Thiotepa
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Boxed warning
WARNING: SEVERE MYELOSUPPRESSION and 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) ] WARNING: SEVERE MYELOSUPPRESSION and CARCINOGENICITY See full prescribing information for complete boxed warning.
May cause severe marrow suppression or ablation with resulting infection or bleeding. Monitor hematologic laboratory parameters. (5.1) Potentially carcinogenic in humans. (5.7)
Alkylating Drug
Dosing in kidney impairment
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 ] . 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.
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 ] . 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.
Dosing in liver impairment
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 ] . 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.
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 ] . 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.
Preparation and administration
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Preparation Instructions TEPADINA is a hazardous drug. Follow applicable special handling and disposal procedures. 1 Use appropriate aseptic technique. Preparation from the Vial Reconstitution of the vial Reconstitute each TEPADINA vial with Sterile Water for Injection using the volumes described in Table 2. Table 2: Reconstitution Volumes for the Vials [See table below.] 100 mg vial 10 mL 10 mg/mL Mix the vial by repeated inversions until the powder is completely dissolved.
Visually inspect reconstituted solution in the vial for particulate matter and discoloration. The reconstituted solution may occasionally show opalescence. Use the reconstituted solution immediately. If not used immediately, store the reconstituted solution in the vial refrigerated at 2°C to 8°C (36°F to 46°F), for up to 80 hours.
Dilution of the reconstituted vial into an infusion bag Withdraw the required volume of the reconstituted solution from the TEPADINA vial. Discard any unused portion. Transfer the reconstituted solution into an intravenous bag containing 0.9% Sodium Chloride Injection to obtain a final concentration between 0.5 mg/mL and 1 mg/mL.
Gently mix the intravenous bag by slowly inverting the bag. Use the diluted solution immediately. If the diluted solution is not used immediately, store refrigerated at 2°C to 8°C (36°F to 46°F) for up to 48 hours or room temperature at 25°C (77°F) for up to 6 hours. Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Use TEPADINA diluted solutions only if free of visible particulate matter. For intravenous administration of high doses in the preparative regimen for allogeneic HSCT for beta thalassemia, administer by intravenous infusion via central venous catheter over 3 hours using an infusion set equipped with 0.2 micron filter. For intravesicular administration into the bladder by catheter, see further instructions in Dosage and Administration Section 2.1.
For all other indications, see further instructions in Dosage and Administration Section 2.1. Preparation from the Multichamber Flexible Bag See the Instructions for Use in Subsection 2.3 for illustrated steps for preparation and administration of TEPADINA from the multichamber flexible bag . Activation of the TEPADINA Multichamber Flexible Bag Activate the multichamber flexible bag by pressing firmly and applying uniform pressure with the palms of your overlapped hands until the peel seal is broken.
Mix gently until the reconstituted solution is completely dissolved. Administer TEPADINA immediately after reconstitution of the multichamber flexible bag. If not used immediately, store refrigerated at 2°C to 8°C (36°F to 46°F) for up to 168 hours or at room temperature at 20°C to 25°C (68°F to 77°F) up to 56 hours. Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Solution should be colorless and without particulate matter. After activation, the resultant concentration is 1 mg/mL. 200 mg or 400 mg dose can be directly administered from the multichamber flexible bag after activation. For doses other than 200 mg or 400 mg, withdraw the patient-specific dose from the multichamber flexible bag for transfer to a separate empty bag for administration.
No further dilution is necessary. Administer using a 0.2 micron filter.
Preparation Instructions TEPADINA is a hazardous drug. Follow applicable special handling and disposal procedures. 1 Use appropriate aseptic technique. Preparation from the Vial Reconstitution of the vial Reconstitute each TEPADINA vial with Sterile Water for Injection using the volumes described in Table 2. Table 2: Reconstitution Volumes for the Vials [See table below.] 100 mg vial 10 mL 10 mg/mL Mix the vial by repeated inversions until the powder is completely dissolved.
Visually inspect reconstituted solution in the vial for particulate matter and discoloration. The reconstituted solution may occasionally show opalescence. Use the reconstituted solution immediately. If not used immediately, store the reconstituted solution in the vial refrigerated at 2°C to 8°C (36°F to 46°F), for up to 80 hours.
Dilution of the reconstituted vial into an infusion bag Withdraw the required volume of the reconstituted solution from the TEPADINA vial. Discard any unused portion. Transfer the reconstituted solution into an intravenous bag containing 0.9% Sodium Chloride Injection to obtain a final concentration between 0.5 mg/mL and 1 mg/mL.
