Tepadina
Generic
Name: Thiotepa (thye oh TEP a)
Brand Name: Tepadina
WARNING: SEVERE MYELOSUPPRESSION,
CARCINOGENICITY
·
TEPADINA may
cause severe marrow suppression, and high doses may cause marrow ablation with
resulting infection or bleeding. Monitor hematologic laboratory parameters.
Hematopoietic progenitor (stem) cell transplantation (HSCT) is required to
prevent potentially fatal complications of the prolonged myelosuppression after
high doses of TEPADINA [see Warnings and Precautions (5.1)
·
TEPADINA should
be considered potentially carcinogenic in humans [see Warnings and
Precautions (5.7)]
Indications and Usage for Tepadina Injection
Class 3
Beta-Thalassemia
TEPADINA is indicated to
reduce the risk of graft rejection when used in conjunction with high-dose
busulfan and cyclophosphamide as a preparative regimen for allogeneic
hematopoietic progenitor (stem) cell transplantation (HSCT) for pediatric
patients with class 3 beta-thalassemia [see Clinical Studies (14)].
Adenocarcinoma
of the Breast or Ovary
TEPADINA is indicated for
treatment of adenocarcinoma of the breast or ovary.
Malignant
Effusions
TEPADINA is indicated for
controlling intracavitary effusions secondary to diffuse or localized
neoplastic diseases of various serosal cavities.
Superficial
Papillary Carcinoma of the Urinary Bladder
TEPADINA is indicated for
treatment of superficial papillary carcinoma of the urinary bladder.
Tepadina Injection Dosage and Administration
Recommended
Dosage
The recommended dose of
TEPADINA in pediatric patients is two administrations of 5 mg/kg given
intravenously approximately 12 hours apart on Day -6 before allogeneic HSCT in
conjunction with high-dose busulfan and cyclophosphamide as outlined in Table
1. See Prescribing Information for cyclophosphamide and busulfan for
information on these drugs.
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Table 1: Dosage Regimen For Allogeneic
HSCT In Pediatric Patients With Class 3 Beta-Thalassemia
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Day prior to transplantation
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Treatment
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Day
-10
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Day
-9
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Day
-8
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Day
-7
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Day
-6
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Day
-5
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Day
-4
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Day
-3
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Day
-2
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Day
-1
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Day
-0
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Busulfan IV weight-based dose *Busulfan IV
weight-based dose *
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TEPADINA IV 5 mg/kg twiceTEPADINA IV 5 mg/kg twice
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Cyclophosphamide IV 40 mg/kg/day
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Stem cell InfusionStem cell Infusion
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*Busulfan IV
weight-based dose: 1.0 mg/kg every 6 hours for patients less than 9 kg; 1.2
mg/kg every 6 hours for patients 9 to 16 kg; 1.1 mg/kg every 6 hours for
patients 16.1 to 23 kg; 0.95 mg/kg every 6 hours for patients 23.1 to 34 kg;
0.8 mg/kg every 6 hours for patients more than 34 kg.
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Infuse TEPADINA via a central
venous catheter over 3 hours using an infusion set equipped with a 0.2 micron
in-line filter. Prior to and following each infusion, flush the catheter with
approximately 5 ml sodium chloride 0.9% solution for injection.
TEPADINA is excreted through
the skin of patients receiving high-dose therapy. Take precautions to prevent
skin toxicity [ see Warnings and Precautions ( 5.3)].
Adenocarcinoma
of the Breast or Ovary
The recommended dose of
TEPADINA 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
TEPADINA 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 TEPADINA
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.
Preparation
Instructions
TEPADINA is a cytotoxic drug. Follow applicable special handling and disposal
procedures1.
Reconstitution
Reconstitute TEPADINA 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 TEPADINA 100 mg with 10 ml of sterile water for injection. Using a
syringe fitted with a needle, aseptically
withdraw 10 ml of sterile water for injection. Inject the content of the
syringe into the vial through the rubber stopper.
Remove the syringe and needle, and mix manually by repeated inversions.
