DOCIVYX is a microtubule inhibitor indicated for: Breast Cancer (BC) : single agent for locally advanced or metastatic BC after chemotherapy failure; and with doxorubicin and cyclophosphamide as adjuvant treatment of operable node-positive BC ( 1.1 ) Non-small Cell Lung Cancer (NSCLC): single agent for locally advanced or metastatic NSCLC after platinum therapy failure; and with cisplatin for unresectable, locally advanced or metastatic untreated NSCLC ( 1.2 ) Castration- Resistant Prostate Cancer (CRPC) : with prednisone in metastatic CRPC ( 1.3 ) Gastric Adenocarcinoma (GC): with cisplatin and fluorouracil for untreated, advanced GC, including the gastroesophageal junction ( 1.4 ) Squamous Cell Carcinoma of the Head and Neck (SCCHN): with cisplatin and fluorouracil for induction treatment of locally advanced SCCHN ( 1.5 )
1.1Breast Cancer
DOCIVYX is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy. DOCIVYX in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node-positive breast cancer.
1.2Non-small Cell Lung Cancer
DOCIVYX as a single agent is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior platinum-based chemotherapy. DOCIVYX in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer who have not previously received chemotherapy for this condition.
1.3Prostate Cancer
DOCIVYX in combination with prednisone is indicated for the treatment of patients with metastatic CRPC.
1.4Gastric Adenocarcinoma
DOCIVYX in combination with cisplatin and fluorouracil is indicated for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotherapy for advanced disease.
1.5Head and Neck Cancer
DOCIVYX in combination with cisplatin and fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).
DOCIVYX is contraindicated in patients with: neutrophil counts of <1500 cells/mm3 [see Warnings and Precautions (5.3) ]. a history of severe hypersensitivity reactions to docetaxel. Severe reactions, including anaphylaxis, have occurred [see Warnings and Precautions (5.5) ] . Hypersensitivity to docetaxel ( 4 ) Neutrophil counts of <1500 cells/mm 3 ( 4 )
Warnings and precautions
Second primary malignancies: In patients treated with DOCIVYX-containing regimens, monitor for delayed AML, MDS, NHL, and renal cancer. ( 5.7 ) Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may occur. Severe cutaneous adverse reactions have been reported. Severe skin toxicity may require dose adjustment or permanent treatment discontinuation. ( 5.8 ) Neurologic reactions: Reactions including paresthesia, dysesthesia, and pain may occur.
Severe neurosensory symptoms require dose adjustment or discontinuation if persistent. ( 5.9 ) Eye disorders: Cystoid macular edema (CME) has been reported and requires treatment discontinuation. ( 5.10 ) Asthenia: Severe asthenia may occur and may require treatment discontinuation. ( 5.11 ) Embryo-fetal toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception.
( 5.12, 8.1, 8.3 ) Alcohol content: The alcohol content in a dose of DOCIVYX may affect the central nervous system. This may include impairment of a patient's ability to drive or use machines immediately after infusion. ( 5.13 ) Tumor lysis syndrome: Tumor lysis syndrome has been reported. Patients at risk should be well hydrated and closely monitored during treatment. ( 5.14 )
5.1Toxic Deaths Breast Cancer
DOCIVYX administered at 100 mg/m 2 was associated with deaths considered possibly or probably related to treatment in 2.0% (19/965) of metastatic breast cancer patients, both previously treated and untreated, with normal baseline liver function and in 11.5% (7/61) of patients with various tumor types who had abnormal baseline liver function (AST and/or ALT >1.5 times ULN together with AP >2.5 times ULN). Among patients dosed at 60 mg/m 2 , mortality related to treatment occurred in 0.6% (3/481) of patients with normal liver function, and in 3 of 7 patients with abnormal liver function.
Approximately half of these deaths occurred during the first cycle. Sepsis accounted for the majority of the deaths. Non-small Cell Lung Cancer DOCIVYX administered at a dose of 100 mg/m 2 in patients with locally advanced or metastatic non-small cell lung cancer who had a history of prior platinum-based chemotherapy was associated with increased treatment-related mortality (14% and 5% in two randomized, controlled studies).
There were 2.8% treatment-related deaths among the 176 patients treated at the 75 mg/m 2 dose in the randomized trials. Among patients who experienced treatment-related mortality at the 75 mg/m 2 dose level, 3 of 5 patients had an ECOG PS of 2 at study entry [see Dosage and Administration (2.2) , Clinical Studies (14) ] .
5.2Hepatic Impairment Patients
with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at increased risk for the development of severe neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. Avoid DOCIVYX in patients with bilirubin > upper limit of normal (ULN), or to patients with AST and/or ALT >1.5 × ULN concomitant with alkaline phosphatase >2.5 × ULN [see Warnings and Precautions (5.1) ] .
For patients with isolated elevations of transaminase >1.5 × ULN, consider DOCIVYX dose modifications [see Dosage and Administration (2.7) ] . Measure bilirubin, AST or ALT, and alkaline phosphatase prior to each cycle of DOCIVYX therapy.
