Products – AVYXA

CYCLOPHOSPHAMIDE INJECTION

INDICATIONS AND IMPORTANT safety INFORMATION

INDICATIONS

Malignant Diseases

Cyclophosphamide Injection is indicated for the treatment of adult and pediatric patients with: • malignant lymphomas (Stages III and IV of the Ann Arbor staging system), Hodgkin's disease, lymphocytic lymphoma (nodular or diffuse), mixed-cell type lymphoma, histiocytic lymphoma, Burkitt's lymphoma

multiple myeloma
leukemias: chronic lymphocytic leukemia, chronic granulocytic leukemia (it is usually ineffective in acute blastic crisis), acute myelogenous and monocytic leukemia, acute lymphoblastic (stem-cell) leukemia (cyclophosphamide given during remission is effective in prolonging its duration)
mycosis fungoides (advanced disease)
neuroblastoma (disseminated disease)
adenocarcinoma of the ovary
retinoblastoma
carcinoma of the breast

Cyclophosphamide Injection, although effective alone in susceptible malignancies, is more frequently used concurrently or sequentially with other antineoplastic drugs.

IMPORTANT SAFETY INFORMATION

DOSAGE AND ADMINISTRATION

Important Dosing Information

During or immediately after the administration, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urinary tract toxicity. Therefore, Cyclophosphamide Injection should be administered in the morning.

CONTRAINDICATIONS

Hypersensitivity

Cyclophosphamide Injection is contraindicated in patients who have a history of severe hypersensitivity reactions to it, any of its metabolites, or to other components of the product. Anaphylactic reactions including death have been reported with cyclophosphamide. Possible cross-sensitivity with other alkylating agents can occur.

Urinary Outflow Obstruction

Cyclophosphamide Injection is contraindicated in patients with urinary outflow obstruction.

WARNINGS AND PRECAUTIONS

Myelosuppression, Immunosuppression, Bone Marrow Failure and Infections

Cyclophosphamide can cause myelosuppression (leukopenia, neutropenia, thrombocytopenia and anemia), bone marrow failure, and severe immunosuppression which may lead to serious and sometimes fatal infections, including sepsis and septic shock. Latent infections can be reactivated.

Antimicrobial prophylaxis may be indicated in certain cases of neutropenia at the discretion of the managing physician. In case of neutropenic fever, antibiotic therapy is indicated. Antimycotics and/or antivirals may also be indicated.

Monitoring of complete blood counts is essential during cyclophosphamide treatment so that the dose can be adjusted, if needed. Cyclophosphamide Injection should not be administered to patients with neutrophils ≤1,500/mm3and platelets < 50,000/mm3. Cyclophosphamide Injection treatment may not be indicated, or should be interrupted, or the dose reduced, in patients who have or who develop a serious infection. G-CSF may be administered to reduce the risks of neutropenia complications associated with cyclophosphamide use. Primary and secondary prophylaxis with G-CSF should be considered in all patients considered to be at increased risk for neutropenia complications. The nadirs of the reduction in leukocyte count and thrombocyte count are usually reached in weeks 1 and 2 of treatment. Peripheral blood cell counts are expected to normalize after approximately 20 days. Bone marrow failure has been reported. Severe myelosuppression may be expected particularly in patients pretreated with and/or receiving concomitant chemotherapy and/or radiation therapy.

Urinary Tract and Renal Toxicity

Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria have been reported with cyclophosphamide. Medical and/or surgical supportive treatment may be required to treat protracted cases of severe hemorrhagic cystitis. Discontinue Cyclophosphamide Injection therapy in case of severe hemorrhagic cystitis. Urotoxicity (bladder ulceration, necrosis, fibrosis, contracture and secondary cancer) may require interruption of Cyclophosphamide Injection treatment or cystectomy. Urotoxicity can be fatal. Urotoxicity can occur with short-term or long term use of cyclophosphamide.

Before starting treatment, exclude or correct any urinary tract obstructions. Urinary sediment should be checked regularly for the presence of erythrocytes and other signs of urotoxicity and/or nephrotoxicity. Cyclophosphamide Injection should be used with caution, if at all, in patients with active urinary tract infections. Aggressive hydration with forced diuresis and frequent bladder emptying can reduce the frequency and severity of bladder toxicity. Mesna has been used to prevent severe bladder toxicity.

Cardiotoxicity

Myocarditis, myopericarditis, pericardial effusion including cardiac tamponade, and congestive heart failure, which may be fatal, have been reported with cyclophosphamide therapy.

Supraventricular arrhythmias (including atrial fibrillation and flutter) and ventricular arrhythmias (including severe QT prolongation associated with ventricular tachyarrhythmia) have been reported after treatment with regimens that included cyclophosphamide.

The risk of cardiotoxicity may be increased with high doses of cyclophosphamide, in patients with advanced age, and in patients with previous radiation treatment to the cardiac region and/or previous or concomitant treatment with other cardiotoxic agents.

Particular caution is necessary in patients with risk factors for cardiotoxicity and in patients with preexisting cardiac disease.

Monitor patients with risk factors for cardiotoxicity and with pre-existing cardiac disease.

Pulmonary Toxicity

Pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease and other forms of pulmonary toxicity leading to respiratory failure have been reported during and following treatment with cyclophosphamide. Late onset pneumonitis (greater than 6 months after start of cyclophosphamide) appears to be associated with increased mortality. Pneumonitis may develop years after treatment with cyclophosphamide.

Monitor patients for signs and symptoms of pulmonary toxicity.

Secondary Malignancies

Cyclophosphamide is genotoxic. Secondary malignancies (urinary tract cancer, myelodysplasia, acute leukemias, lymphomas, thyroid cancer, and sarcomas) have been reported in patients treated with cyclophosphamide-containing regimens. The risk of bladder cancer may be reduced by prevention of hemorrhagic cystitis.

Veno-occlusive Liver Disease

Veno-occlusive liver disease (VOD) including fatal outcome has been reported in patients receiving cyclophosphamide-containing regimens. A cytoreductive regimen in preparation for bone marrow transplantation that consists of cyclophosphamide in combination with whole-body irradiation, busulfan, or other agents has been identified as a major risk factor. VOD has also been reported to develop gradually in patients receiving long-term low-dose immunosuppressive doses of cyclophosphamide.

Other risk factors predisposing to the development of VOD include preexisting disturbances of hepatic function, previous radiation therapy of the abdomen, and a low performance status.

Alcohol Content

The alcohol content in a dose of Cyclophosphamide Injection may affect the central nervous system and should be taken into account for patients in whom alcohol intake should be avoided or minimized. Consideration should be given to the alcohol content in Cyclophosphamide Injection on the ability to drive or use machines immediately after the infusion.