The reconstituted solution is hypotonic and must be diluted in saline prior to
administration. Reconstituted solutions, free of
visible particulate matter, may occasionally show opalescence; such solutions
can still be used for further dilution.
If not used immediately after reconstitution, the product is stable for 8 hours
when stored at 2°C to 8°C (36° to 46°F).
Dilution in the infusion bag
Prior to administration, dilute the reconstituted solution further with an
appropriate volume of sodium chloride 0.9% solution
for injection to obtain a final TEPADINA concentration between 0.5 and 1 mg/mL.
Dilute TEPADINA as recommended in
Table 2.
Table
2: Dilution of TEPADINA in the infusion bag
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Calculated TEPADINA Dose
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Dilution Volume (Sodium Chloride 0.9%
solution for injection)
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Less than 250 mg
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Appropriate volume to obtain a final concentration
of 0.5 to 1 mg/mL
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250 mg to 500 mg
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500 mL or appropriate volume to obtain a final
concentration of 0.5 to 1 mg/mL
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Greater than 500 mg
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1000 mL or appropriate volume to obtain a final
concentration of 0.5 to 1 mg/mL
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After dilution the product is
stable for 24 hours when stored at 2°C to 8°C (36° to 46°F) and for 4 hours
when stored at 25°C
(77°F). From a microbiological point of view, the product should be used
immediately.
Inspect the diluted solution visually for particulate matter and discoloration
prior to administration. Use TEPADINA 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
Dosage Forms and StrengthsFor injection, 15 mg, lyophilized white powder in
single-dose vial for reconstitutionFor injection, 100 mg, lyophilized white powder in
single-dose vial for reconstitution
Contraindications
TEPADINA 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)].
Warnings and Precautions
Myelosuppression
The consequence of treatment
with high doses of TEPADINA together with other chemotherapy at the recommended
dose and schedule in the preparative regimen for class 3 beta- thalassemia is
profound myelosuppression occurring in all patients. Do not begin the
preparative regimen if a stem cell donor is not available. Monitor complete
blood counts, and provide supportive care for infections, anemia and
thrombocytopenia until there is adequate hematopoietic recovery.
For patients receiving
TEPADINA for treatment of adenocarcinoma of the breast, adenocarcinoma of the
ovary, malignant effusions and superficial papillary carcinoma of the urinary
bladder, if the bone marrow has been compromised by prior irradiation or
chemotherapy, or is recovering from chemotherapy, the risk of severe
myelosuppression with TEPADINA may be increased. Perform periodic complete
blood counts during the course of treatment with TEPADINA. Provide supportive
care for infections, bleeding, and symptomatic anemia [see
Adverse Reactions (6.1)].
Hypersensitivity
Clinically significant
hypersensitivity reactions, including anaphylaxis, have occurred following
administration of TEPADINA. If anaphylactic or other clinically significant
allergic reaction occurs, discontinue treatment with TEPADINA, initiate
appropriate therapy, and monitor until signs and symptoms resolve [see Contraindications (4), Adverse Reactions (6.1)].
Cutaneous
Toxicity
TEPADINA and/or its active
metabolites may be excreted in part via skin patients receiving high-dose
therapy. Treatment with TEPADINA 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 TEPADINA. Change occlusive dressing and clean the covered
skin at least twice daily through 48 hours after administration of TEPADINA.
Change bed sheets daily during treatment.
Skin reactions associated with
accidental exposure to TEPADINA may also occur. Wash the skin thoroughly with
soap and water in case TEPADINA solution contacts the skin. Flush mucous
membranes in case of TEPADINA contact with mucous membranes.
Concomitant
Use of Live and Attenuated Vaccines
Do not administer live or
attenuated viral or bacterial vaccines to a patient treated with TEPADINA until
the immunosuppressive effects have resolved.