Gently mix the intravenous bag by slowly inverting the bag. Use the diluted solution immediately. If the diluted solution is not used immediately, store refrigerated at 2°C to 8°C (36°F to 46°F) for up to 48 hours or room temperature at 25°C (77°F) for up to 6 hours. Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Use TEPADINA diluted solutions only if free of visible particulate matter. For intravenous administration of high doses in the preparative regimen for allogeneic HSCT for beta thalassemia, administer by intravenous infusion via central venous catheter over 3 hours using an infusion set equipped with 0.2 micron filter. For intravesicular administration into the bladder by catheter, see further instructions in Dosage and Administration Section 2.1.
For all other indications, see further instructions in Dosage and Administration Section 2.1. Preparation from the Multichamber Flexible Bag See the Instructions for Use in Subsection 2.3 for illustrated steps for preparation and administration of TEPADINA from the multichamber flexible bag . Activation of the TEPADINA Multichamber Flexible Bag Activate the multichamber flexible bag by pressing firmly and applying uniform pressure with the palms of your overlapped hands until the peel seal is broken.
Mix gently until the reconstituted solution is completely dissolved. Administer TEPADINA immediately after reconstitution of the multichamber flexible bag. If not used immediately, store refrigerated at 2°C to 8°C (36°F to 46°F) for up to 168 hours or at room temperature at 20°C to 25°C (68°F to 77°F) up to 56 hours. Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Solution should be colorless and without particulate matter. After activation, the resultant concentration is 1 mg/mL. 200 mg or 400 mg dose can be directly administered from the multichamber flexible bag after activation. For doses other than 200 mg or 400 mg, withdraw the patient-specific dose from the multichamber flexible bag for transfer to a separate empty bag for administration.
No further dilution is necessary. Administer using a 0.2 micron filter.
| Treatment | Day prior to transplantation | ||||||||||
| Day ‑10 | Day ‑9 | Day ‑8 | Day ‑7 | Day ‑6 | Day ‑5 | Day ‑4 | Day ‑3 | Day ‑2 | Day ‑1 | Day 0 | |
| Busulfan intravenous weight-based dose * | ▲ | ▲ | ▲ | ▲ | |||||||
| TEPADINA intravenous 5 mg/kg twice | ▲ | ||||||||||
| Cyclophosphamide intravenous 40 mg/kg/day | ▲ | ▲ | ▲ | ▲ | |||||||
| Stem cell Infusion | ▲ | ||||||||||
| Strength | Amount of Sterile Water for Injection required for reconstitution | Final concentration |
| 15 mg vial | 1.5 mL | 10 mg/mL |
| 100 mg vial | 10 mL | 10 mg/mL |
| Multichamber Flexible Bag Use Instructions | ||
| Figure A 1 - Overwrap Notch | Figure B 2 – NEVER use this port3 – Luer Port 4 – Twist off Port 5 – Label Area 6 – Peel Seal (Must break to activate) 7 – Hole (For hanging the bag) 8 – Diluent chamber 9 – Lyophilized powder chamberTEPADINA® 200 mg TEPADINA® 400 mg | |
| 1 – REMOVE OVERWRAP | ||
| a) Place bag on a clean, stable surface before opening.b) Tear from overwrap notch, located close to the ports (Figure A – point 1).c) Tear short sides open to access the inner bag as per Figure C. Figure C | d) Remove the multichamber flexible bag from the aluminum overwrap and unfold the bag Figure D.Figure D | |
| 2 - INSPECT BAG PRIOR TO ACTIVATION | 3 – ACTIVATE THE BAG | |
| Place bag on a clean, stable surface with the ports pointing away from you, as per Figure E.Check that there are no liquid or product leakages from the connection ports 2, 3, 4 and from the chambers 8, 9.Check the integrity of peel seal 6, verifying the absence of liquid in the chamber 9.Figure ETEPADINA 200 mg® TEPADINA® 400 mg | Overlap your hands, on the lower portion of chamber 8 (as per Figure F).Press firmly and apply uniform pressure until peel seal 6 is completely activated (it may take up to 5 seconds of continued pressure to break the peel seal 6).Figure FTEPADINA 200 mg® TEPADINA® 400 mg | |
| BAG BEFORE ACTIVATION | BAG AFTER ACTIVATION | |
| Figure G | Figure H | |
| Do NOT squeeze. | Figure I | |
| 4 – INSPECT BAG TO CONFIRM ACTIVATION | ||
| Check the peel seal 6 is now completely activated.Chamber 8 and 9 are merged. If the bag is not activated, refer to Step 3.Figure J | Mix gently until complete dissolution of product.After activation, the resultant concentration is 1 mg/mL.A dose of 200 mg or 400 mg may be directly infused from the bag (see Step 6). For doses less than 200 mg or 400 mg see Step 5. Figure K | |
