Docivyx Drug Information

Non-small Cell Lung Cancer

For treatment after failure of prior platinum-based chemotherapy, DOCIVYX was evaluated as monotherapy, and the recommended dose is 75 mg/m 2 administered intravenously over 1 hour every 3 weeks. A dose of 100 mg/m 2 in patients previously treated with chemotherapy was associated with increased hematologic toxicity, infection, and treatment-related mortality in randomized controlled trials. For chemotherapy-naive patients, DOCIVYX was evaluated in combination with cisplatin.

Treatment is repeated every three weeks. Patients must receive premedication with antiemetics and appropriate hydration for 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. Induction Chemotherapy Followed by Radiotherapy (TAX323) For the induction treatment of locally advanced inoperable SCCHN, the recommended dose of DOCIVYX is 75 mg/m 2 as a 1-hour intravenous infusion followed by cisplatin 75 mg/m 2 intravenously over 1 hour, on day one, followed by fluorouracil as a continuous intravenous infusion at 750 mg/m 2 per day for five days.

This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy. Following chemotherapy, patients should receive chemoradiotherapy.

Premedication Regimen

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. If the patient continues to experience these reactions, the dosage should either be decreased from or the treatment should be discontinued. Conversely, patients who are dosed initially at 60 mg/m 2 and who do not experience febrile neutropenia, neutrophils <500 cells/mm 3 for 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. Combination Therapy with DOCIVYX Injection in the Adjuvant Treatment of Breast Cancer DOCIVYX in combination with doxorubicin and cyclophosphamide should be administered when the neutrophil count is ≥1,500 cells/mm 3. 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/m 2. 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. If the patient continues to experience these reactions at 60 mg/m 2, treatment should be discontinued.

Non-small Cell Lung Cancer Monotherapy with DOCIVYX for NSCLC treatment after failure of prior platinum-based chemotherapy Patients who are dosed initially at 75 mg/m 2 and who experience either febrile neutropenia, neutrophils <500 cells/mm 3 for 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/m 2. Combination therapy with DOCIVYX for chemotherapy-naive NSCLC For patients who are dosed initially at DOCIVYX 75 mg/m 2 in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is <25,000 cells/mm 3, 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/m 2. In patients who require a further dose reduction, a dose of 50 mg/m 2 is recommended.

For cisplatin dosage adjustments, see manufacturers' prescribing information. Prostate Cancer Combination therapy with DOCIVYX for metastatic CRPC DOCIVYX should be administered when the neutrophil count is ≥1,500 cells/mm 3. Gastric or Head and Neck Cancer 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. If subsequent episodes of complicated neutropenia occur the DOCIVYX dose should be reduced from.

In case of grade 4 thrombocytopenia the DOCIVYX dose should be reduced from. Do not retreat patients with subsequent cycles of DOCIVYX until neutrophils recover to a level >1,500 cells/mm 3. Avoid retreating patients until platelets recover to a level >100,000 cells/mm 3.

Discontinue treatment if these toxicities persist. Recommended dose modifications for toxicities in patients treated with DOCIVYX in combination with cisplatin and fluorouracil are shown in Table 1. 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. Table 2: Dose Reductions for Evaluation of Creatinine Clearance 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. Combination Therapy with Strong CYP3A4 Inhibitors 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.

Administration Precautions 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.

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.

Use only a 21-gauge needle to withdraw DOCIVYX from the vial because larger bore needles (e.g., 18 and 19 gauge) may result in stopper coring and rubber particulates. 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.

Stability

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).

Clinical Trials Experience Breast Cancer Monotherapy with DOCIVYX for locally advanced or metastatic breast cancer after failure of prior chemotherapy DOCIVYX 100 mg/m 2: Adverse drug reactions occurring in at least 5% of patients are compared for three populations who received DOCIVYX administered at 100 mg/m 2 as a 1-hour infusion every 3 weeks: 2045 patients with various tumor types and normal baseline liver function tests; the subset of 965 patients with locally advanced or metastatic breast cancer, both previously treated and untreated with chemotherapy, who had normal baseline liver function tests; and an additional 61 patients with various tumor types who had abnormal liver function tests at baseline. These reactions were described using COSTART terms and were considered possibly or probably related to DOCIVYX. At least 95% of these patients did not receive hematopoietic support.