Hepatic
Veno-Occlusive Disease
Hepatic veno-occlusive disease
may occur in patients who have received high-dose TEPADINA in conjunction with
busulfan and cyclophosphamide [see Adverse
Reactions (6.1)]. Monitor by physical examination, serum
transaminases and bilirubin daily through BMT Day +28, and provide supportive
care to patients who develop hepatic veno-occlusive disease.
Central
Nervous System Toxicity
Fatal encephalopathy has
occurred in patients treated with high doses of thiotepa. Other central nervous
system toxicities, such as headache, apathy, psychomotor retardation,
disorientation, confusion, amnesia, hallucinations, drowsiness, somnolence,
seizures, coma, inappropriate behaviour and forgetfulness have been reported to
occur in a dose-dependent manner during or shortly after administration of
high-dose thiotepa. In pediatric patients treated with TEPADINA at the
recommended dose in combination with busulfan and cyclophosphamide, 8%
developed central nervous system toxicity (seizures and intracranial
hemorrhage). Do not exceed the recommended dose of TEPADINA. If severe or
life-threatening central nervous system toxicity occurs, discontinue
administration of TEPADINA and provide supportive care.
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 TEPADINA.
Embryo-Fetal
Toxicity
Based on the mechanism of
action and findings in animals, TEPADINA can cause fetal harm when administered
to a pregnant woman. There are no adequate and well-controlled studies of
TEPADINA in pregnant women. Thiotepa given by the intraperitoneal (IP) route
was teratogenic in mice at doses ≥ 1 mg/kg (3.2 mg/m 2), approximately 8-fold less
than the maximum recommended human therapeutic dose (0.8 mg/kg, 27 mg/m 2), based on body-surface area.
Thiotepa given by the IP route was teratogenic in rats at doses ≥ 3 mg/kg (21
mg/m 2), approximately equal to the maximum recommended human
therapeutic dose, based on body-surface area. Thiotepa was lethal to rabbit
fetuses at a dose of 3 mg/kg (41 mg/m 2), approximately two times the
maximum recommended human therapeutic dose based on body-surface area.
Advise pregnant women of the
potential risk to the fetus [ see Use in Specific
Populations (8.1, 8.3)].
Advise females of reproductive potential to use highly effective contraception
during and after treatment with TEPADINA for at least 6 months after therapy.
Advise males of reproductive potential to use effective contraception during
and after treatment with TEPADINA for at least 1 year after therapy [ see Use in Specific Populations (8.1, 8.3)].
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)]
Clinical
Trials Experience
Because clinical trials are
conducted under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates observed in
practice.
Adverse
Reactions With the Preparative Regimen for Class 3 Beta-Thalassemia
The safety of TEPADINA was
evaluated by retrospective analysis of 76 pediatric patients with class 3 beta-thalassemia
who underwent allogeneic hematopoietic progenitor (stem) cell transplantation
(HSCT) using busulfan and cyclophosphamide with TEPADINA (n=25) or without
TEPADINA (n=51) [ ]. Adverse reactions were abstracted retrospectively from the
medical records.
Serious adverse events that
occurred in the TEPADINA-treated and control cohort were, respectively:
gastrointestinal hemorrhage (4% vs 2%), pneumonia (4% vs 0), seizure (4% vs
2%), subarachnoid hemorrhage (4% vs 0) and veno-occlusive disease (4% vs 2%).
By 90 days after HSCT, grades 2 to 4 acute graft-versus-host disease was
observed in 7 (28%) patients in the TEPADINA cohort and in 13 (26%) patients in
the control cohort. By 1-year after transplantation, chronic graft-versus-host
disease was observed in 8 (35%) of 23 evaluable patients in the TEPADINA
cohort, and 7 (14%) of 49 evaluable patients in the control cohort.
Adverse
reactions occurring in at least 5% of patients treated with TEPADINA from start
of the preparative regimen through 30 days after transplantation are shown in
Table 3.