Each administration of Cyclophosphamide Injection at 50 mg per kg delivers 0.0448 g/kg of ethanol. For a 75 kg patient this would deliver 3.36 grams of ethanol. Other cyclophosphamide products may have a different amount of alcohol or no alcohol.

Embryo-Fetal Toxicity

Based on its mechanism of action and published reports of effects in pregnant patients or animals, Cyclophosphamide Injection can cause fetal harm when administered to a pregnant woman. Exposure to cyclophosphamide during pregnancy may cause birth defects, miscarriage, fetal growth retardation, and fetotoxic effects in the newborn. Cyclophosphamide is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys.

Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with Cyclophosphamide Injection and for up to 1 year after completion of therapy. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Cyclophosphamide Injection and for 4 months after completion of therapy.

Infertility

Male and female reproductive function and fertility may be impaired in patients being treated with Cyclophosphamide Injection. Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes. Development of sterility appears to depend on the dose of cyclophosphamide, duration of therapy, and the state of gonadal function at the time of treatment. Cyclophosphamide induced sterility may be irreversible in some patients. Advise patients on the potential risks for infertility.

Impairment of Wound Healing

Cyclophosphamide may interfere with normal wound healing.

Hyponatremia

Hyponatremia associated with increased total body water, acute water intoxication, and a syndrome resembling SIADH (syndrome of inappropriate secretion of antidiuretic hormone), which may be fatal, has been reported.

ADVERSE REACTIONS

Please see “Warnings and Precautions, Contraindications, and Use in Specific Populations” for more information on the following adverse reactions:

Hypersensitivity
Myelosuppression, Immunosuppression, Bone Marrow Failure, and Infections • Urinary Tract and Renal Toxicity
Cardiotoxicity
Pulmonary Toxicity
Secondary Malignancies
Veno-occlusive Liver Disease
Alcohol Content
Infertility
Impaired Wound Healing
Hyponatremia

Clinical Trials and Postmarketing Experience

The following adverse reactions associated with the use of cyclophosphamide were identified in clinical studies or postmarketing reports. Because some of these reactions were 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 most common adverse reactions were neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and diarrhea.

Cardiac: cardiac arrest, ventricular fibrillation, ventricular tachycardia, cardiogenic shock, pericardial effusion (progressing to cardiac tamponade), myocardial hemorrhage, myocardial infarction, cardiac failure (including fatal outcomes), cardiomyopathy, myocarditis, pericarditis, carditis, atrial fibrillation, supraventricular arrhythmia, ventricular arrhythmia, bradycardia, tachycardia, palpitations, QT prolongation.

Congenital, Familial and Genetic: intra-uterine death, fetal malformation, fetal growth retardation, fetal toxicity (including myelosuppression, gastroenteritis).

Ear and Labyrinth: deafness, hearing impaired, tinnitus.

Endocrine: water intoxication.

Eye: visual impairment, conjunctivitis, lacrimation.

Gastrointestinal: gastrointestinal hemorrhage, acute pancreatitis, colitis, enteritis, cecitis, stomatitis, constipation, parotid gland inflammation, nausea, vomiting, diarrhea.

General Disorders and Administrative Site Conditions: multiorgan failure, general physical deterioration, influenza-like illness, injection/infusion site reactions (thrombosis, necrosis, phlebitis, inflammation, pain, swelling, erythema), pyrexia, edema, chest pain, mucosal inflammation, asthenia, pain, chills, fatigue, malaise, headache, febrile neutropenia.

Hematologic: myelosuppression, bone marrow failure, disseminated intravascular coagulation and hemolytic uremic syndrome (with thrombotic microangiopathy).

Hepatic: veno-occlusive liver disease, cholestatic hepatitis, cytolytic hepatitis, hepatitis, cholestasis; hepatotoxicity with hepatic failure, hepatic encephalopathy, ascites, hepatomegaly, blood bilirubin increased, hepatic function abnormal, hepatic enzymes increased.

Immune: immunosuppression, anaphylactic shock and hypersensitivity reaction.

Infections: The following manifestations have been associated with myelosuppression and immunosuppression caused by cyclophosphamide: increased risk for and severity of pneumonias (including fatal outcomes), other bacterial, fungal, viral, protozoal and, parasitic infections; reactivation of latent infections, (including viral hepatitis, tuberculosis), Pneumocystis jiroveci, herpes zoster, Strongyloides, sepsis and septic shock.

Investigations: blood lactate dehydrogenase increased, C-reactive protein increased.

Metabolism and Nutrition: hyponatremia, fluid retention, blood glucose increased, blood glucose decreased.

Musculoskeletal and Connective Tissue: rhabdomyolysis, scleroderma, muscle spasms, myalgia, arthralgia.

Neoplasms: acute leukemia, myelodysplastic syndrome, lymphoma, sarcomas, renal cell carcinoma, renal pelvis cancer, bladder cancer, ureteric cancer, thyroid cancer.

Nervous System: encephalopathy, convulsion, dizziness, neurotoxicity has been reported and manifested as reversible posterior leukoencephalopathy syndrome, myelopathy, peripheral neuropathy, polyneuropathy, neuralgia, dysesthesia, hypoesthesia, paresthesia, tremor, dysgeusia, hypogeusia, parosmia.

Pregnancy: premature labor.

Psychiatric: confusional state.

Renal and Urinary: renal failure, renal tubular disorder, renal impairment, nephropathy toxic, hemorrhagic cystitis, bladder necrosis, cystitis ulcerative, bladder contracture, hematuria, nephrogenic diabetes insipidus, atypical urinary bladder epithelial cells.

Reproductive System: infertility, ovarian failure, ovarian disorder, amenorrhea, oligomenorrhea, testicular atrophy, azoospermia, oligospermia.

Respiratory: pulmonary veno-occlusive disease, acute respiratory distress syndrome, interstitial lung disease as manifested by respiratory failure (including fatal outcomes), obliterative bronchiolitis, organizing pneumonia, alveolitis allergic, pneumonitis, pulmonary hemorrhage; respiratory distress, pulmonary hypertension, pulmonary edema, pleural effusion, bronchospasm, dyspnea, hypoxia, cough, nasal congestion, nasal discomfort, oropharyngeal pain, rhinorrhea.

Skin and Subcutaneous Tissue: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, palmar-plantar erythrodysesthesia syndrome, radiation recall dermatitis, toxic skin eruption, urticaria, dermatitis, blister, pruritus, erythema, nail disorder, facial swelling, hyperhidrosis, alopecia.