The safety profile is generally similar in patients receiving DOCIVYX for the treatment of breast cancer and in patients with other tumor types. (See Table 3.) Table 3: Summary of reactions Reversible marrow suppression was the major dose-limiting toxicity of DOCIVYX. Thrombocytopenia (<100,000 cells/mm 3 ) associated with fatal gastrointestinal hemorrhage has been reported. Hypersensitivity reactions Severe hypersensitivity reactions have been reported.

Minor events, including flushing, rash with or without pruritus, chest tightness, back pain, dyspnea, drug fever, or chills, have been reported and resolved after discontinuing the infusion and instituting appropriate therapy. Fluid retention Fluid retention can occur with the use of DOCIVYX. Cutaneous reactions Severe skin toxicity is discussed elsewhere in the label.

Reversible cutaneous reactions characterized by a rash including localized eruptions, mainly on the feet and/or hands, but also on the arms, face, or thorax, usually associated with pruritus, have been observed. Eruptions generally occurred within 1 week after DOCIVYX infusion, recovered before the next infusion, and were not disabling. Severe nail disorders were characterized by hypo or hyperpigmentation, and occasionally by onycholysis (in 0.8% of patients with solid tumors) and pain.

Neurologic reactions Neurologic reactions are discussed elsewhere in the label. Gastrointestinal reactions Nausea, vomiting, and diarrhea were generally mild to moderate. Severe reactions occurred in 3%–5% of patients with solid tumors and to a similar extent among metastatic breast cancer patients.

The incidence of severe reactions was 1% or less for the 92 breast cancer patients premedicated with 3-day corticosteroids. Cardiovascular reactions Hypotension occurred in 2.8% of patients with solid tumors; 1.2% required treatment. Clinically meaningful events such as heart failure, sinus tachycardia, atrial flutter, dysrhythmia, unstable angina, pulmonary edema, and hypertension have occurred.

Seven of 86 (8.1%) of metastatic breast cancer patients receiving DOCIVYX 100 mg/m 2 in a randomized trial and who had serial left ventricular ejection fractions assessed developed deterioration of LVEF by ≥10% associated with a drop below the institutional lower limit of normal. Infusion site reactions Infusion site reactions were generally mild and consisted of hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, extravasation, or swelling of the vein. Hepatic reactions In patients with normal LFTs at baseline, bilirubin values greater than the ULN occurred in 8.9% of patients.

While on DOCIVYX, increases in AST and/or ALT >1.5 times ULN concomitant with alkaline phosphatase >2.5 times ULN occurred in 4.3% of patients with normal LFTs at baseline. Whether these changes were related to the drug or underlying disease has not been established. Hematologic and other toxicity: Relation to dose and baseline liver chemistry abnormalities Hematologic and other toxicity is increased at higher doses and in patients with elevated baseline liver function tests (LFTs).

Combination therapy with DOCIVYX in the adjuvant treatment of breast cancer The following table presents treatment-emergent adverse reactions observed in 744 patients, who were treated with DOCIVYX 75 mg/m 2 every 3 weeks in combination with doxorubicin and cyclophosphamide (see Table 6). Table 6: Clinically Important Treatment-Emergent Adverse Reactions Regardless of Causal Relationship in Patients Receiving DOCIVYX in Combination with Doxorubicin and Cyclophosphamide TAX.3% experienced severe treatment-emergent adverse reactions compared to 26.6% of the 736 patients treated with FAC. Dose reductions due to hematologic toxicity occurred in 1% of cycles in the TAC arm versus 0.1% of cycles in the FAC arm.

Six percent of patients treated with TAC discontinued treatment due to adverse reactions, compared to 1.1% treated with FAC; fever in the absence of infection and allergy being the most common reasons for withdrawal among TAC-treated patients. Two patients died in each arm within 30 days of their last study treatment; 1 death per arm was attributed to study drugs. Fever and infection During the treatment period, fever in the absence of infection was seen in 46.5% of TAC-treated patients and in 17.1% of FAC-treated patients.

