Docivyx

• For locally advanced or metastatic breast cancer after failure of prior chemotherapy, the recommended dose of DOCIVYX is 60 mg/m²to 100 mg/m²administered intravenously over 1 hour every 3 weeks.
• For the adjuvant treatment of operable node-positive breast cancer, the recommended DOCIVYX dose is 75 mg/m²administered 1 hour after doxorubicin 50 mg/m²and cyclophosphamide 500 mg/m²every 3 weeks for 6 courses. Prophylactic G-CSF may be used to mitigate the risk of hematological toxicities
  [see Dosage and Administration (2.7)]
  .

• For treatment after failure of prior platinum-based chemotherapy, DOCIVYX was evaluated as monotherapy, and the recommended dose is 75 mg/m²administered intravenously over 1 hour every 3 weeks. A dose of 100 mg/m²in patients previously treated with chemotherapy was associated with increased hematologic toxicity, infection, and treatment-related mortality in randomized controlled trials
  [see Boxed Warning, Dosage and Administration (2.7), Warnings and Precautions (5), Clinical Studies (14)]
  .
• For chemotherapy-naive patients, DOCIVYX was evaluated in combination with cisplatin. The recommended dose of DOCIVYX is 75 mg/m²administered intravenously over 1 hour immediately followed by cisplatin 75 mg/m²over 30–60 minutes every 3 weeks
  [see Dosage and Administration (2.7)]
  .

• For metastatic CRPC, the recommended dose of DOCIVYX is 75 mg/m²every 3 weeks as a 1-hour intravenous infusion. Prednisone 5 mg orally twice daily is administered continuously
  [see Dosage and Administration (2.7)]
  .

• For gastric adenocarcinoma, the recommended dose of DOCIVYX is 75 mg/m²as a 1-hour intravenous infusion, followed by cisplatin 75 mg/m², as a 1 to 3 hour intravenous infusion (both on day 1 only), followed by fluorouracil 750 mg/m²per day given as a 24-hour continuous intravenous infusion for 5 days, starting at the end of the cisplatin infusion. Treatment is repeated every three weeks. Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration
  [see Dosage and Administration (2.7)]
  .

Patients must receive premedication with antiemetics, and appropriate hydration (prior to and after cisplatin administration). Prophylaxis for neutropenic infections should be administered. All patients treated on the DOCIVYX containing arms of the TAX323 and TAX324 studies received prophylactic antibiotics.

For the induction treatment of locally advanced inoperable SCCHN, the recommended dose of DOCIVYX is 75 mg/m²as a 1-hour intravenous infusion followed by cisplatin 75 mg/m²intravenously over 1 hour, on day one, followed by fluorouracil as a continuous intravenous infusion at 750 mg/m²per day for five days. This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy

For the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN, the recommended dose of DOCIVYX is 75 mg/m²as a 1-hour intravenous infusion on day 1, followed by cisplatin 100 mg/m²administered as a 30-minute to 3 hour infusion, followed by fluorouracil 1000 mg/m²/day as a continuous infusion from day 1 to day 4. This regimen is administered every 3 weeks for 3 cycles. Following chemotherapy, patients should receive chemoradiotherapy

All patients should be premedicated with oral corticosteroids (see below for CRPC) such as dexamethasone 16 mg per day (e.g., 8 mg twice daily) for 3 days starting 1 day prior to DOCIVYX administration in order to reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions

For metastatic CRPC, given the concurrent use of prednisone, the recommended premedication regimen is oral dexamethasone 8 mg at 12 hours, 3 hours, and 1 hour before the DOCIVYX infusion

Patients who are dosed initially at 100 mg/m²and who experience either febrile neutropenia, neutrophils <500 cells/mm³for more than 1 week, or severe or cumulative cutaneous reactions during DOCIVYX therapy should have the dosage adjusted from 100 mg/m²to 75 mg/m². If the patient continues to experience these reactions, the dosage should either be decreased from 75 mg/m²to 55 mg/m²or the treatment should be discontinued. Conversely, patients who are dosed initially at 60 mg/m²and who do not experience febrile neutropenia, neutrophils <500 cells/mm³for more than 1 week, severe or cumulative cutaneous reactions, or severe peripheral neuropathy during DOCIVYX therapy may tolerate higher doses. Patients who develop ≥grade 3 peripheral neuropathy should have DOCIVYX treatment discontinued entirely.