Tumor lysis syndrome: like other cytotoxic drugs, cyclophosphamide may induce tumor-lysis syndrome and hyperuricemia in patients with rapidly growing tumors.

Vascular: pulmonary embolism, venous thrombosis, vasculitis, peripheral ischemia, hypertension, hypotension, flushing, hot flush.

DRUG INTERACTIONS

Effect of Other Drugs on Cyclophosphamide Exposure

Protease inhibitors:

Cyclophosphamide is a pro-drug that is activated by cytochrome P450s.

Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen.

Drugs that Potentiate Cyclophosphamide Toxicities

Drugs or agents with similar toxicities to Cyclophosphamide Injection and can potentiate these effects are listed below.

Drugs that increase hematotoxicity and/or immunosuppression

ACE inhibitors: ACE inhibitors can cause leukopenia.
Natalizumab
Paclitaxel: Increased hematotoxicity has been reported when cyclophosphamide was administered after paclitaxel infusion.
Thiazide diuretics
Zidovudine

Drugs that increase cardiotoxicity

Anthracyclines
Cytarabine
Pentostatin
Radiation therapy of the cardiac region
Trastuzumab

Drugs that increase pulmonary toxicity

Amiodarone
G-CSF, GM-CSF (granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor)

Drugs that increase nephrotoxicity

Amphotericin B
Indomethacin: Acute water intoxication has been reported with concomitant use of indomethacin

Drugs that potentiate increase in other toxicities

Azathioprine: Increased risk of hepatotoxicity (liver necrosis)
Busulfan: Increased incidence of hepatic veno-occlusive disease and mucositis has been reported.
Protease inhibitors: Increased incidence of mucositis

Drugs that increase the risk of hemorrhagic cystitis

Radiation treatment: Increased risk of hemorrhagic cystitis may result from a combined effect of cyclophosphamide and past or concomitant radiation treatment.

Effect of Cyclophosphamide on Other Drugs

Etanercept

A higher incidence of non-cutaneous malignant solid tumors in patients with Wegener's granulomatosis occurred with the addition of etanercept to cyclophosphamide treatment.

Metronidazole

Acute encephalopathy has been reported in a patient receiving cyclophosphamide and metronidazole. In an animal study, the combination of cyclophosphamide with metronidazole was associated with increased cyclophosphamide toxicity.

Tamoxifen

Concomitant use of tamoxifen and chemotherapy may increase the risk of thromboembolic complications.

Coumarins

Both increased and decreased warfarin effect have been reported in patients receiving warfarin and cyclophosphamide.

Cyclosporine

Lower serum concentrations of cyclosporine have been observed in patients receiving a combination of cyclophosphamide and cyclosporine than in patients receiving only cyclosporine. This interaction may result in an increased incidence of graft-versus-host disease.

Depolarizing Muscle Relaxants

If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, alert the anesthesiologist.

Cyclophosphamide treatment causes a marked and persistent inhibition of cholinesterase activity. Prolonged apnea may occur with concurrent depolarizing muscle relaxants (e.g., succinylcholine).

USE IN SPECIFIC POPULATIONS

Pregnancy

Risk Summary

Based on its mechanism of action and published reports of effects in pregnant patients or animals, Cyclophosphamide Injection can cause fetal harm when administered to a pregnant woman.

Exposure to cyclophosphamide during pregnancy may cause fetal malformations, miscarriage, fetal growth retardation, and toxic effects in the newborn [see Data below]. Cyclophosphamide is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys [see Data below]. 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 population is unknown. In the U.S. general population, the estimated background risk of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies.

Data

Human Data

Malformations of the skeleton, palate, limbs and eyes as well as miscarriage have been reported after exposure to cyclophosphamide in the first trimester. Fetal growth retardation and toxic effects manifesting in the newborn, including leukopenia, anemia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis have been reported after exposure to cyclophosphamide.

Animal Data

Administration of cyclophosphamide to pregnant mice, rats, rabbits and monkeys during the period of organogenesis at doses at or below the dose in patients based on body surface area resulted in various malformations, which included neural tube defects, limb and digit defects and other skeletal anomalies, cleft lip and palate, and reduced skeletal ossification.

Lactation

Risk Summary

Cyclophosphamide is present in breast milk. Neutropenia, thrombocytopenia, low hemoglobin, and diarrhea have been reported in infants breast fed by women treated with cyclophosphamide. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment with Cyclophosphamide Injection and for 1 week after the last dose.

Females and Males of Reproductive Potential

Cyclophosphamide Injection can cause fetal harm when administered to a pregnant woman.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to the initiation of Cyclophosphamide Injection.

Contraception

Females

Advise female patients of reproductive potential to use effective contraception during treatment with Cyclophosphamide Injection and for up to 1 year after completion of therapy.

Males

Based on findings in genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment with Cyclophosphamide Injection and for 4 months after completion of therapy.

Infertility

Females

Amenorrhea, transient or permanent, associated with decreased estrogen and increased gonadotropin secretion develops in a proportion of women treated with cyclophosphamide. Affected patients generally resume regular menses within a few months after cessation of therapy. The risk of premature menopause with cyclophosphamide increases with age. Oligomenorrhea has also been reported in association with cyclophosphamide treatment.

Animal data suggest an increased risk of failed pregnancy and malformations may persist after discontinuation of cyclophosphamide as long as oocytes/follicles exist that were exposed to cyclophosphamide during any of their maturation phases. The exact duration of follicular development in humans is not known but may be longer than 12 months.

Males

Men treated with cyclophosphamide may develop oligospermia or azoospermia which are normally associated with increased gonadotropin but normal testosterone secretion.

Pediatric Use

The safety and effectiveness of Cyclophosphamide Injection have been established in pediatric patients and information on this use is discussed throughout the full Patient information.

The alcohol content of Cyclophosphamide Injection should be taken into account when given to pediatric patients.

Pre-pubescent girls treated with cyclophosphamide generally develop secondary sexual characteristics normally and have regular menses. Ovarian fibrosis with apparently complete loss of germ cells after prolonged cyclophosphamide treatment in late pre-pubescence has been reported. Girls treated with cyclophosphamide who have retained ovarian function after completing treatment are at increased risk of developing premature menopause.

Pre-pubescent boys treated with cyclophosphamide develop secondary sexual characteristics normally, but may have oligospermia or azoospermia and increased gonadotropin secretion. Some degree of testicular atrophy may occur. Cyclophosphamide-induced azoospermia is reversible in some patients, though the reversibility may not occur for several years after cessation of therapy.