5.3Hematologic Effects
Perform frequent peripheral blood cell counts on all patients receiving DOCIVYX. Do not retreat patients with subsequent cycles of DOCIVYX until neutrophils recover to a level >1500 cells/mm 3 [see Contraindications (4) ] . Avoid retreating patients until platelets recover to a level >100,000 cells/mm 3 . A 25% reduction in the dose of DOCIVYX is recommended during subsequent cycles following severe neutropenia (<500 cells/mm 3 ) lasting 7 days or more, febrile neutropenia, or a grade 4 infection in a DOCIVYX cycle [see Dosage and Administration (2.7) ] .
Neutropenia (<2000 neutrophils/mm 3 ) occurs in virtually all patients given 60 mg/m 2 to 100 mg/m 2 of DOCIVYX and grade 4 neutropenia (<500 cells/mm 3 ) occurs in 85% of patients given 100 mg/m 2 and 75% of patients given 60 mg/m 2 . Frequent monitoring of blood counts is, therefore, essential so that dose can be adjusted. DOCIVYX should not be administered to patients with neutrophils <1500 cells/mm 3 . Febrile neutropenia occurred in about 12% of patients given 100 mg/m 2 but was very uncommon in patients given 60 mg/m 2 .
Hematologic responses, febrile reactions and infections, and rates of septic death for different regimens are dose related [see Adverse Reactions (6.1), Clinical Studies (14) ] . Three breast cancer patients with severe liver impairment (bilirubin >1.7 times ULN) developed fatal gastrointestinal bleeding associated with severe drug-induced thrombocytopenia. In gastric cancer patients treated with docetaxel in combination with cisplatin and fluorouracil (TCF), febrile neutropenia and/or neutropenic infection occurred in 12% of patients receiving G-CSF compared to 28% who did not.
Patients receiving TCF should be closely monitored during the first and subsequent cycles for febrile neutropenia and neutropenic infection [see Dosage and Administration (2.7), Adverse Reactions (6) ] .
5.4Enterocolitis and Neutropenic Colitis Enterocolitis
and neutropenic colitis (typhlitis) have occurred in patients treated with DOCIVYX alone and in combination with other chemotherapeutic agents, despite the coadministration of G-CSF. Caution is recommended for patients with neutropenia, particularly at risk for developing gastrointestinal complications. Enterocolitis and neutropenic enterocolitis may develop at any time, and could lead to death as early as the first day of symptom onset.
Monitor patients closely from onset of any symptoms of gastrointestinal toxicity. Inform patients to contact their healthcare provider with new, or worsening symptoms of gastrointestinal toxicity [see Dosage and Administration (2), Warnings and Precautions (5.3), Adverse Reactions (6.2) ] .
5.5Hypersensitivity Reactions
Monitor patients closely for hypersensitivity reactions, especially during the first and second infusions. Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or fatal anaphylaxis, have been reported in patients premedicated with 3 days of corticosteroids. Severe hypersensitivity reactions require immediate discontinuation of the DOCIVYX infusion and aggressive therapy.
Do not rechallenge patients with a history of severe hypersensitivity reactions with DOCIVYX [see Contraindications (4) ] . Patients who have previously experienced a hypersensitivity reaction to paclitaxel may develop a hypersensitivity reaction to docetaxel that may include severe or fatal reactions such as anaphylaxis. Monitor patients with a previous history of hypersensitivity to paclitaxel closely during initiation of DOCIVYX therapy.
Hypersensitivity reactions may occur within a few minutes following initiation of a DOCIVYX infusion. If minor reactions such as flushing or localized skin reactions occur, interruption of therapy is not required. All patients should be premedicated with an oral corticosteroid prior to the initiation of the infusion of DOCIVYX [see Dosage and Administration (2.6) ] .
5.6Fluid Retention
Severe fluid retention has been reported following DOCIVYX therapy. Patients should be premedicated with oral corticosteroids prior to each DOCIVYX administration to reduce the incidence and severity of fluid retention [see Dosage and Administration (2.6) ] . Patients with pre-existing effusions should be closely monitored from the first dose for the possible exacerbation of the effusions. When fluid retention occurs, peripheral edema usually starts in the lower extremities and may become generalized with a median weight gain of 2
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Interactions
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 [see Dosage and Administration (2.7), Clinical Pharmacology (12.3) ]. Cytochrome P450 3A4 inducers, inhibitors, or substrates: May alter docetaxel metabolism.
( 7 )
Pregnancy and breastfeeding
8.1Pregnancy 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 [see Clinical Pharmacology (12.1) ] . 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 [see Clinical Considerations] .
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 [ see Data ]. 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 2% to 4% and 15% to 20%, respectively. Clinical Considerations DOCIVYX contains alcohol [see Warnings and Precautions (5.13) ] .
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.