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Table 3: Common Adverse
Reactions (>5%) Occurring Through 30 Days After Transplantation In
Patients With Class 3 Beta-Thalassemia Using Busulfan And Cyclophosphamide
With Or Without TEPADINA in the Preparative Regimen
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Preparative Regimen of
Busulfan and Cyclophosphamide
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With TEPADINA
N=25 patients (%)
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Without TEPADINA
N=51 patients (%)
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Adverse Reaction
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Any Grade
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Grade 3-5 1
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Any Grade
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Grade 3-5 1
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Mucositis 2
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16 (64%)16 (64%)
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4 (16%)4 (16%)
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22 (43%)22 (43%)
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1 (2%)1 (2%)
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Cytomegalovirus InfectionCytomegalovirus Infection
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12 (48%)12 (48%)
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00
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15 (29%)15 (29%)
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0
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Hemorrhage 3
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7 (28%)7 (28%)
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2 (8%)2 (8%)
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12 (24%)12 (24%)
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3 (6%)3 (6%)
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Diarrhea
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6 (24%)6 (24%)
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0
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7 (14%)7 (14%)
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2 (4%)2 (4%)
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Hematuria 4
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5 (20%)5 (20%)
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0
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10 (20%)10 (20%)
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3 (6%)3 (6%)
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Rash 5
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3 (12%)3 (12%)
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0
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11 (22%)11 (22%)
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0
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Intracranial Hemorrhage 6
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2 (8%)2 (8%)
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1 (4%)1 (4%)
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0
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0
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Pseudomonas Infection
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2 (8%)2 (8%)
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0
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0
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0
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1Severe, life-threatening or fatal
2Mucositis
includes mouth hemorrhage, mucosal inflammation and stomatitis
3Hemorrhage
includes all hemorrhage terms
4Hematuria
includes cystitis hemorrhagic and hematuria
5Rash includes
dermatitis exfoliative, palmar erythema, rash, rash maculo-papular, rash
pruritic and skin toxicity
6Hemorrhage Intracranial includes hemorrhage intracranial and
subarachnoid hemorrhage
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All patients in
the TEPADINA-treated and control cohorts developed profound cytopenias,
including neutropenia, anemia, thrombocytopenia. Table 4 shows the selected
chemistry abnormalities that occurred from start of the preparative regimen
through 30 days after transplantation.
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Preparative Regimen of
Busulfan and Cyclophosphamide
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With TEPADINA
N=25 patients (%)
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Without TEPADINA
N=51 patients (%)
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Adverse Reaction
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Any Grade
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Grade 3-4
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Any Grade
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Grade 3-4
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Elevated alanine aminotransferase
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22 (88%)22 (88%)
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6 (24%)6 (24%)
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49 (96%)49 (96%)
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14 (27%)14 (27%)
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Elevated aspartate aminotransferase
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20 (80%)20 (80%)
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4 (16%)4 (16%)
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45 (88%)45 (88%)
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9 (18%)9 (18%)
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Elevated total bilirubin
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20 (80%)20 (80%)
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4 (16%)4 (16%)
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39 (77%)39 (77%)
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2 (4%)2 (4%)
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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.
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 TEPADINA in
preparative regimens prior to allogeneic or autologous hematopoietic progenitor
(stem) cell transplantation (HSCT) in adult and pediatric patients.
Blood
and lymphatic system disorders:
Febrile bone marrow aplasia.
Cardiac
disorder: 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.
Infection
and infestation: 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.
Drug Interactions
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 TEPADINA due to the potential effects on efficacy and
toxicity [see Clinical Pharmacology (12.2)].
Consider alternative medications with no or minimal potential to inhibit or
induce CYP3A4. If concomitant use of strong CYP3A4 modulators cannot be
avoided, closely monitor for adverse drug reactions.
Effect of
TEPADINA on Cytochrome CYP2B6 Substrates
In vitro studies suggest
that thiotepa inhibits CYP2B6. TEPADINA may increase the exposure of drugs that
are substrates of CYP2B6 in patients; however, the clinical relevance of
this in vitro interaction is
unknown [see Clinical Pharmacology (12.2)].
