered. All transfer procedures require strict adherence to aseptic techniques, preferably employing a vertical laminar flow safety hood.

Thiotepa for Injection USP is cytotoxic, carcinogenic, mutagenic and teratogenic. Pregnant staff and breastfeeding mothers should be excluded from the reconstitution and administration of Thiotepa for Injection USP. Use caution during handling and preparation. Avoid ingestion, inhalation, or skin and eye contact. Skin reactions may occur with accidental exposure. Use of gloves and protective clothing to prevent accidental skin contact is recommended. If Thiotepa for Injection USP solution contacts the skin or mucosa, immediately wash the skin thoroughly with soap and water or rinse the mucosa with copious amounts of water, and seek medical attention.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION Drug Substance

Proper name: Thiotepa

Chemical name: N,N ́,N ́ -́ triethylenethiophosphoramide

Aziridine,1,1’,1’’-phosphinothioylidynetris Tris(1-aziridinyl)phosphine sulfide

CAS Number: 52-24-4

Molecular formula and molecular mass: C₆H₁₂N₃PS, 189.23 g/mol

Structural formula:

Physicochemical properties: White crystalline powder.

Unstable in acid medium.

Solubility in water: 19g/100mL (25°C)

Solubility in other solvents: 1:2 in ethanol; 1:2 in chloroform; 1:~4 in ether

14 CLINICAL TRIALS

14.1 Trial Design and Study Demographics

Clinical evidence in support of the use of thiotepa for injection as part of a high-dose chemotherapy (HDCT) regimen followed by autologous stem cell transplantation (ASCT) for the consolidation treatment of adult patients with CNS lymphoma is derived from 18 published open-label clinical trials, 7 of which consisted of retrospective analyses. The majority of the studies were non-comparative; seven of them included a comparator group which consisted of patients considered ineligible to receive HDCT followed by ASCT. Patients received doses that ranged from 185 mg/m²/day to 370 mg/m²/day as one or two daily infusions administered intravenously over 2 to 3 consecutive days prior to ASCT, without exceeding the total maximum cumulative dose of 750 mg/m².

A total of 303 adult patients with CNS lymphoma received consolidation therapy consisting of thiotepa for injection-containing HDCT followed by ASCT. All patients were immunocompetent. CNS lymphomas were mostly primary B-cell types and their location included the brain parenchyma, the meninges, the spinal cord, and or the eye(s).

Table 10 - Summary of patient demographics for clinical trials in adult CNS lymphoma patients treated with a thiotepa for injection-containing HDCT regimen

^a of patients treated with thiotepa for injection-containing HDCT

* data on all enrolled patients

n.s. = Not Specified; KPS: Karnosfsky performance status; ECOG PS: Eastern Cooperative Oncology Group performance status

14.2 Study Results

Response rate was the main efficacy endpoint to assess the benefit of thiotepa for injection-containing HDCT regimens in CNS lymphoma patients. Survival analyses were conducted for the majority of studies. Overall survival (OS), progression free-survival (PFS) or disease-free survival (DFS) are included in Tables 9 to 13 when reported. Due to differences across studies in defining and reporting efficacy endpoints, study results were not pooled.

Table 11 - Efficacy results in newly diagnosed PCNSL patients administered with a thiotepa for injection-containing HDCT regimen

^aNumber of patients treated with a thiotepa for injection-containing HDCT regimen followed by ASCT;

^bpercentage calculated on the whole patients who received the mobilization therapy (N=26)

ORR: Objective Response rate; CR: complete response, PR: partial response, SD: stable disease; PD: progressive disease; SU: status unknown; DFS: disease-free survival; PFS: progression-free survival; OS: overall survival; N.R.: not reported in the publication.

Table 12 - Efficacy results in relapsed/refractory PCNSL patients administered with a thiotepa for injection-containing HDCT regimen

^aNumber of patients treated with a thiotepa for injection-containing HDCT regimen followed by ASCT;

CR: complete response, PR: partial response, SD: stable disease; PD: progressive disease; SU: status unknown; DFS: disease-free survival; PFS: progression-free survival; OS: overall survival; N.R.: not reported in the publication.

