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Navelbine

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Navelbine

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Myelosuppression

Myelosuppression manifested by neutropenia, anemia and thrombocytopenia occur with NAVELBINE® as a single agent and in combination with cisplatin [see ADVERSE REACTIONS]. Neutropenia is the major dose-limiting toxicity with NAVELBINE. Grade 3-4 neutropenia occurred in 53% of patients treated with NAVELBINE at 30 mg/m² per week. Dose adjustment due to myelosuppression occurred in 51% of patients (Study 2). In clinical trials with NAVELBINE administered at 30 mg/m² per week, neutropenia resulted in hospitalizations for pyrexia and/or sepsis in 8% of patients. Death due to sepsis occurred in 1% of patients. Neutropenia nadirs occur between 7 and 10 days after dosing with neutropenia count recovery usually occurring within the following 7 to 14 days.

Monitor complete blood counts prior to each dose of NAVELBINE. Do not administer NAVELBINE to patients with neutrophil counts < 1,000 cells/mm³. Adjustments in the dosage of NAVELBINE should be based on neutrophil counts obtained on the day of treatment [see DOSAGE AND ADMINISTRATION].

Hepatic Toxicity

Drug-induced liver injury manifest by elevations of aspartate aminotransferase and bilirubin can occur in patients receiving NAVELBINE alone or in combination with cytotoxic agents. Assess hepatic function prior to initiation of NAVELBINE and periodically during treatment. Reduce the dose of NAVELBINE for patients who develop elevations in total bilirubin > 2 times upper limit of normal [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

Severe Constipation And Bowel Obstruction

Severe and fatal paralytic ileus, constipation, intestinal obstruction, necrosis, and perforation occur with NAVELBINE administration. Institute a prophylactic bowel regimen to mitigate potential constipation, bowel obstruction and/or paralytic ileus, considering adequate dietary fiber intake, hydration, and routine use of stool softeners.

Extravasation And Tissue Injury

Extravasation of NAVELBINE can result in severe irritation, local tissue necrosis and/or thrombophlebitis. If signs or symptoms of extravasation occur, immediately stop administration of NAVELBINE and institute recommended management procedures. [see DOSAGE AND ADMINISTRATION and ADVERSE REACTION]

Neurologic Toxicity

Sensory and motor neuropathies, including severe neuropathies, occur in patients receiving NAVELBINE. Monitor patients for new or worsening signs and symptoms of neuropathy such as paresthesia, hyperesthesia, hyporeflexia and muscle weakness while receiving NAVELBINE. Discontinue NAVELBINE for NCI CTCAE Grade 2 or greater neuropathy [see DOSAGE AND ADMINISTRATION and ADVERSE REACTION]

Pulmonary Toxicity And Respiratory Failure

Pulmonary toxicity, including severe acute bronchospasm, interstitial pneumonitis, acute respiratory distress syndrome (ARDS) occurs with use of NAVELBINE. Interstitial pneumonitis and ARDS included fatalities. The mean time to onset of interstitial pneumonitis and ARDS after vinorelbine administration was one week (range 3 to 8 days) [see ADVERSE REACTIONS].

Interrupt NAVELBINE in patients who develop unexplained dyspnea, or have any evidence of pulmonary toxicity. Permanently discontinue NAVELBINE for confirmed interstitial pneumonitis or ARDS.

Embryo-Fetal Toxicity

NAVELBINE can cause fetal harm when administered to a pregnant woman. In animal reproduction studies in mice and rabbits, embryo and fetal toxicity were observed with administration of vinorelbine at doses approximately 0.33 and 0.18 times the human therapeutic dose, respectively. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during therapy with NAVELBINE [see Use In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

The carcinogenic potential of NAVELBINE has not been studied. Vinorelbine has been shown to affect chromosome number and possibly structure in vivo (polyploidy in bone marrow cells from Chinese hamsters and a positive micronucleus test in mice). It was not mutagenic in the Ames test and gave inconclusive results in the mouse lymphoma TK Locus assay.