The administration of thiotepa
with cyclophosphamide in patients reduces the conversion of cyclophosphamide to
the active metabolite, 4-hydroxycyclophosphamide; the effect appears sequence
dependent with a greater reduction in the conversion to
4-hydroxycyclophosphamide when thiotepa is administered 1.5 hours prior to the
intravenous administration of cyclophosphamide compared to administration of
thiotepa after intravenous cyclophosphamide [see Clinical
Pharmacology (12.2)]. The reduction in 4-hydroxycyclophosphamide
levels may potentially reduce efficacy of cyclophosphamide treatment.
USE IN SPECIFIC POPULATIONS
Pregnancy
Risk
Summary
TEPADINA 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 TEPADINA 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 rats and rabbits during organogenesis produced teratogenic
effects (alterations in embryo development, anomalies 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 TEPADINA for the
mother and possible risks to the fetus when prescribing TEPADINA 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 bodysurface
area.
Lactation
Risk
Summary
There is no information
regarding the presence of thiotepa in human milk, the effects on the breastfed infant,
or the effects on milk production.
Because of the potential for
serious adverse reactions, including the potential for tumorigenicity shown for
thiotepa in animal studies, advise patients not to breastfeed during TEPADINA
treatment.
Females and
Males of Reproductive Potential
Pregnancy
testing
TEPADINA can cause fetal harm
when administered to a pregnant female. Verify the pregnancy status of females
of reproductive potential prior to initiating TEPADINA therapy.
Contraception
Females
Advise females of reproductive
potential to avoid pregnancy during TEPADINA treatment and for at least 6
months after the final dose of TEPADINA. Advise females to immediately report
pregnancy [seeUse in Specific Populations (8.1)].
Males
TEPADINA may damage
spermatozoa and testicular tissue, resulting in possible genetic abnormalities.
Males with female sexual partners of reproductive potential should use
effective contraception during TEPADINA treatment and for at least 1 year after
the final dose of TEPADINA [ see Nonclinical
Toxicology (13.1)].
Infertility
Based on nonclinical findings,
male and female fertility may be compromised by treatment with TEPADINA. Inform
male patients about the possibility of sperm conservation before the start of
therapy [see Nonclinical Toxicology (13.1)].
Pediatric Use
The safety and effectiveness
of TEPADINA for prevention of graft rejection in pediatric patients undergoing
allogeneic HSCT for class 3 beta-thalassemia was established in one prospective
study and one retrospective study [ see Clinical
Studies (14)] that included 1 infant (1 month to 1 year), 23
children (2 to 11 years) and 13 adolescents (12 to 16 years) who received
TEPADINA as part of their preparative regimen. Safety and effectiveness of
TEPADINA in neonates have not been established.
Safety and effectiveness of
TEPADINA for treatment of adenocarcinoma of the breast, adenocarcinoma of the
ovary, malignant effusions and superficial papillary carcinoma of the urinary
bladder in pediatric patients have not been established.
Geriatric Use
The safety and effectiveness
of TEPADINA as a preparative regimen prior to allogeneic hematopoietic
progenitor (stem) cell transplantation (HSCT) for patients with class 3
beta-thalassemia have not been established in geriatric patients. Clinical
studies of TEPADINA for this indication did not include subjects aged 65 and
over.
Clinical studies of TEPADINA
for treatment of adenocarcinoma of the breast, adenocarcinoma of the ovary,
malignant effusions and superficial papillary carcinoma of the urinary bladder
did not include sufficient numbers of subjects aged 65 and over to determine
whether elderly subjects respond differently from younger subjects, and other
reported clinical experience has not identified differences in responses
between the elderly and younger patients. In general, dose selection for an
elderly patient should be cautious, usually starting at the low end of the
dosing range, reflecting the greater frequency of decreasing hepatic, renal or
cardiac function, and of concomitant disease or other drug therapy.
Renal
Impairment
In patients with moderate
(creatinine clearance (CLcr) of 30 mL/min to 59 mL/min) renal impairment,
decreased renal excretion may result in increased plasma levels of thiotepa and
TEPA [see Clinical Pharmacology (12.2)].