Grade 3/4 fever in the absence of infection was seen in 1.3% and 0% of TAC and FAC-treated patients, respectively. Infection was seen in 39.4% of TAC- treated patients compared to 36.3% of FAC-treated patients. Grade 3/4 infection was seen in 3.9% and 2.2% of TAC-treated and FAC-treated patients, respectively.

There were no septic deaths in either treatment arm during the treatment period. Gastrointestinal reactions In addition to gastrointestinal reactions reflected in the table above, 7 patients in the TAC arm were reported to have colitis/enteritis/large intestine perforation versus one patient in the FAC arm. Five of the 7 TAC-treated patients required treatment discontinuation; no deaths due to these events occurred during the treatment period.

Twenty-six patients (3.5%) in the TAC arm and 17 patients (2.3%) in the FAC arm developed CHF during the study period. All except one patient in each arm were diagnosed with CHF during the follow-up period. Two patients in TAC arm and 4 patients in FAC arm died due to CHF.

The risk of CHF was higher in the TAC arm in the first year, and then was similar in both treatment arms. Adverse reactions during the follow-up period (median follow-up time of 8 years) In study TAX316, the most common adverse reactions that started during the treatment period and persisted into the follow-up period in TAC and FAC patients are described below (median follow-up time of 8 years). Nervous system disorders In study TAX316, peripheral sensory neuropathy started during the treatment period and persisted into the follow-up period in 84 patients (11.3%) in TAC arm and 15 patients (2%) in FAC arm.

Acute myeloid leukemia (AML)/Myelodysplastic syndrome (MDS) AML occurred in the adjuvant breast cancer trial (TAX316). The cumulative risk of developing treatment-related AML at median follow-up time of 8 years in TAX316 was 0.4% for TAC-treated patients and 0.1% for FAC-treated patients. AML occurs at a higher frequency when these agents are given in combination with radiation therapy.

Lung Cancer Monotherapy with DOCIVYX for unresectable, locally advanced or metastatic NSCLC previously treated with platinum-based chemotherapy DOCIVYX 75 mg/m 2: Treatment-emergent adverse drug reactions are shown in Table 7. Included in this table are safety data for a total of 176 patients with non-small cell lung carcinoma and a history of prior treatment with platinum-based chemotherapy who were treated in two randomized, controlled trials. These reactions were described using NCI Common Toxicity Criteria regardless of relationship to study treatment, except for the hematologic toxicities or where otherwise noted.

Table 7: Treatment-Emergent Adverse Reactions Regardless of Relationship to Treatment in Patients Receiving DOCIVYX as Monotherapy for Non-small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy* Combination therapy with DOCIVYX in chemotherapy-naïve advanced unresectable or metastatic NSCLC Table 8 presents safety data from two arms of an open label, randomized controlled trial (TAX326) that enrolled patients with unresectable stage IIIB or IV non-small cell lung cancer and no history of prior chemotherapy. Table 8: Adverse Reactions Regardless of Relationship to Treatment in Chemotherapy-Naive Advanced Non-small Cell Lung Cancer Patients Receiving DOCIVYX in Combination with Cisplatin days of last study treatment occurred in 31 patients (7.6%) in the docetaxel+cisplatin arm and 37 patients (9.3%) in the vinorelbine+cisplatin arm. The second comparison in the study, vinorelbine+cisplatin versus DOCIVYX+carboplatin (which did not demonstrate a superior survival associated with DOCIVYX ) demonstrated a higher incidence of thrombocytopenia, diarrhea, fluid retention, hypersensitivity reactions, skin toxicity, alopecia and nail changes on the DOCIVYX+carboplatin arm, while a higher incidence of anemia, neurosensory toxicity, nausea, vomiting, anorexia and asthenia was observed on the vinorelbine+cisplatin arm.