Table 13 - Efficacy results in SCNSL patients administered with a thiotepa for injection-containing HDCT regimen

^aNumber of patients treated with a thiotepa for injection-containing HDCT regimen followed by ASCT;

^bpercentage calculated on the whole patients who completed the induction therapy (N=27)

CR: complete response, PR: partial response, SD: stable disease; PD: progressive disease; SU: status unknown; DFS: disease-free survival; PFS: progression-free survival; OS: overall survival; N.R.: not reported in the publication.

TTF: time to treatment failure, measured from start of study therapy (for HD-ASCT from time of ASCT) to first progression, relapse or death due to lymphoma or to therapy-related toxicity.

Table 14 - Efficacy results in relapsed PCNSL patients administered with a thiotepa for injection- containing HDCT regimen

^a Number of patients treated with a thiotepa for injection-containing HDCT regimen followed by ASCT.

CR: complete response; DFS: disease-free survival; PFS: progression-free survival; OS: overall survival.

Table 15 - Efficacy results in PCNSL and SCNSL patients administered with a thiotepa for injection- containing HDCT regimen

^a Number of patients treated with a thiotepa for injection-containing HDCT regimen followed by ASCT;

^b 7 relapsed PCNSL patients and 8 relapsed SCNSL patients

^c 18 PCNSL patients and 11 SCNSL patients

^d 16 PCNSL patients and 16 SCNSL patients

CR: complete response, PR: partial response, SD: stable disease; PD: progressive disease; SU: status unknown; DFS: disease- free survival; PFS: progression-free survival; OS: overall survival; N.R.: not reported in the publication.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology: Non-conventional acute and repeat dose toxicity studies were performed. As to be expected with a nitrogen mustard-based alkylating agent, application of thioTEPA was shown to have relevant mutagenic, teratogenic and genotoxic unwanted effects. The major side effect of thioTEPA is bone marrow suppression in all animal models and in man. Bleeding, disturbance of coagulation, various organotoxic effects on CNS, liver, skin and most importantly the impairment of fertility have been recognised in preclinical models and observed in clinical settings, too.

Carcinogenicity: Thiotepa was shown to be carcinogenic in mice and rats.

Genotoxicity: Thiotepa was shown to be genotoxic in vitro and in vivo.

Reproductive and Developmental Toxicology: Thiotepa was shown to impair fertility by interfering with spermatogenesis in male mice and impairing ovarian function in female mice. It was teratogenic in mice and in rats, and fetolethal in rabbits. These effects were seen at doses lower than those used in humans.

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. ^PrTEPADINA^® (powder for solution, 15 mg / vial and 100 mg / vial), submission control #252188, Product Monograph, ADIENNE SA. (December 29, 2021).

References

1. 1. Soussain C, Merle-Béral H, Reux I, Sutton L, Fardeau C, Gerber S et al. A Single-Center Study of 11 patients with Intraocular Lymphoma Treated with Conventional Chemotherapy Followed by High-Dose Chemotherapy and Autologous Bone Marrow Transplantation in 5 Cases. Leukemia and Lymphoma. 1996; 23: 339-45
2. 2. Soussain C, Suzan F, Hoang-Xuan K, Cassoux N, Levvy V, Azar N et al. Results of Intensive Chemotherapy Followed by Hemapoietic Stem-Cell Rescue in 22 Patients With Refractory or Recurrent Primary CNS Lymphoma or Intraocular Lymphoma. 2001; 19:742-9
3. 3. Cheng T, Forsyth P, Chaudhry A, Morris D, Glück S, Russel J A, et al. High-dose thiotepa, busulfan, cyclophosphamide and ASCT without whole-brain radiotherapy for poor prognosis primary CNS lymphoma. Bone Marrow Transplantation 2003; 31: 679-685
4. 4.