Adverse reactions
The most serious adverse reactions from DOCIVYX are: Toxic Deaths [see Boxed Warning , Warnings and Precautions (5.1) ] Hepatic Impairment [see Boxed Warning , Warnings and Precautions (5.2) ] Hematologic Effects [see Boxed Warning , Warnings and Precautions (5.3) ] Enterocolitis and Neutropenic Colitis [see Warnings and Precautions (5.4) ] Hypersensitivity Reactions [see Boxed Warning , Warnings and Precautions (5.5) ] Fluid Retention [see Boxed Warning , Warnings and Precautions (5.6) ] Second Primary Malignancies [see Warnings and Precautions (5.7) ] Cutaneous Reactions [see Warnings and Precautions (5.8) ] Neurologic Reactions [see Warnings and Precautions (5.9) ] Eye Disorders [see Warnings and Precautions (5.10)] Asthenia [see Warnings and Precautions (5.11) ] Alcohol Content [see Warnings and Precautions (5.13) ] The most common adverse reactions across all DOCIVYX indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia.
Incidence varies depending on the indication. Adverse reactions are described according to indication. 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. Responding patients may not experience an improvement in performance status on therapy and may experience worsening.
The relationship between changes in performance status, response to therapy, and treatment-related side effects has not been established. Most common adverse reactions across all DOCIVYX indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia.
( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Avyxa Pharma,LLC at 1-888-520-0954 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1Clinical 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 Adverse Reactions in Patients Receiving DOCIVYX at 100 mg/m 2 * Normal Baseline LFTs: Transaminases ≤1.5 times ULN or alkaline phosphatase ≤2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN † Elevated Baseline LFTs: AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN ‡ Febrile Neutropenia: ANC grade 4 with fever >38°C with intravenous antibiotics and/or hospitalization Adverse Reaction All Tumor Types Normal LFTs* n=2045 % All Tumor Types Elevated LFTs † n=61 % Breast Cancer Normal LFTs * n=965 % Hematologic Neutropenia <2000 cells/mm3 96 96 99 <500 cells/mm3 75 88 86 Leukopenia <4000 cells/mm3 96 98 99 <1000 cells/mm3 32 47 44 Thrombocytopenia <100,000 cells/mm3 8 25 9 Anemia <11 g/dL 90 92 94 <8 g/dL 9 31 8 Febrile Neutropenia‡ 11 26 12 Septic Death 2 5 1 Non-Septic Death 1 7 1 Infections Any Severe 22 6 33 16 22 6 Fever in Absence of Infection Any Severe 31 2 41 8 35 2 Hypersensitivity Reactions Regardless of Premedication Any 21 20 18 Severe 4 10 3 With 3-day Premedication n=92 n=3 n=92 Any 15 33 15 Severe 2 0 2 Fluid Retention Regardless of Premedication Any 47 39 60 Severe 7 8 9 With 3-day Premedication n=92 n=3 n=92 Any 64 67 64 Severe 7 33 7 Neurosensory Any Severe 49 4 34 0 58 6 Cutaneous Any Severe 48 5 54 10 47 5 Nail Changes Any Severe 31 3 23 5 41 4 Gastrointestinal Nausea Vomiting Diarrhea Severe 39 22 39 5 38 23 33 5 42 23 43 6 Stomatitis Any Severe 42 6 49 13 52 7 Alopecia 76 62 74 Asthenia Any Severe 62 13 53 25 66 15 Myalgia Any Severe 19 2 16 2 21 2 Arthralgia 9 7 8 Infusion Site Reactions 4 3 4 Hematologic reactions Reversible marrow suppression was the major dose-limiting toxicity of DOCIVYX [see Warnings and Precautions (5.3) ].
The median time to nadir was 7 days, while the median duration of severe neutropenia (<500 cells/mm 3 ) was 7 days. Among 2045 patients with solid tumors and normal baseline LFTs, severe neutropenia occurred in 75.4% and lasted for more than 7 days in 2.9% of cycles. Febrile neutropenia (<500 cells/mm 3 with fever >38°C with intravenous antibiotics and/or hospitalization) occurred in 11% of patients with solid tumors, in 12.3% of patients with metastatic breast cancer, and in 9.8% of 92 breast cancer patients premedicated with 3-day corticosteroids.
Severe infectious episodes occurred in 6.1% of patients with solid tumors, in 6.4% of patients with metastatic breast cancer, and in 5.4% of 92 breast cancer patients premedicated with 3-day corticosteroids. Thrombocytopenia (<100,000 cells/mm 3 ) associated with fatal gastrointestinal hemorrhage has been reported. Hypersensitivity reactions Severe hypersensitivity reactions have been reported [see Boxed Warning , Warnings and Precautions (5.5) ] .
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 [see Boxed Warning , Dosage and Administration (2.6) , Warnings and Precautions (5.6) ]. Cutaneous reactions Severe skin toxicity is discussed elsewhere in the label [see Warnings and Precautions (5.8) ].
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 [see Warnings and Precautions (5.9) ]. 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.
Severe stomatitis occurred in 5.5% of patients with solid tumors, in 7.4% of patients with metastatic breast cancer, and in 1.1% of 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, dysrhyt
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Composition
Active ingredients
DOCETAXEL 80MG/8ML (10MG/ML)
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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