Vinorelbine did not affect fertility to a statistically significant extent when administered to rats on either a once-weekly (9 mg/m², approximately one third the human dose) or alternate-day schedule (4.2 mg/m², approximately 0.14 times the human recommended dose) prior to and during mating. In male rats, administration of vinorelbine twice weekly for 13 or 26 weeks at dose levels of 2.1 and 7.2 mg/m² (approximately 0.07 and 0.24 times the recommended human dose), respectively, resulted in decreased spermatogenesis and prostate/seminal vesicle secretion.

Use In Specific Population

Pregnancy

Pregnancy Category D

Risk Summary

NAVELBINE can cause fetal harm when administered to a pregnant woman. In animal reproduction studies in mice and rabbits, embryo and fetal toxicity were observed with administration of vinorelbine at doses approximately 0.33 and 0.18 times the human therapeutic dose, respectively. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

Animal Data

In a mouse embryofetal development study, administration of a single dose of vinorelbine at a dose level of 9 mg/m² or greater (approximately 0.33 times the recommended human dose based on body surface area) was embryotoxic and fetotoxic. Vinorelbine was embryotoxic and fetotoxic to pregnant rabbits when administered every 6 days during the period of organogenesis at doses of 5.5 mg/m² (approximately 0.18 times the recommended human dose based on body surface area) or greater. At doses that did not cause maternal toxicity in either species, vinorelbine administration resulted in reduced fetal weight and delayed ossification.

Nursing Mothers

It is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from vinorelbine, a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of NAVELBINE in pediatric patients have not been established. Results from a single-arm study of NAVELBINE administered at the dose of 33.75 mg/m² (for 35 patients) or at the dose of 30mg/m² (for 11 patients) every week during 6 weeks followed by 2 weeks of rest was evaluated (courses of 8 weeks). Forty-six patients age 1 to 25 (median 11 years) with recurrent solid malignant tumors, including rhabdomyosarcoma or undifferentiated sarcoma (N=21 patients), neuroblastoma (N= 4 patients), and central nervous system (CNS) tumors (N=21 patients) were enrolled. The most significant grade 3 or 4 hematological adverse reactions were neutropenia (70%) and anemia (33%). The most significant grade 3 or 4 nonhematological toxicity adverse reactions were motor (15%) or cranial (13%) neuropathy, hypoxia (13%) and dyspnea (11%). Objective tumor response was observed in 2 out of 21 patients with rhabdomyosarcoma or undifferentiated sarcoma. No objective tumor response was observed in patients with CNS tumors (N=21) or neuroblastoma (N=4).

Geriatric Use

Of the 769 number of patients who received NAVELBINE alone and NAVELBINE in combination with Cisplatin in studies 1, 2 and 3, 247 patients were 65 years of age or older. No overall differences in safety, efficacy and pharmacokinetic parameters were observed between these patients and younger patients. [see CLINICAL PHARMACOLOGY].

Hepatic Impairment

The influence of hepatic impairment on the pharmacokinetics of NAVELBINE has not been evaluated, but the liver plays an important role in the metabolism of NAVELBINE. Elevations of aspartate aminotransferase occur in > 60% of the patients receiving NAVELBINE alone (6% Grade 3-4). Therefore, exercise caution in patients with hepatic impairment. Reduce the dose of NAVELBINE for patients with bilirubin elevation [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Females And Males Of Reproductive Potential

Contraception

Females

NAVELBINE can cause fetal harm when administered to a pregnant woman [see Use In Specific Populations]. Advise female patients of reproductive potential to use highly effective contraception during therapy with NAVELBINE.

Males

NAVELBINE may damage spermatozoa [see Nonclinical Toxicology]. Males with female sexual partners of reproductive potential should use highly effective contraception during and for 3 months after therapy with NAVELBINE.

Fertility

Males

Based on animal findings, NAVELBINE may cause decreased fertility in males [see Nonclinical Toxicology]

Last reviewed on RxList: 4/7/2014
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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