   Soussain C, Hoang-Xuan K, Levy V. Results of intensive chemotherapy followed by

   1. hemapoietic stem cell rescue in 22 patients with refractory or recurrent primary CNS lymphoma or intraocular lymphoma. [French]. Bull Cancer 2004; 91 (2): 189-92
5. 5. Illerhaus G, Marks R, Ihorst G, Guttenberger R, Ostertag, Derigs G, et al. High-Dose Chemotherapy With Autologous Stem-Cell Transplantation and Hyperfractionated Radiotherapy As First-Line Treatment of Primary CNS Lymphoma. Journal of Clinical Oncology 2006 Aug; 24 (24):3865-70
6. 6. Montemurro M, Kiefer T, Schüler F, Al-Ali H. K., Wolf H.-H, Herbst R et al. Primary central nervous system lymphoma treated with high-dose methotrexate, high-dose busulfan/thiotepa, autologous stem-cell transplantation and response-adapted whole- brain radiotherapy: results of the multicenter Ostdeutsche Studiengruppe Hämato- Onkologie OSHO-53 phase II study. Annals of Oncology 2007; 18:665-71
7. 7. Illerhaus G, Müller F, Feuerhake F, Schäfer AO, Ostertag C, Finke J. High-dose chemotherapy and autologous stem-cell transplantation without consolidating radiotherapy as first-line treatment for primary lymphoma of the central nervous system. Haematologica 2008 Jan; 93 (1): 147-148s
8. 8. Soussain C, Hoang-Xuan K, Taillandier L, Fourme E, Choquet S, Witz F et al. Intensive Chemotherapy Followed by Hematopoietic Stem-Cell Rescue for Refractory and Recurrent Primary CNS and Intraocular Lymphoma: Société Française de Greffe Greffe de Moëlle Osseuse-Thérapie Cellulaire Journal of Clinical Oncology 2008 May 20; 26 (15): 2512-18
9. 9. Kiefer T, Hirt C, Späth C, Schüler F, Al-Ali H, Wolf HH et al. Long-term follow-up of high- dose chemotherapy with autologous stem-cell transplantation and response-adapted whole-brain radiotherapy for newly diagnosed primary CNS lymphoma: results of the multicenter Ostdeutsche studiengruppe Hämatologie und Onkologie OSHO-53 phase II study. Annals of Oncology 2012; 23:1809-12
10. 10. Alimohamed N, Daly A, Owen C, Duggan P, Stewart DA . Upfront thiotepa, busulfan, cyclophosphamide, and autologous stem celi transplantation for primary CNS lymphoma: a single centre experience Leukemia & Lymphoma, 2012 May; 53(5): 862-7
11. 11. Cote G M, Hochberg E P, Muzikansky A, Hochberg F H, Drappatz J, McAfee SL et al. Autologous Stem Cell Transplantation with Thiotepa, Busulfan, and Cyclophosphamide (TBC) Conditioning in Patients with CNS Involvement by Non-Hodgkin Lymphoma. Biol Blood Marrow Transplant 2012; 18: 76-83
12. 12. Soussain C, Choquet S, Fourme E, Delgadillo D, Bouabdallah K, Ghesquières H et al. Intensive chemotherapy with thiotepa, busulfan and cyclophosphamide and hematopoietic stem cell rescue in relapsed or refractory primary central nervous system lymphoma and intraocular lymphoma: a retrospective study of 79 cases. Haematologica 2012 Nov; 97(11):1751-56.