Geriatric Use

There is insufficient data from clinical studies of cyclophosphamide available for patients 65 years of age and older to determine whether they respond differently than 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 decreased hepatic, renal, or cardiac functioning, and of concomitant disease or other drug therapy.

Renal Impairment

In patients with severe renal impairment, decreased renal excretion may result in increased plasma levels of cyclophosphamide and its metabolites. This may result in increased toxicity. Monitor patients with severe renal impairment (CrCl =10 mL/min to 24 mL/min) for signs and symptoms of toxicity.

Cyclophosphamide and its metabolites are dialyzable although there are probably quantitative differences depending upon the dialysis system being used. In patients requiring dialysis, use of a consistent interval between Cyclophosphamide Injection administration and dialysis should be considered.

Hepatic Impairment

Patients with severe hepatic impairment have reduced conversion of cyclophosphamide to the active 4-hydroxyl metabolite, potentially reducing efficacy.

The alcohol content of Cyclophosphamide Injection should be taken into account when given to patients with hepatic impairment.

OVERDOSAGE

No specific antidote for cyclophosphamide is known.

Overdosage should be managed with supportive measures, including appropriate treatment for any concurrent infection, myelosuppression, or cardiac toxicity should it occur.

Serious consequences of overdosage include manifestations of dose dependent toxicities such as myelosuppression, urotoxicity, cardiotoxicity (including cardiac failure), veno occlusive hepatic disease, and stomatitis.

Patients who received an overdose should be closely monitored for the development of toxicities, and hematologic toxicity in particular.

Cyclophosphamide and its metabolites are dialyzable. Therefore, rapid hemodialysis is indicated when treating any suicidal or accidental overdose or intoxication.

Cystitis prophylaxis with mesna may be helpful in preventing or limiting urotoxic effects with cyclophosphamide overdose.

Please see the full Prescribing information for safety information, and dosing guidelines.

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.

DOCIVYX™

(DOCETAXEL INJECTION)

Indications and Important Safety Information, Including Black Box Warning

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, AND FLUID RETENTION

Treatment-related mortality associated with DOCIVYX is increased in patients with abnormal liver function, in patients receiving higher doses, and in patients with non-small cell lung carcinoma and a history of prior treatment with platinum-based chemotherapy who receive DOCIVYX as a single agent at a dose of 100 mg/m².

Avoid the use of DOCIVYX in patients with bilirubin > upper limit of normal (ULN), or to patients with AST and/or ALT >1.5 x ULN concomitant with alkaline phosphatase >2.5 x ULN. 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. Patients with isolated elevations of transaminase >1.5 x ULN also had a higher rate of febrile neutropenia. Measure bilirubin, AST or ALT, and alkaline phosphatase prior to each cycle of DOCIVYX.

Do not administer DOCIVYX to patients with neutrophil counts of <1500 cells/mm³. Monitor blood counts frequently as neutropenia may be severe and result in infection.

Do not administer DOCIVYX to patients who have a history of severe hypersensitivity reactions to DOCIVYX. Severe hypersensitivity reactions have been reported in patients despite dexamethasone premedication. Hypersensitivity reactions require immediate discontinuation of the DOCIVYX infusion and administration of appropriate therapy.

Severe fluid retention occurred in 6.5% (6/92) of patients despite use of dexamethasone premedication. It was characterized by one or more of the following events: poorly tolerated peripheral edema, generalized edema, pleural effusion requiring urgent drainage, dyspnea at rest, cardiac tamponade, or pronounced abdominal distention (due to ascites).

INDICATIONS

Breast 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.

Non-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.

Prostate Cancer

DOCIVYX in combination with prednisone is indicated for the treatment of patients with metastatic CRPC.

Gastric 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.

Head 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).

IMPORTANT SAFETY INFORMATION CONTRAINDICATION 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.