This may result in increased toxicity. Monitor patients with moderate to severe
(CLcr < 30 mL/min) renal impairment for signs and symptoms of toxicity
following treatment with TEPADINA for an extended period of time.
Hepatic
Impairment
Thiotepa is extensively
metabolized in the liver. Patients with moderate (bilirubin levels greater than
1.5 times to 3 times the upper limit of normal and any AST) hepatic impairment
may have increased plasma levels of thiotepa [ see
Clinical Pharmacology (12.2)] . This
may result in toxicity. Monitor patients with moderate to severe (bilirubin
levels greater than 3 times upper limit of normal and any AST) hepatic
impairment for signs and symptoms of toxicity following treatment with TEPADINA
for an extended period of time.
OVERDOSE
There is no experience with
overdoses of thiotepa. The most important adverse reactions expected in case of
overdose are myeloablation and pancytopenia [see
Nonclinical Toxicology (13.2)]. There is no known antidote for
thiotepa. Monitor the hematological status closely and provide vigorous
supportive measures as medically indicated.
Tepadina Injection Description
TEPADINA (thiotepa) is an
alkylating agent. TEPADINA (thiotepa) for injection is supplied as a
non-pyrogenic, sterile lyophilized white powder for intravenous, intracavitary,
or intravesical use after reconstitution and dilution.
TEPADINA is available in a
single-dose vial containing:
15 mg thiotepa. After reconstitution with 1.5 ml of
water for injection, each ml contains 10 mg thiotepa.
100 mg thiotepa. After reconstitution with 10 ml of
water for injection, each ml contains 10 mg thiotepa.
Thiotepa is a synthetic
product with antitumor activity. The chemical name for thiotepa is
Tris(1-aziridinyl)phosphine sulfide. Thiotepa has the following structural
formula:
Thiotepa has the molecular
formula C 6H 12N 3PS, and a molecular weight of 189.23, and it appears as fine,
white crystalline flakes, with a melting range of 52°C to 57°C. It is soluble
in water and organic solvents. When reconstituted with sterile water for
injection, the resulting solution has a pH of approximately 5.5 to 7.5.
Thiotepa is unstable in acid medium.
Tepadina Injection - Clinical Pharmacology
Mechanism 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.
Pharmacokinetics
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/m 2 (44%) or 1.2 L/kg (47%)
following a single intravenous infusion of TEPADINA at a dose of 5 mg/kg over 3
hours in pediatric population. In adults administered intravenous thiotepa
between 20 mg to 250 mg/m 2 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 1.9 L/kg
(17%).
Elimination
Following a single intravenous
infusion over 3 hours of TEPADINA 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 13.8 L/hr/m 2 (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/m 2 as an intravenous bolus
or infusion up to 4 hours, the mean thiotepa clearance ranged from 14.6
L/hr/m 2(23%) to 27.9 L/hr/m 2 (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.
Excretion
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.
Specific
Populations
Hepatic
Impairment
The clearance of thiotepa
following a single TEPADINA 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/m 2/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 TEPADINA.
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.
Nonclinical Toxicology
Carcinogenesis,
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 vitrowith
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.
Clinical Studies
TEPADINA 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 TEPADINA 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 TEPADINA was 0% (95% CI: [0, 0.12]).
Of the 51 patients who received the same preparative regimen, historically,
without TEPADINA, the incidence of graft rejection reported was 25.5% (95% CI:
[0.13, 0.37]).
REFERENCES
1.
OSHA Hazardous Drugs. OSHA.
[Accessed from http://www.osha.gov/SLTC/hazardousdrugs/index.html].
How Supplied/Storage and Handling
How Supplied
TEPADINA is supplied as Unit
carton with one single-dose Type I clear glass vial with a bromobutyl stopper.
TEPADINA
15 mg
One vial contains 15 mg
thiotepa ( NDC 70121-1630-1).
TEPADINA
100 mg
One vial contains 100 mg
thiotepa ( NDC 70121-1631-1).