13. 13. Bierman PJ. et al. (2003) Syngenic hematopoietic stem cell transplantation for Non Hodgkin’s lymphoma: a comparison with allogeneic and autologous transplantation. The Lymphoma Working Coommittee of The International Bone Marrow Transplant Registry and the European Group for Blood and Marrow Transplantation; JCO, Vol 21, No 20, 2003.
14. 14. Cohen BE, Egorin ML, Kohlhepp EA, Alsner J and Guiterrez PL Human plasma pharmacokinetics and urinary excretion of thiotepa and its metabolites. Cancer Treat Rep 1986; 70: 859-64.
15. 15. O'Dwyer PJ, LaCreta F, Engstrom PF, Peter R, Tartaglia L, Diane C et al. Phase I/Pharmacokinetic Reevaluation of Thiotepa. Cancer research 1991 June 15; 51: 3171- 3176
16. 16. Hagen B, Walseth F, Walstad RA, Iversen T, and Nilsen O. Single and repeated dose pharmacokinetics of thio-TEPA in patients treated for ovarian carcinoma. Chemotherapy and Pharmacology 1987; 19: 143-48
17. 17. Hagen B. Pharmacokinetics of thio-TEPA and TEPA in the conventional dose-range and its correlation to myelosuppressive effects. Cancer Chemotherapy and Pharmacology 1991; 27: 373-78.
18. 18. Feun LG, Blyden G, Yrizarry J, Dorvil M, Waldman S, Benedetto P et al. Cancer Biotherapy 1993; 8 (1): 43-48
19. 19. Wadler S, Egorin M J, Zuhowski E G, Tortorello L, Salva K, Runokwicz CD et al. Phase I clinical and pharmacokinetic study of thioteopa administered intraperitoneally in patients with advanced malignancies. Journal of Clinical Oncology 1989; 7:132-9
20. 20. Masters JRW, McDermott BJ, Harland S, Bibby MC, Loadman PM Cancer Chemother Pharmacol 1996; 38: 59-64
21. 21. Henner WD, Shea TC, Furlong EA, Flaherty MD, Eder JP, Elias A, et al. Pharmacokinetics of Continuos-Infusion High-Dose Thiotepa. Cancer Treat Rep 1987;71:1043-47
22. 22. Nieto Y, Vaughan WP. Pharmacokinetics of high-dose chemotherapy. Bone Marrow Transplantation 2004; 33:259-69
23. 23. M de Jonge, RAA Mathot, SM van Dam, JH Beijnen, rodenhuis S. Extremely high exposures in an obese patient receiving high-dose cyclophosphamide, thiotepa and carboplatin.Cancer Chemother Phannacol (2002) 50: 251-255
24. 24. JM Rae, VN Soukhova, DA. Flockhart, Z Desta. Triethylenethiophosphoramide is a specific inhibitor of cytochrome P450 2B6: implications for cyclophosphamide metabolism. Drug Metabolism And Disposition (2002) 30: 525-530
25. 25. van Maanen M.J., I.M. Tijhof, J. M. A. Damen, C. Versluis, J.J. Ketteness van den Bosch, A.J.R. Heck, S.Rodenhuis and J.H.Beijnen. A search for new metabolites of N,N’,N’’- triethylenethiophosphoramide, Cancer Research 2000; 59: 4720-4724
26. 26. Ackland SP, Choi KE, Ratain MJ, Egorin MJ, Williams SF, Sinkule JA et al.. Human Plasma Pharmacokinetics of Thiotepa Following Administration of High-Dose Thiotepa and Cyclophosphamide. Journal of Clinical Oncology 1988; 6:1192-6
27. 27. Hagën B, Walstad RW, Nilsen OG. Pharmacokinetics of thio-TEPA at two different doses. Cancer Chemotherapy and Pharmacology 1988; 22: 356-8
28. 28.