WARNINGS AND PRECAUTIONS Toxic Deaths Breast Cancer DOCIVYX administered at 100 mg/m² 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/m², 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/m² 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/m² dose in the randomized trials. Among patients who experienced treatment-related mortality at the 75 mg/m² dose level, 3 of 5 patients had an ECOG PS of 2 at study entry. Hepatic 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 x ULN concomitant with alkaline phosphatase >2.5 x ULN. For patients with isolated elevations of transaminase >1.5 x ULN, consider DOCIVYX dose modifications. Measure bilirubin, AST or ALT, and alkaline phosphatase prior to each cycle of DOCIVYX therapy. Hematologic 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/mm³. Avoid retreating patients until platelets recover to a level >100,000 cells/mm³. A 25% reduction in the dose of DOCIVYX is recommended during subsequent cycles following severe neutropenia (<500 cells/mm³) lasting 7 days or more, febrile neutropenia, or a grade 4 infection in a DOCIVYX cycle. Neutropenia (<2000 neutrophils/mm³) occurs in virtually all patients given 60 mg/m² to 100 mg/m² of DOCIVYX and grade 4 neutropenia (<500 cells/mm³) occurs in 85% of patients given 100 mg/m2 and 75% of patients given 60 mg/m². 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/mm³. Febrile neutropenia occurred in about 12% of patients given 100 mg/m² but was very uncommon in patients given 60 mg/m². Hematologic responses, febrile reactions and infections, and rates of septic death for different regimens are dose related. 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. Enterocolitis 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. Hypersensitivity 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. 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. Fluid 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. 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 kg. Among 92 breast cancer patients premedicated with 3-day corticosteroids, moderate fluid retention occurred in 27.2% and severe fluid retention in 6.5%. The median cumulative dose to onset of moderate or severe fluid retention was 819 mg/m². Nine of 92 patients (9.8%) of patients discontinued treatment due to fluid retention: 4 patients discontinued with severe fluid retention; the remaining 5 had mild or moderate fluid retention. The median cumulative dose to treatment discontinuation due to fluid retention was 1021 mg/m². Fluid retention was completely, but sometimes slowly, reversible with a median of 16 weeks from the last infusion of DOCIVYX to resolution (range: 0 to 42+ weeks). Patients developing peripheral edema may be treated with standard measures, e.g., salt restriction, oral diuretic(s). Second Primary Malignancies Second primary malignancies, notably acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), and renal cancer, have been reported in patients treated with docetaxel-containing regimens. These adverse reactions may occur several months or years after docetaxel-containing therapy. Treatment-related AML or MDS has occurred in patients given anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer. In the adjuvant breast cancer trial (TAX316) AML occurred in 3 of 744 patients who received DOCIVYX, doxorubicin and cyclophosphamide (TAC) and in 1 of 736 patients who received fluorouracil, doxorubicin, and cyclophosphamide. In TAC-treated patients, the risk of delayed myelodysplasia or myeloid leukemia requires hematological follow-up. Monitor patients for second primary malignancies. Cutaneous Reactions Localized erythema of the extremities with edema followed by desquamation has been observed. In case of severe skin toxicity, an adjustment in dosage is recommended. The discontinuation rate due to skin toxicity was 1.6% (15/965) for metastatic breast cancer patients. Among 92 breast cancer patients premedicated with 3-day corticosteroids, there were no cases of severe skin toxicity reported and no patient discontinued DOCIVYX due to skin toxicity. Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with docetaxel treatment. Patients should be informed about the signs and symptoms of serious skin manifestations and monitored closely. Permanent treatment discontinuation should be considered in patients who experience SCARs. Neurologic Reactions Severe neurosensory symptoms (e.g., paresthesia, dysesthesia, pain) were observed in 5.5% (53/965) of metastatic breast cancer patients and resulted in treatment discontinuation in 6.1%. When these symptoms occur, dosage must be adjusted. If symptoms persist, treatment should be discontinued. Patients who experienced neurotoxicity in clinical trials and for whom follow-up information on the complete resolution of the event was available had spontaneous reversal of symptoms with a median of 9 weeks from onset (range: 0 to 106 weeks). Severe peripheral motor neuropathy mainly manifested as distal extremity weakness occurred in 4.4% (42/965). Eye Disorders Cystoid macular edema (CME) has been reported in patients treated with DOCIVYX. Patients with impaired vision should undergo a prompt and comprehensive ophthalmologic examination. If CME is diagnosed, DOCIVYX treatment should be discontinued and appropriate treatment initiated. Alternative non-taxane cancer treatment should be considered. Asthenia Severe asthenia has been reported in 14.9% (144/965)of metastatic breast cancer patients but has led to treatment discontinuation in only 1.8%. Symptoms of fatigue and weakness may last a few days up to several weeks and may be associated with deterioration of performance status in patients with progressive disease. Embryo-Fetal Toxicity 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. Based on findings in animal studies and its mechanism of action, DOCIVYX can cause fetal harm when administered to a pregnant woman. DOCIVYX contains alcohol which is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify pregnancy status in females of reproductive potential prior to initiating DOCIVYX. Advise females of reproductive potential to use effective contraception during treatment and for 2 months after the last dose of DOCIVYX. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of DOCIVYX. Alcohol Content Cases of intoxication have been reported with some formulations of docetaxel due to the alcohol content. The alcohol content in a dose of DOCIVYX may affect the central nervous system and should be taken into account for patients in whom alcohol intake should be avoided or minimized. Consideration should be given to the alcohol content in DOCIVYX on the ability to drive or use machines immediately after the infusion. Each administration of DOCIVYX at 100 mg/m² delivers 2.0 g/m² of ethanol. For a patient with a BSA of 2.0 m², this would deliver 4.0 grams of ethanol. Other docetaxel products may have a different amount of alcohol. Tumor Lysis Syndrome Tumor lysis syndrome has been reported with docetaxel. Patients at risk of tumor lysis syndrome (e.g., with renal impairment, hyperuricemia, bulky tumor) should be closely monitored prior to initiating DOCIVYX and periodically during treatment. Correction of dehydration and treatment of high uric acid levels are recommended prior to initiation of treatment. ADVERSE REACTIONS The most serious adverse reactions from DOCIVYX are Toxic Deaths, Hepatic Impairment, Hematologic Effects, Enterocolitis and Neutropenic Colitis, Hypersensitivity Reactions, Fluid Retention, Second Primary Malignancies, Cutaneous Reactions, Neurologic Reactions, Eye Disorders, Asthenia, Alcohol Content. 