Storage and
Handling
TEPADINA vials must be stored
and transported refrigerated at 2°C to 8°C (36° to 46°F). Do not freeze.
TEPADINA is a cytotoxic drug.
Follow applicable special handling and disposal procedures 1.
Patient Counseling Information
Hypersensitivity
Counsel patients on the signs
and symptoms of hypersensitivity and to seek immediate emergency assistance if
they develop any of these signs and symptoms [see
Warnings and Precautions (5.2)].
Myelosuppression
Inform patients of the
possibility of developing low blood cell counts and the need for hematopoietic
progenitor cell infusion. Instruct patients to immediately report to their
healthcare provider if bleeding or fever occurs [see
Warnings and Precautions (5.1)].
Females
and Males of Reproductive Potential
TEPADINA can cause fetal harm.
Advise females receiving TEPADINA to avoid pregnancy during TEPADINA treatment
and for at least 6 months after the final dose of TEPADINA [see Warnings and Precautions (5.8)].
Advise males with female
sexual partners of reproductive potential to use effective contraception during
TEPADINA treatment and for at least 1 year after the final dose of
TEPADINA [see Use in Specific Populations (8.3)].
Advise females to report
pregnancy immediately [see Warnings and Precautions
(5.8)].
Advise patients that TEPADINA
can produce infertility. Inform male patients about the possibility of sperm
conservation before the start of therapy [see Use
in Specific Populations (8.3)].
Lactation
Advise patients to avoid
breastfeeding while receiving TEPADINA [see Use in
Specific Populations (8.2)].
Secondary
malignancies
Inform patients that TEPADINA
can increase the risk of secondary malignancy [see
Warnings and Precautions (5.7)].
Distributed by:
Amneal
Biosciences LLC
Bridgewater, NJ 08807
for
ADIENNE SA
Switzerland
Tepadina 15 mg Carton NDC: 70121-1630-1
Tepadina 15 mg Label NDC: 70121-1630-1
Tepadina 100 mg Carton NDC: 70121-1631-1
Tepadina 100 mg Label NDC: 70121-1631-1
|
TEPADINA thiotepa injection, powder,
for solution
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:70121-1630
|
|
Route of
Administration
|
INTRAVENOUS,
INTRACAVITARY, INTRAVESICAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
THIOTEPA (THIOTEPA)
|
THIOTEPA
|
15 mg
|
|
|
Product
Characteristics
|
|
Color
|
white
|
Score
|
|
|
Shape
|
|
Size
|
|
|
Flavor
|
|
Imprint Code
|
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:70121-1630-1
|
1 VIAL, GLASS
in 1 BOX
|
|
|
1
|
|
1 INJECTION,
POWDER, FOR SOLUTION in 1 VIAL, GLASS
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA208264
|
08/15/2017
|
|
|
|
TEPADINA thiotepa injection, powder,
for solution
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:70121-1631
|
|
Route of
Administration
|
INTRAVENOUS,
INTRACAVITARY, INTRAVESICAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
THIOTEPA (THIOTEPA)
|
THIOTEPA
|
100 mg
|
|
|
Product
Characteristics
|
|
Color
|
white
|
Score
|
|
|
Shape
|
|
Size
|
|
|
Flavor
|
|
Imprint Code
|
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:70121-1631-1
|
1 VIAL, GLASS
in 1 BOX
|
|
|
1
|
|
1 INJECTION,
POWDER, FOR SOLUTION in 1 VIAL, GLASS
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA208264
|
08/15/2017
|
|
|
|
Labeler - Amneal Biosciences LLC (079785595)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Cenexi-Laboratoires
Thissen S.A
|
|
370088959
|
analysis(70121-1631,
70121-1630), manufacture(70121-1631, 70121-1630)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
IDT Australia Limited
|
|
743859243
|
manufacture(70121-1631,
70121-1630), analysis(70121-1631, 70121-1630)
|
Revised:
05/2017
Amneal Biosciences LLC