DOCIVYX in combination with doxorubicin and cyclophosphamide should be administered when the neutrophil count is ≥1,500 cells/mm³. Patients who experience febrile neutropenia should receive G- CSF in all subsequent cycles. Patients who continue to experience this reaction should remain on G- CSF and have their DOCIVYX dose reduced to 60 mg/m². Patients who experience grade 3 or 4 stomatitis should have their DOCIVYX dose decreased to 60 mg/m². Patients who experience severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during DOCIVYX therapy should have their dosage of DOCIVYX reduced from 75 mg/m²to 60 mg/m². If the patient continues to experience these reactions at 60 mg/m², treatment should be discontinued.

Monotherapy with DOCIVYX for NSCLC treatment after failure of prior platinum-based chemotherapy

Patients who are dosed initially at 75 mg/m²and who experience either febrile neutropenia, neutrophils <500 cells/mm³for more than one week, severe or cumulative cutaneous reactions, or other grade 3/4 non-hematological toxicities during DOCIVYX treatment should have treatment withheld until resolution of the toxicity and then resumed at 55 mg/m². Patients who develop ≥grade 3 peripheral neuropathy should have DOCIVYX treatment discontinued entirely.

Combination therapy with DOCIVYX for chemotherapy-naive NSCLC

For patients who are dosed initially at DOCIVYX 75 mg/m²in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is <25,000 cells/mm³, in patients who experience febrile neutropenia, and in patients with serious non-hematologic toxicities, the DOCIVYX dosage in subsequent cycles should be reduced to 65 mg/m². In patients who require a further dose reduction, a dose of 50 mg/m²is recommended. For cisplatin dosage adjustments, see manufacturers' prescribing information.

Combination therapy with DOCIVYX for metastatic CRPC

DOCIVYX should be administered when the neutrophil count is ≥1,500 cells/mm³. Patients who experience either febrile neutropenia, neutrophils <500 cells/mm³for more than one week, severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during DOCIVYX therapy should have the dosage of DOCIVYX reduced from 75 mg/m²to 60 mg/m². If the patient continues to experience these reactions at 60 mg/m², the treatment should be discontinued.

DOCIVYX in combination with cisplatin and fluorouracil in gastric cancer or head and neck cancer

Patients treated with DOCIVYX in combination with cisplatin and fluorouracil must receive antiemetics and appropriate hydration according to current institutional guidelines. In both studies, G- CSF was recommended during the second and/or subsequent cycles in case of febrile neutropenia, or documented infection with neutropenia, or neutropenia lasting more than 7 days. If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs despite G-CSF use, the DOCIVYX dose should be reduced from 75 mg/m²to 60 mg/m². If subsequent episodes of complicated neutropenia occur the DOCIVYX dose should be reduced from 60 mg/m²to 45 mg/m². In case of grade 4 thrombocytopenia the DOCIVYX dose should be reduced from 75 mg/m²to 60 mg/m². Do not retreat patients with subsequent cycles of DOCIVYX until neutrophils recover to a level >1,500 cells/mm³

Recommended dose modifications for toxicities in patients treated with DOCIVYX in combination with cisplatin and fluorouracil are shown in Table 1.

Liver dysfunction: In case of AST/ALT >2.5 to ≤5 × ULN and AP ≤2.5 × ULN, or AST/ALT >1.5 to ≤5 × ULN and AP >2.5 to ≤5 × ULN, DOCIVYX should be reduced by 20%.

In case of AST/ALT >5 × ULN and/or AP >5 × ULN DOCIVYX should be stopped.

The dose modifications for cisplatin and fluorouracil in the gastric cancer study are provided below.