    Heideman RL, Cole DE, Balis F, Sato J, Reaman GH, Packer RJ et al. Phase I and pharmacokinetic evaluation of thiotepa in the cerebrospinal fluid and plasma of

    1. pediatric patients: evidence for dose-dependent plasma clearance of thiotepa. Cancer Research 1989 February 1; 49: 736-41
29. 29. Lazarus HM, Reed MD, Spitzer TR, Rabaa MS and Blumer JL. High-dose i.v. thiotepa and cryopreserved autologous bone marrow transplantation for therapy of refractory cancer. Cancer Treat Rep 1987; 71: 689-95.
30. 30. Ackland S.P, Choi KE, Ratain MJ, Egorin MJ, Williams SF, Sinkule JA et al. Human plasma pharmacokinetics of thiotepa following administration of high-dose thiotepa and cyclophosphamide. Journal of Clinical Oncology 1988; 6: 1192-96.
31. 31. Przepiorka D, Madden T, Ippoliti C, Estrov Z, Dimopoulos. Dosing of thioTEPA for myeloablative therapy. Cancer Chemother Pharmacol 1995; 37: 155-60.
32. 32. Huitema ADR, Mathöt RAA, Tibben MM, Schellens JHM, Rodenhuis S and Beijnen JH. Population pharmacokinetics of thioTEPA and its active metabolite TEPA in patients undergoing high-dose chemotherapy. Br J Clin Pharmacol 2001; 51: 61-70.
33. 33. Strong JM, Collins JM, Lester C, and Polack DG. Pharmacokinetics of Intraventricular and Intravenous N,N’,N’’ Triethylenethiophosphoramide (Thiotepa) in Rhesus Monkeys and Humans. Cancer Research 1986 December; 46: 6101-04
34. 34. Kletzel M, Kearns GL, Wells TG, Thompson HC. Pharmacokinetics of high dose thiotepa in children undergoing autologous bone marrow transplantation. Bone Marrow Transplantation. 1992; 10: 171-75.
35. 35. O’Dwyer, LaCreta FP, Schilder R, Nash S, McAleer C, Miller L et al. Phase I Trial of Thiotepa in Combination With Recombinant Human Granulocyte-Macrophage Colony- Stimulating Factor. Journal of Clinical Oncology 1992; 10:1352-58
36. 36. Huitema ADR, Mathôt RAA, Tibben MM, Rodenhuis S, and Beijnen JH. A Mechanism- Based Pharmacokinetic Model for the Cytochrome P450 Drug-Drug Interaction between Cyclophosphamide and ThioTEPA and the Autoinduction of Cyclophosphamide. Journal of Pharmacokinetics and Pharmacodinamics 2001 February 19; 28 (3): 211-30
37. 37. de Jonge ME, Mathôt RAA, Dalesio O, Huitema ADR, Rodenhuis S, Beijnen JH. Relationship between irreversible alopecia and exposure to cyclophosphamide, thiotepa and carboplatin (CTC) in high-dose chemotherapy. Bone Marrow Transplant 2002; 30: 593-97.
38. 38. Chen TL, Passos-Coelho JL, Noe DA, Kennedy MJ, Black KC, Colvin M, Grochow LB. Nonlinear Pharmacokinetics of Cyclophosphamide in Patients with Metastatic Breast Cancer Receiving High-Dose Chemotherapy followed by Autologous Bone Marrow Transplantation. Cancer Research 1995; 55: 810-816.
39. 39. Rzeski W, Pruskil, S, Macke A, Felderhoff-Mueser U, Reiher AK, Hoemer F et al, Anticancer Agents Are Potent Neurotoxins In vitro and In Vivo. Ann Neurol 2004;56:351- 60
40. 40.

    Antman K, Eder JP, Elias A, Ayash L, Shea TC, Weissman L et al. High-dose Thiotepa and

    1. in Combination Regimens With Bone Marrow Support. Seminars in Oncology 1990 February; 17 (1) Suppl 3: 33-38.
41. 41. Wolff SN, Herzig RH, Fay JW, LeMaistre CF, Frei-Lahr D, Lowder J et al. High-dose Thiotepa With Autologous Bone Marrow Transplantation for Metastatic Malignant Melanoma: Results of Phase I and II Studies of the North American Bone Marrow Transplantation Group. Journal of Clinical Oncology 1989; 7:245-49
42. 42. Przepiorka D, Nath R, Ippoliti C, Mehra R, Hagemeister F, Diener K et al. A phase I-II study of high-dose thiotepa, busulfan and cyclophosphamide as a preparative regimen for Autologous Transplantation for Malignant Lymphoma. Leukemia and Lymphoma 1995; 17: 427-33
43. 43. Jakacki RI, Jatnison Heifetz SA, Caldemeyer K, Hanna M," Sender L. Feasibility of Sequential High-Dose Chemotherapy and Peripheral Blood Stem Cell Support for Pediatric Central Nervous System Malignancies. Medical and Pediatric Oncology 1997, 29: 553-9
44. 44. Hussein AM, Petros WP, Ross M, Vredemburgh JJ, Affronti ML, Jones RB et al. A phase I/II study of high-dose cyclophosphamide, cisplatin, and thioTEPA followed by autologous bone marrow and granulocyte colony-stimulating factor-primed peripheral-blood progenitor cells in patients with advanced malignancies. Cancer Chemother Pharmacol 1996; 37: 561-68
45. 45. Pession A, Prete A, Locatelli F, Bella S, Melchionda F, Garaventa A et al. Phase I study of high-dose thiotepa with busulfan, etoposide, and autologous stem cell support in children with disseminated solid tumors. Medical and Pediatric Oncology 1999; 33: 450- 54.
46. 46. TD Horn, RA Beveridge, MJ Egorin et al. Observations and Proposed Mechanism of N,N',N''-Triethylenethiophosphoramide (Thiotepa)-Induced Hyperpigmentation. Archives of Dermatology 1989 Apr;125(4):524-7.