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. Clinical Trials Experience Adverse events occurring in at least 5% of patients with various tumor types Adverse reactions occurring in breast cancer patients, both treated and untreated with chemotherapy, with normal liver function tests at baseline who were treated with DOCIVYX 100 mg/m²and those occurring in patients with various tumor types who had normal or elevated liver function tests at baseline who were treated with DOCIVYX 100 mg/m²were neutropenia <2000 cells/mm³ (96% all tumor types with normal liver function tests, 96% all tumor types with elevated liver function tests, 99% breast cancer with normal liver function tests, respectively), neutropenia <500 cells/mm³(75%, 88%, 86%, respectively), leukopenia <4000 cells/mm³(96%, 98%, 99%, respectively), leukopenia <1000 cells/mm³(32%, 47%, 44%, respectively), thrombocytopenia <100,000 cells/mm³(8%, 25%, 9%, respectively), anemia <11 g/dL (90%, 92%, 94%, respectively), anemia <8 g/dL (9%, 31%, 8%, respectively), severe febrile neutropenia (11%, 26%, 12%, respectively), infections (severe; 6%, 16%, 6%, respectively), infections (any; 22%, 33%, 22%, respectively), fever in the absence of infection (severe; 2%, 8%, 2%, respectively), fever in the absence of infection (any; 31%, 41%, 35%, respectively), hypersensitivity reactions regardless of premedication (severe; 4%, 10%, 3%, respectively), hypersensitivity reactions regardless of premedication (any; 21%, 20%, 18%, respectively), hypersensitivity reactions with 3-day premedication (sever; 2%, 0%, 2%, respectively), hypersensitivity reactions with 3-day premedication (any; 15%, 33%, 15%, respectively), fluid retention regardless of premedication (severe; 7%, 8%, 9%, respectively), fluid retention regardless of premedication (any; 47%, 39%, 60%, respectively, fluid retention with 3-day premedication (severe; 7%, 33%, 7%, respectively), fluid retention with 3-day premedication (any; 64%, 67%, 64%, respectively), neurosensory (severe; 4%, 0%, 6%, respectively), neurosensory (any; 49%, 34%, 58%, respectively), cutaneous (severe; 5%, 10%, 5%, respectively), cutaneous (any; 48%, 54%, 47%, respectively), nail changes (severe; 3%, 5%, 4%, respectively), nail changes (any; 31%, 23%, 41%, respectively), gastrointestinal (severe; 5%, 5%, 6%, respectively), nausea (39%, 38%, 42%, respectively), vomiting (22%, 23%, 23%, respectively), diarrhea (39%, 33%, 43%, respectively), stomatitis (severe; 6%, 13%, 7%, respectively), stomatitis (any; 42%, 49%, 52%, respectively), alopecia (76%, 62%, 74%, respectively), asthenia (severe; 13%, 25%, 15%, respectively), asthenia (any; 62%, 53%, 66%, respectively), myalgia (severe; 2%, 2%, 2%, respectively), myalgia (any; 19%, 16%, 21%, respectively), arthralgia (9%, 7%, 8%, respectively), and infusion site reactions (4%, 3%, 4%, respectively). Septic death (2%, 5%, 1%, respectively) and non-septic death (1%, 7%, 1%, respectively) also occurred. Monotherapy with DOCIVYX for locally advanced or metastatic breast cancer after failure of prior chemotherapy Hematologic adverse reactions (Grade 3/4) occurring in breast cancer patients previously treated with chemotherapy with normal or elevated liver function tests who were treated with DOCIVYX 100 mg/m² or those with normal liver function tests who were treated with DOCIVYX 60 mg/m² were neutropenia <500 cells/mm³ (84%, 94%, and 75% at 100 mg/m² with normal liver function tests, 100 mg/m² with elevated liver function test, and at 60 mg/m² with normal liver function tests, respectively), thrombocytopenia <20,000 cells/mm³(1%,17%,1%, respectively), infection (7%,33%,0%, respectively), febrile neutropenia by patient (12%,33%,0%, respectively), and febrile neutropenia by course (2%,9%,0%, respectively). Hematologic adverse reactions (any) occurring in breast cancer patients previously treated with chemotherapy with normal or elevated liver function tests who were treated with DOCIVYX 100 mg/m² or those with normal liver function tests who were treated with DOCIVYX 60 mg/m² were neutropenia <2,000 cells/mm³(98%,100%, and 95% at 100 mg/m² with normal liver function tests, 100 mg/m² with elevated liver function tests, and at 60 mg/m² with normal liver function tests, respectively), thrombocytopenia <100,000 cells/mm³(11%,44%,14%, respectively), anemia <11 g/dL (95%,94%,65%, respectively), and infection (23%,39%,1%, respectively). Severe non-hematologic adverse reactions occurring in breast cancer patients previously treated with chemotherapy with normal or elevated liver function tests who were treated with DOCIVYX 100 mg/m² or those with normal liver function tests who were treated with DOCIVYX 60 mg/m² were acute hypersensitivity reaction regardless of premedication (1%,0%, and 0% at 100 mg/m² with normal liver function tests, 100 mg/m² with elevated liver function test, and at 60 mg/m² with normal liver function tests, respectively), fluid retention regardless of premedication (8%,17%,0%, respectively), neurosensory (6%,0%,0%, respectively), cutaneous (5%,17%,0%, respectively), asthenia (17%,22%,0%, respectively), diarrhea (6%,11%, NA, respectively), and stomatitis (8%, 39%, 1%, respectively). Non-hematologic adverse reactions (any) occurring in breast cancer patients previously treated with chemotherapy with normal or elevated liver function tests who were treated with DOCIVYX 100 mg/m² or those with normal liver function tests who were treated with DOCIVYX 60 mg/m² were acute hypersensitivity reaction regardless of premedication (13% ,6%, and 1% at 100 mg/m² with normal liver function tests, 100 mg/m² with elevated liver function test, and at 60 mg/m² with normal liver function tests, respectively), fluid retention regardless of premedication (56%,61%,13, respectively), neurosensory (57%,50%,20%, respectively), myalgia (23%,33%,3%, respectively), cutaneous (45%,61%,31%, respectively), asthenia (65%,44%,66%, respectively), diarrhea (42%,28%,NA, respectively), and stomatitis (53%,67%,19%, respectively). Septic death (2%,6%,1%, respectively), and non-septic death (1%,11%,0%, respectively) also occurred. Monotherapy trial (TAX313) comparing DOCIVYX 60 mg/m², 75 mg/m² and 100 mg/m² in advanced breast cancer The following adverse reactions were associated with increasing docetaxel doses: fluid retention (26%, 38%, and 46% at 60 mg/m², 75 mg/m², and 100 mg/m², respectively), thrombocytopenia (7%,11%,12%, respectively), neutropenia (92%, 94%, 97% respectively), febrile neutropenia (5%,7%,14%, respectively), treatment-related grade 3 or 4 infection (2%, 3%, 7%, respectively) and anemia (87%, 94%, 97%, respectively). Combination therapy with DOCIVYX in the adjuvant treatment of breast cancer Adverse reactions (Grade 3/4) occurring in patients with breast cancer who were treated with DOCIVYX 75 mg/m²every 3 weeks in combination with doxorubicin 50 mg/m²and cyclophosphamide 500 mg/m²(TAX316) were anemia (4%), neutropenia (66%), fever in the absence of infection (1%), infection (4%), thrombocytopenia (2%), hypersensitivity reactions (1%), fluid retention (1%), neuro-cortical (1%), syncope (1%), skin toxicity (1%), nausea (5%), stomatitis (7%), vomiting (4%), diarrhea (4%), constipation (1%), taste perversion (1%), anorexia (2%), abdominal pain (1%), vasodilation (1%), asthenia (11%), myalgia (1%), and arthralgia (1%). Adverse reactions (any) occurring in patients with breast cancer who were treated with DOCIVYX 75 mg/m² every 3 weeks in combination with doxorubicin 50 mg/m²and cyclophosphamide 500 mg/m²(TAX316) were anemia (92%), neutropenia (71%), fever in the absence of infection (47%), infection (39%), thrombocytopenia (39%), febrile neutropenia (25%), neutropenic infection (12%), hypersensitivity reactions (13%), lymphedema (4%), fluid retention (35%), peripheral edema (27%), weight gain (13%), neuropathy sensory (26%), neuro-cortical (5%), neuropathy motor (4%), neuro-cerebellar (2%), syncope (2%), alopecia (98%), skin toxicity (27%), nail disorders (19%), nausea (81%), stomatitis (69%), vomiting (45%), diarrhea (35%), constipation (34%), taste perversion (28%), anorexia (22%), abdominal pain (11%), amenorrhea (62%), cough (14%), cardiac dysrhythmias (8%), vasodilation (27%), hypotension (2%), phlebitis (1%), asthenia (81%), myalgia (27%), arthralgia (19%), lacrimation disorder (11%), and conjunctivitis (5%). Monotherapy with DOCIVYX for unresectable, locally advanced or metastatic non-small cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy Adverse reactions (Grade 3/4 or severe ) occurring in patients with locally advanced or metastatic NSCLC and a history of prior treatment with platinum-based chemotherapy who were treated with DOCIVYX 75 mg/m² monotherapy were neutropenia (65%), leukopenia (49%), thrombocytopenia (3%), anemia (9%), febrile neutropenia (6%), infection (10%), hypersensitivity reactions (3%), fluid retention (3%), neurosensory (2%), neuromotor (5%), skin (1%), nausea (5%), vomiting (3%), diarrhea (3%), asthenia (18%), stomatitis (2%), pulmonary (21%), nail disorder (1%), taste perversion (1%), and treatment related mortality (3%). Adverse reactions (any) occurring in patients with locally advanced or metastatic NSCLC and a history of prior treatment with platinum-based chemotherapy who were treated with DOCIVYX 75 mg/m² monotherapy were neutropenia (84%), leukopenia (84%), thrombocytopenia (8%), anemia (91%), infection (34%), hypersensitivity reactions (6%), fluid retention (34%), neurosensory (23%), neuromotor (16%), skin (20%), nausea (34%), vomiting (22%), diarrhea (23%), alopecia (56%), asthenia (53%), stomatitis (26%), pulmonary (41%), nail disorder (11%), myalgia (6%), arthralgia (3%), and taste perversion (6%). Combination therapy with DOCIVYX in chemotherapy-naïve advanced unresectable or metastatic NSCLC Adverse reactions (Grade 3/4 or severe) occurring in patients with unresectable stage IIIB or IV NSCLC and no history of prior chemotherapy who were treated with DOCIVYX 75 mg/m² in combination with cisplatin 75 mg/m² (TAX326) were neutropenia (74%), thrombocytopenia (3%), anemia (7%), infection (8%), fever in the absence of infection (<1%), hypersensitivity reaction (3%), fluid retention (2%), pleural effusion (2%), peripheral edema (<1%), weight gain (<1%), neurosensory (4%), neuromotor (3%), skin (<1%), nausea (10%), vomiting (8%), diarrhea (7%), anorexia (5%), stomatitis (2%), alopecia (<1%), asthenia (12%), nail disorders (<1%), and myalgia (<1%). Adverse reactions (any) occurring in patients with advanced unresectable or metastatic NSCLC and no history of prior chemotherapy who were treated with DOCIVYX 75 mg/m² in combination with cisplatin 75 mg/m² (TAX326) were neutropenia (91%), febrile neutropenia (5%), thrombocytopenia (15%), anemia (89%), infection (35%), fever in the absence of infection (33%), hypersensitivity reaction (12%), fluid retention (54%), pleural effusion (23%), peripheral edema (34%), weight gain (15%), neurosensory (47%), neuromotor (19%), skin reaction (16%), nausea (72%), vomiting (55%), diarrhea (47%), anorexia (42%), stomatitis (24%), alopecia (75%), asthenia (74%), nail disorders (14%), and myalgia (18%). Combination therapy with DOCIVYX in patients with castration-resistant prostate cancer (CRPC) Adverse reactions (Grade 3/4) occurring in patients with CRPC who were treated with DOCIVYX 75 mg/m² every 3 weeks in combination with prednisone 5 mg orally twice daily (TZX327) were anemia (5%), neutropenia (32%), thrombocytopenia (1%), infection (6%), allergic reactions (1%), fluid retention (1%), neuropathy sensory (2%), neuropathy motor (2%), nausea (3%), diarrhea (2%), stomatitis/pharyngitis (1%), vomiting (2%), anorexia (1%), dyspnea (3%), fatigue (5%), tearing (1%), and arthralgia (1%). Adverse reactions (any) occurring in patients with CRPC who were treated with DOCIVYX 75 mg/m² every 3 weeks in combination with prednisone 5 mg orally twice daily (TZX327) were anemia (67%), neutropenia (41%), thrombocytopenia (3%), febrile neutropenia (3%), infection (32%), epistaxis (6%), allergic reactions (8%), fluid retention (24%), weight gain (8%), peripheral edema (18%), neuropathy sensory (30%), neuropathy motor (7%), rash or desquamation (6%), alopecia (65%), nail changes (30%), nausea (41%), diarrhea (32%), stomatitis/pharyngitis (20%), taste disturbance (18%), vomiting (17%), anorexia (17%), cough (12%), dyspnea (15%), cardiac left ventricular function (10%), fatigue (53%), myalgia (15%), tearing (10%), and arthralgia (8%). Combination therapy with DOCIVYX in gastric adenocarcinoma Adverse reactions (Grade 3/4) occurring in patients with advanced gastric adenocarcinoma and no history of prior chemotherapy for advanced disease who were treated with DOCIVYX 75 mg/m² in combination with cisplatin 75 mg/m² and fluorouracil 750 mg/m² include anemia (18%), neutropenia (82%), fever in the absence of infection (2%), thrombocytopenia (8%), infection (16%), allergic reactions (2%), lethargy (21%), neurosensory (8%), neuromotor (3%), dizziness (5%), alopecia (5%), rash/itch (1%), nausea (16%), vomiting (15%), anorexia (13%), stomatitis (21%), diarrhea (20%), constipation (2%), esophagitis/dysphagia/odynophagia (2%), gastrointestinal pain/cramping (2%), and cardiac dysrhythmias (2%). Adverse reactions (any) occurring in patients with advanced gastric adenocarcinoma and no history of prior chemotherapy for advanced disease who were treated with DOCIVYX 75 mg/m² in combination with cisplatin 75 mg/m² and fluorouracil 750 mg/m² were anemia (97%), neutropenia (96%), fever in the absence of infection (36%), thrombocytopenia (26%), infection (29%), febrile neutropenia (16%), neutropenic infection (16%), allergic reactions (10%), fluid retention (15%), edema (13%), lethargy (63%), neurosensory (38%), neuromotor (9%), dizziness (16%), alopecia (67%), rash/itch (12%), nail changes (8%), skin desquamation (2%), nausea (73%), vomiting (67%), anorexia (51%), stomatitis (59%), diarrhea (78%), constipation (25%), esophagitis/dysphagia/odynophagia (16%), gastrointestinal pain/cramping (11%), cardiac dysrhythmias (5%), myocardial ischemia (1%), tearing (8%), and altered hearing (6%). Combination therapy with DOCIVYX in head and neck cancer Adverse reactions (Grade 3/4) occurring in patients with squamous cell carcinoma of the head and neck (SCCHN) who