Table 9: Clinically Important Treatment-Emergent Adverse Reactions (Regardless of Relationship) in Patients with Prostate Cancer Who Received DOCIVYX in Combination with Prednisone TAX 5 1 Gastric Cancer Combination therapy with DOCIVYX in gastric adenocarcinoma Data in the following table are based on the experience of 221 patients with advanced gastric adenocarcinoma and no history of prior chemotherapy for advanced disease who were treated with DOCIVYX 75 mg/m 2 in combination with cisplatin and fluorouracil (see Table 10). Table 10: Clinically Important Treatment-Emergent Adverse Reactions Regardless of Relationship to Treatment in the Gastric Cancer Study 2 Head and Neck Cancer Combination therapy with DOCIVYX in head and neck cancer Table 11 summarizes the safety data obtained from patients that received induction chemotherapy with DOCIVYX 75 mg/m 2 in combination with cisplatin and fluorouracil followed by radiotherapy (TAX323; 174 patients) or chemoradiotherapy (TAX324; 251 patients). The treatment regimens are described in Section 14.6.

Table 11: Clinically Important Treatment-Emergent Adverse Reactions (Regardless of Relationship) in Patients with SCCHN Receiving Induction Chemotherapy with DOCIVYX in Combination with Cisplatin and Fluorouracil Followed by Radiotherapy TAX 0

Postmarketing Experience

The following adverse reactions have been identified from clinical trials and/or postmarketing surveillance. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a whole: diffuse pain, chest pain, radiation recall phenomenon, injection site recall reaction (recurrence of skin reaction at a site of previous extravasation following administration of docetaxel at a different site) at the site of previous extravasation.

Cardiovascular: atrial fibrillation, deep vein thrombosis, ECG abnormalities, thrombophlebitis, pulmonary embolism, syncope, tachycardia, myocardial infarction. Ventricular arrhythmia, including ventricular tachycardia, in patients treated with docetaxel in combination regimens including doxorubicin, 5-fluorouracil and/or cyclophosphamide may be associated with fatal outcome. Cutaneous: cutaneous lupus erythematosus, bullous eruptions such as erythema multiforme and severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome, toxic epidermal necrolysis and acute generalized exanthematous pustulosis, scleroderma-like changes (usually preceded by peripheral lymphedema), severe palmar-plantar erythrodysesthesia, and permanent alopecia.

Gastrointestinal: enterocolitis, including colitis, ischemic colitis, and neutropenic enterocolitis, which may be fatal. Abdominal pain, anorexia, constipation, duodenal ulcer, esophagitis, gastrointestinal hemorrhage, gastrointestinal perforation, intestinal obstruction, ileus, and dehydration as a consequence of gastrointestinal events. Hearing: ototoxicity, hearing disorders and/or hearing loss, including during use with other ototoxic drugs.

Hematologic: bleeding episodes, disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure. Hepatic: hepatitis, sometimes fatal, primarily in patients with pre-existing liver disorders. Hypersensitivity: anaphylactic shock with fatal outcome in patients who received premedication.

Severe hypersensitivity reactions with fatal outcome with docetaxel in patients who previously experienced hypersensitivity reactions to paclitaxel. Metabolism and nutrition disorders: electrolyte imbalance, including hyponatremia, hypokalemia, hypomagnesemia, and hypocalcemia. Tumor lysis syndrome, sometimes fatal.

Neurologic: confusion, seizures or transient loss of consciousness, sometimes appearing during the infusion of the drug. Ophthalmologic: conjunctivitis, lacrimation or lacrimation with or without conjunctivitis, cystoid macular edema (CME). Excessive tearing which may be attributable to lacrimal duct obstruction.

Transient visual disturbances (flashes, flashing lights, scotomata), typically occurring during drug infusion and reversible upon discontinuation of the infusion, in association with hypersensitivity reactions. Respiratory: dyspnea, acute pulmonary edema, acute respiratory distress syndrome/pneumonitis, interstitial lung disease, interstitial pneumonia, respiratory failure, and pulmonary fibrosis, which may be fatal. Radiation pneumonitis in patients receiving concomitant radiotherapy.

Renal: renal insufficiency and renal failure, the majority of cases were associated with concomitant nephrotoxic drugs. Second primary malignancies: second primary malignancies, including AML, MDS, NHL, and renal cancer. Musculoskeletal disorder: myositis.

Docetaxel is a CYP3A4 substrate. In vitro studies have shown that the metabolism of docetaxel may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4. In vivo studies showed that the exposure of docetaxel increased 2.2-fold when it was coadministered with ketoconazole, a potent inhibitor of CYP3A4.