| 5 – DOSE PREPARATION – for doses less than 200 mg or 400 mg withdraw the patient-specific dose from the TEPADINA® multichamber flexible bag and transfer to an appropriately-sized, empty, sterile bag for intravenous infusion. | ||
| Identify the Luer Port 3 if withdrawing a dose is needed. Remove the plastic cap from Luer Port.Figure L | Screw the luer lock device as per Figure M.Do not use unproper non luer lock devices on port 3.Figure MEnsure that the connection is fully seated and tighten. | Withdraw the desired dose from TEPADINA® bag. This may require multiple graduated syringes depending on the desired dose. Unscrew each syringe counter-clockwise when finished.Figure NReplace the plastic cap on the Luer-Lock port 3.Attach a needle or an appropriate closed-system transfer device to each syringe containing thiotepa solution and transfer the contents to an appropriately-sized, empty, sterile bag for intravenous infusion.Discard the unused portion of the TEPADINA® bag. Follow applicable special handling and disposal procedures. |
| 6 – CONNECTION for administration of 200 mg or 400 mg - The infusion set may be connected to the bag through either the spike connector OR the luer connector. | ||
| OPTION A – SPIKE CONNECTIONIdentify Twist off port 4.Twist off the plastic cap before inserting the spike.Figure OInsert the spike connector.Figure P | OPTION B– LUER CONNECTIONSelect luer cap port 3.Remove the plastic cap from luer port 3 before connecting the luer connector.Figure QInsert the luer connector.Figure REnsure that the connection is fully seated and tighten. | |
| 7 – HANG THE BAG | ||
| Hang the bag by the hole 7. | Figure S | |
Drug interactions
Check thiotepa against a medication listLabel text (7 paragraphs)
7 DRUG INTERACTIONS
7.1 Effect of Cytochrome CYP3A Inhibitors and Inducers In vitro studies suggest that thiotepa is metabolized by CYP3A4 and CYP2B6 to its active metabolite TEPA. Avoid co-administration 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 ( 12.3 ) ] . Consider alternative medications with no or minimal potential to inhibit or induce CYP3A4. If concomitant use of strong CYP3A4 modulators cannot be avoided, closely monitor for adverse drug reactions.
7.2 Effect of 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 ( 12.3 ) ] .
The administration of thiotepa with cyclophosphamide in patients reduces the conversion of cyclophosphamide to the active metabolite, 4-hydroxycyclophosphamide; the effect appears sequence dependent with a greater reduction in the conversion to 4-hydroxycyclophosphamide when thiotepa is administered 1.5 hours prior to the intravenous administration of cyclophosphamide compared to administration of thiotepa after intravenous cyclophosphamide [see Clinical Pharmacology ( 12.3 ) ] . The reduction in 4-hydroxycyclophosphamide levels may potentially reduce efficacy of cyclophosphamide treatment.
7.1 Effect of Cytochrome CYP3A Inhibitors and Inducers In vitro studies suggest that thiotepa is metabolized by CYP3A4 and CYP2B6 to its active metabolite TEPA. Avoid co-administration 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 ( 12.3 ) ] . Consider alternative medications with no or minimal potential to inhibit or induce CYP3A4. If concomitant use of strong CYP3A4 modulators cannot be avoided, closely monitor for adverse drug reactions.
7.2 Effect of 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 ( 12.3 ) ] .
The administration of thiotepa with cyclophosphamide in patients reduces the conversion of cyclophosphamide to the active metabolite, 4-hydroxycyclophosphamide; the effect appears sequence dependent with a greater reduction in the conversion to 4-hydroxycyclophosphamide when thiotepa is administered 1.5 hours prior to the intravenous administration of cyclophosphamide compared to administration of thiotepa after intravenous cyclophosphamide [see Clinical Pharmacology ( 12.3 ) ] . The reduction in 4-hydroxycyclophosphamide levels may potentially reduce efficacy of cyclophosphamide treatment.
Contraindications
4 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) ] Hypersensitivity to the active substance (4) . Concomitant use with live or attenuated vaccines (4) .
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