received induction chemotherapy with DOCIVYX 75 mg/m² in combination with cisplatin 75 mg/m² and fluorouracil 750 mg/m² followed by radiotherapy (TAX323) or chemoradiotherapy (TAX 324), were neutropenia (76%, 84% with combination therapy followed by radiotherapy [TAX323] or chemoradiotherapy [TAX324], respectively), anemia (9%,12%, respectively), thrombocytopenia (5%, 4%, respectively), infection (9%,6%, respectively), cancer pain (5%,9%, respectively), lethargy (3%,5%, respectively), fever in the absence of infection (1%,4%, respectively), myalgia (1%,0%, respectively), weight loss (1%,2%, respectively), fluid retention (0%,1%, respectively), edema (0%,1%, respectively), dizziness (0%,4%, respectively), neurosensory (1%,1%, respectively), altered hearing (0%,1%, respectively), neuromotor (1%,0%, respectively), alopecia (11%,4%, respectively), desquamation (1%,0%, respectively), nausea (1%,14%, respectively), stomatitis (4%,21%, respectively), vomiting (1%,8%, respectively), diarrhea (3%,7%, respectively), constipation (1%,1%, respectively), anorexia (1%,12%, respectively), esophagitis/dysphagia/odynophagia (1%,13%, respectively), gastrointestinal pain/cramping (1%,5%, respectively), heartburn (0%,2%, respectively), gastrointestinal bleeding (2%,1%, respectively), cardiac dysrhythmia (2%,3%, respectively), venous (2%,2%, respectively), and ischemia myocardial (2%,1%, respectively). Adverse reactions (any) occurring in patients with SCCHN who received induction chemotherapy with DOCIVYX 75 mg/m² in combination with cisplatin 75 mg/m² and fluorouracil 750 mg/m² followed by radiotherapy (TAX323) or chemoradiotherapy (TAX 324), respectively, were neutropenia (93%, 95% with combination therapy followed by radiotherapy [TAX323] or chemoradiotherapy [TAX324], respectively), anemia (89%,90%, respectively), thrombocytopenia (24%,28%, respectively), infection (27%,23%, respectively), febrile neutropenia (5%,12%, respectively), neutropenic infection (14%,12%, respectively), cancer pain (21%,17%, respectively), lethargy (41%,61%, respectively), fever in the absence of infection (32%,30%, respectively), myalgia (10%,7%, respectively), weight loss (21%,14%, respectively), allergy (6%,2%, respectively), fluid retention (20%,13%, respectively), edema (13%,12%, respectively), weight gain (6%,0%, respectively), dizziness (2%,16%, respectively), neurosensory (18%,14%, respectively), altered hearing (6%,13%, respectively), neuromotor (2%,9%, respectively), alopecia (81%,68%, respectively), rash/itch (12%,20%, respectively), dry skin (6%,5%, respectively), desquamation (4%,2%, respectively) nausea (47%,77%, respectively), stomatitis (43%,66%, respectively), vomiting (26%,56%, respectively), diarrhea (33%, 48%, respectively), constipation (17%,27%, respectively), anorexia (16%,40%, respectively), esophagitis/dysphagia/odynophagia (13%,25%, respectively), taste, sense of smell altered (10%,20%, respectively), gastrointestinal pain/cramping (8%,15%, respectively), heartburn (6%,13%, respectively), gastrointestinal bleeding (4%,5%, respectively), cardiac dysrhythmia (2%,6%, respectively), venous (3%,4%, respectively), ischemia myocardial (2%,2%, respectively), tearing (2%,2%, respectively), and conjunctivitis (1%,1%, respectively). 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. USE IN SPECIFIC POPULATIONS Pregnancy 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. Based on findings in animal studies and its mechanism of action, DOCIVYX can cause fetal harm when administered to a pregnant woman. DOCIVYX contains alcohol which is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development. Lactation There is no information regarding the presence of docetaxel in human milk, or on its effects on milk production or the breastfed child. Advise women not to breastfeed during treatment with DOCIVYX and for 1 week after the last dose. Females and Males of Reproductive Potential Verify pregnancy status in females of reproductive potential prior to initiating DOCIVYX. Advise females of reproductive potential to use effective contraception during treatment and for 2 months after the last dose of DOCIVYX. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of DOCIVYX. Based on findings in animal studies, DOCIVYX may impair fertility in males of reproductive potential. 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. Geriatric Use Dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in elderly patients. Non-small Cell Lung Cancer Patients ≥65 years of age with non-small cell lung cancer treated with DOCIVYX plus cisplatin were more likely to experience diarrhea (55%), infections (42%), peripheral edema (39%) and stomatitis (28%) compared to patients less than the age of 65 administered the same treatment (43%, 31%, 31% and 21%, respectively). In patients ≥ 65 years of age treated with DOCIVYX+cisplatin, diarrhea (55%), peripheral edema (39%) and stomatitis (28%) were observed more frequently than in the vinorelbine+cisplatin group (diarrhea 24%, peripheral edema 20%, stomatitis 20%). When DOCIVYX was combined with carboplatin for the treatment of chemotherapy-naive, advanced non-small cell lung carcinoma, patients ≥65 years (28%) experienced higher frequency of infection compared to similar patients treated with DOCIVYX+cisplatin, and a higher frequency of diarrhea, infection and peripheral edema than elderly patients treated with vinorelbine+cisplatin. Prostate Cancer In patients ≥65 years of age with prostate cancer treated with DOCIVYX every three weeks plus prednisone, the following treatment-emergent adverse reactions occurred at rates ≥10% higher compared to younger patients: anemia (71% vs 59%), infection (37% vs 24%), nail changes (34% vs 23%), anorexia (21% vs 10%), weight loss (15% vs 5%), respectively. Breast Cancer and Head and Neck Cancer The number of patients ≥65 years of age with breast cancer patients who received DOCIVYX in combination with doxorubicin and cyclophosphamide and the number of head and neck cancer patients who received DOCIVYX in combination with cisplatin and fluorouracil were not sufficient to determine whether elderly and younger patients responded differently. Gastric Cancer The number of patients ≥65 years of age with gastric cancer treated with DOCIVYX in combination with cisplatin and fluorouracil was not sufficient to determine whether they respond differently from younger patients. However, the incidence of serious adverse reactions was higher in patients ≥65 years of age compared to younger patients. The incidence of the following adverse reactions (all grades, regardless of relationship): lethargy, stomatitis, diarrhea, dizziness, edema, febrile neutropenia/neutropenic infection occurred at rates ≥10% higher in patients who were 65 years of age or older compared to younger patients. Elderly patients treated with TCF should be closely monitored. Hepatic Impairment Avoid DOCIVYX in patients with bilirubin >ULN and patients with AST and/or ALT >1.5 × ULN concomitant with alkaline phosphatase >2.5 × ULN. The alcohol content of DOCIVYX should be taken into account when given to patients with hepatic impairment. Please see the full Prescribing information for safety information, including BOXED WARNING, and dosing guidelines. 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.

C-305-0224.