Protease inhibitors, particularly ritonavir, may increase the exposure of docetaxel. Concomitant use of DOCIVYX and drugs that inhibit CYP3A4 may increase exposure to docetaxel and should be avoided. In patients receiving treatment with DOCIVYX, close monitoring for toxicity and a DOCIVYX dose reduction could be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided.

Cytochrome P450 3A4 inducers, inhibitors, or substrates: May alter docetaxel metabolism.

Pregnancy Risk Summary Based on findings in animal reproduction studies and its mechanism of action, DOCIVYX can cause fetal harm when administered to a pregnant woman. Available data from case reports in the literature and pharmacovigilance with docetaxel use in pregnant women are not sufficient to inform the drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. DOCIVYX contains alcohol which can interfere with neurobehavioral development.

In animal reproductive studies, administration of docetaxel to pregnant rats and rabbits during the period of organogenesis caused an increased incidence of embryo-fetal toxicities, including intrauterine mortality, at doses as low as 0.02 and 0.003 times the recommended human dose based on body surface area, respectively. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.

All pregnancies have a background risk of birth defect, miscarriage, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Clinical Considerations DOCIVYX contains alcohol.

Published studies have demonstrated that alcohol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development. Data Animal data Intravenous administration of ≥0.3 and 0.03 mg/kg/day docetaxel to pregnant rats and rabbits, respectively, during the period of organogenesis caused an increased incidence of intrauterine mortality, resorptions, reduced fetal weights, and fetal ossification delays. Maternal toxicity was also observed at these doses, which were approximately 0.02 and 0.003 times the daily maximum recommended human dose based on body surface area, respectively.

Pediatric Use The alcohol content of DOCIVYX should be taken into account when given to pediatric patients. The efficacy of DOCIVYX in pediatric patients as monotherapy or in combination has not been established. The overall safety profile of DOCIVYX in pediatric patients receiving monotherapy or TCF was consistent with the known safety profile in adults.

The recommended dose was 125 mg/m 2 as a 1-hour intravenous infusion every 21 days. The primary dose limiting toxicity was neutropenia. Efficacy was not established with tumor response rates ranging from one complete response (CR) (0.6%) in a patient with undifferentiated sarcoma to four partial responses (2.2%) seen in one patient each with Ewing Sarcoma, neuroblastoma, osteosarcoma, and squamous cell carcinoma.

DOCIVYX in Combination DOCIVYX was studied in combination with cisplatin and 5-fluorouracil (TCF) versus cisplatin and 5- fluorouracil (CF) for the induction treatment of nasopharyngeal carcinoma (NPC) in pediatric patients prior to chemoradiation consolidation. The primary endpoint was the CR rate following induction treatment of NPC. One patient out of 50 in the TCF group (2%) had a complete response while none of the 25 patients in the CF group had a complete response.

Pharmacokinetics Pharmacokinetic parameters for docetaxel were determined in 2 pediatric solid tumor trials. Docetaxel clearance was 17.9±8.75 L/h/m 2, corresponding to an AUC of 4.20±2.57 μg·h/mL. In summary, the body surface area adjusted clearance of docetaxel monotherapy and TCF combination in children were comparable to those in adults.

DOCIVYX is contraindicated in patients with: neutrophil counts of <1500 cells/mm3. a history of severe hypersensitivity reactions to docetaxel. Severe reactions, including anaphylaxis, have occurred. Hypersensitivity to docetaxel Neutrophil counts of <1500 cells/mm 3

There is no known antidote for DOCIVYX overdosage. In case of overdosage, the patient should be kept in a specialized unit where vital functions can be closely monitored. Anticipated complications of overdosage include: bone marrow suppression, peripheral neurotoxicity, and mucositis.

Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed. Both patients experienced severe neutropenia, mild asthenia, cutaneous reactions, and mild paresthesia, and recovered without incident.

In male and female rats, lethality was observed at a dose of 20 mg/kg (comparable to the human dose of 100 mg/m 2 on a mg/m 2 basis) and was associated with abnormal mitosis and necrosis of multiple organs.