Cisplatin dose modifications and delays

Peripheral neuropathy: A neurological examination should be performed before entry into the study, and then at least every 2 cycles and at the end of treatment. In the case of neurological signs or symptoms, more frequent examinations should be performed and the following dose modifications can be made according to NCI-CTCAE grade:

• Grade 2: Reduce cisplatin dose by 20%.
• Grade 3: Discontinue treatment.

Ototoxicity: In the case of grade 3 toxicity, discontinue treatment.

Nephrotoxicity: In the event of a rise in serum creatinine ≥grade 2 (>1.5 × normal value) despite adequate rehydration, CrCl should be determined before each subsequent cycle and the following dose reductions should be considered (see Table 2).

For other cisplatin dosage adjustments, also refer to the manufacturers' prescribing information.

Fluorouracil dose modifications and treatment delays

For diarrhea and stomatitis, see Table 1.

In the event of grade 2 or greater plantar-palmar toxicity, fluorouracil should be stopped until recovery. The fluorouracil dosage should be reduced by 20%.

For other greater than grade 3 toxicities, except alopecia and anemia, chemotherapy should be delayed (for a maximum of 2 weeks from the planned date of infusion) until resolution to grade ≤1 and then recommenced, if medically appropriate.

For other fluorouracil dosage adjustments, also refer to the manufacturers' prescribing information.

Avoid using concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole). There are no clinical data with a dose adjustment in patients receiving strong CYP3A4 inhibitors. Based on extrapolation from a pharmacokinetic study with ketoconazole in 7 patients, consider a 50% docetaxel dose reduction if patients require coadministration of a strong CYP3A4 inhibitor

DOCIVYX is a hazardous anticancer drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing DOCIVYX solutions. The use of gloves is recommended

If DOCIVYX Injection solution, or final infusion solution should come into contact with the skin, immediately and thoroughly wash with soap and water. If DOCIVYX Injection solution, or final infusion solution should come into contact with mucosa, immediately and thoroughly wash with water.

Contact of the DOCIVYX with plasticized polyvinyl chloride (PVC) equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP (di-2- ethylhexyl phthalate), which may be leached from PVC infusion bags or sets, the DOCIVYX final infusion solution should be administered through polyethylene-lined administration sets.

DOCIVYX Injection requires NO prior dilution with a diluent and is ready to add to the infusion solution.

Please follow the preparation instructions provided below.

• DOCIVYX vials should be stored between 2°C and 25°C (36°F and 77°F). If the vials are stored under refrigeration, allow the appropriate number of vials of DOCIVYX vials to stand at room temperature for approximately 5 minutes before use.
• Using
  only
  a 21-gauge needle, aseptically withdraw the required amount of DOCIVYX Injection (10 mg docetaxel/mL) with a calibrated syringe and inject via a single injection (one shot) into a 250 mL infusion bag or bottle of either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to produce a final concentration of 0.3 mg/mL to 0.74 mg/mL.
• If a dose greater than 200 mg of DOCIVYX is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 mg/mL DOCIVYX is not exceeded.
• Thoroughly mix the infusion by gentle manual rotation.
• As with all parenteral products, DOCIVYX should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and container permit. If the DOCIVYX final infusion solution is not clear or appears to have precipitation, it should be discarded.
• DOCIVYX final infusion solution is supersaturated, therefore may crystallize over time. If crystals appear, the solution must no longer be used and shall be discarded.

The DOCIVYX final infusion solution should be administered intravenously as a 1-hour infusion under ambient room temperature (below 25°C) and lighting conditions.

DOCIVYX final infusion solution, if stored between 2°C and 25°C (36°F and 77°F), is stable for 6 hours. DOCIVYX final infusion solution (in either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP) should be used within 6 hours (including the 1-hour intravenous administration).

In addition, physical and chemical in-use stability of the infusion solution prepared as recommended has been demonstrated in non-PVC bags up to 48 hours when stored between 2°C and 8°C (36°F and 46°F).