Professional Drug Information > Navelbine

Vinorelbine (Systemic)

VA CLASSIFICATION
Primary: AN900

Commonly used brand name(s): Navelbine.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antineoplastic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.


Accepted

Carcinoma, lung, non–small cell (treatment)—Vinorelbine is indicated, as a single agent or in combination with cisplatin, for first-line treatment of ambulatory patients with unresectable, advanced non–small cell lung carcinoma (NSCLC) ^{{01} {02} {09}}. Vinorelbine is indicated as a single agent in Stage IV NSCLC and in combination with cisplatin in Stage III or IV NSCLC ^{{01} {02} {05}}.

[Carcinoma, breast (treatment)]—Vinorelbine is indicated for the treatment of patients with metastatic breast cancer who did not respond to standard first-line chemotherapy for metastatic disease ^{02}. Vinorelbine is also indicated for the treatment of patients with metastatic breast cancer who have relapsed within 6 months of anthracycline-based adjuvant therapy ^{02}.

[Carcinoma, cervical (treatment)]¹—Vinorelbine is indicated as reasonable medical therapy at some point in the treatment of cervical carcinoma.^{{28}{29}{30}{31}{32}}

[Carcinoma, ovarian, epithelial (treatment) ]¹—Vinorelbine is indicated as reasonable medical therapy at some point in the treatment of epithelial ovarian carcinoma.^{{33}{34}{35}{36}{37}{38}{39}{40}{41}}

Acceptance not established
Use of vinorelbine for the treatment of non-Hodgkin's lymphoma has not been established.^{{42}{43}{44}{45}{46}{47}}

Use of vinorelbine for the treatment of hormone-refractory prostate carcinoma has not been established,^{{48}{49}{50}{51}{52}{53}{54}{55}{56}{57}} due to insufficient data supporting efficacy.^{{80}{81}{82}{83}{84}{85}{86}{87}{88}{89}{90}{91}{92}{93}}

Note: The USP medical experts chose to not include recurrent, untreated/unresectable, and/or metastatic squamous cell carcinoma of the head and neck as an indication for vinorelbine. Vinorelbine is appropriate for use in the treatment of this indication only in a clinical trial setting.^{{59}{60}{61}{62}{63}{64}{65}{66}{67}{68}{69}{70}{71}{72}{73}{74}{75}{76}{77}{78}{79}}

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Note: Vinorelbine pharmacokinetics were analyzed in preclinical animal studies and in patients enrolled in disparate clinical trials ^{05}. Concentrations of vinorelbine and its metabolites in biological fluids have been determined by measuring total radioactivity, by radioimmunoassay, and by high-performance liquid chromatography (HPLC) ^{03}. Most of the early studies involved the total-radioactivity assay, which measures both unchanged vinorelbine and all metabolites that retain the labeled moiety ^{03}. The total-radioactivity assay is highly sensitive but lacks the specificity needed in pharmacokinetic studies ^{03}. Radioimmunoassay was primarily used in animal studies and in some early clinical studies ^{03}. Although radioimmunoassay is more specific than measuring total radioactivity, there is cross-sensitivity with metabolites of the vindoline ring structure ^{03}. Three HPLC methods were developed for analyzing vinorelbine ^{03}. HPLC has complete specificity for the parent drug and allows for measurement of its metabolites ^{03}. Therefore, clinical studies in which HPLC is used are thought to provide the most valid pharmacokinetic estimates for vinorelbine ^{{03} {05}}.


Physicochemical characteristics:
Source—
    Vinorelbine is a semisynthetic vinca alkaloid ^{{01} {08} {11} {21}}, derived from vinblastine ^{13}. Vinorelbine differs in structure from other vinca alkaloids in that it contains an eight-member catharanthine ring structure, whereas vincristine and vinblastine contain a nine-member catharanthine ring structure ^{{05} {21}}.
Molecular weight—
    1079.13 ^{24}

Mechanism of action/Effect:

Vinca alkaloids appear to exert their antitumor activity by binding to tubulin with high affinity ^{{03} {10} {21}}. Two types of tubulin, alpha and beta, exist as dimers that polymerize to form microtubules, of which many cellular structures, including the mitotic spindle, are constituted ^{03}. The cellular functions of microtubules include neurotransmission and mitosis ^{03}. Vinca alkaloids are cell cycle–specific agents that arrest mitosis by interfering with microtubule assembly and inducing depolarization of microtubules ^{{01} {02} {03} {10} {13} {21}}. Like other vinca alkaloids, vinorelbine may also interfere with amino acid, cyclic adenosine monophosphate (cAMP), and glutathione metabolism; with calmodulin-dependent calcium-transport–adenosinetriphosphatase activity; with cellular respiration; and with nucleic acid and lipid biosynthesis ^{{01} {02} {03}}.

All vinca alkaloids are thought to have slightly different mechanisms of action due in part to differences in their interaction with microtubule-associated proteins, which are believed to modify the interaction of vinca alkaloids with tubulin ^{03}. At least two sites of vinca alkaloid fixation on tubulin have been reported: one site with high affinity, which is responsible for depolymerization activity, and one site with low affinity, which induces unwinding of microtubules and spiral formation ^{03}. Researchers found that vinorelbine was as active as vincristine and vinblastine in inducing the assembly of tubulin in vitro but was uniquely inefficient in causing spiral formation ^{03}. This observation led to the hypothesis that vinorelbine may have a mechanism of action differing slightly from that of other vinca alkaloids and may be potentially less toxic ^{03}.

Vinorelbine appears to have selective activity against mitotic microtubules ^{03}. Researchers compared the effect of vinorelbine, vinblastine, and vincristine on mitotic and axonal microtubules in postimplantation mouse embryos at the earliest stage of neuronal development ^{03}. Mitotic microtubule activity appeared to be correlated with antitumor activity, while axonal microtubule activity was thought to be correlated with neurotoxicity ^{03}. At low concentrations (2 micromolar), vincristine, vinblastine, and vinorelbine inhibited spindle assembly by arresting cell division at metaphase ^{03}. At higher concentrations (25 micromolar), only vinorelbine arrested mitosis at prophase ^{03}. Depolymerization of axonal microtubules was concentration-dependent and occurred at markedly higher concentrations of vinorelbine (40 micromolar) than of vincristine (5 micromolar) or vinblastine (30 micromolar); presumably this accounts for the decreased neurotoxicity of vinorelbine ^{03}. Further research is needed to describe clearly the interaction of vinorelbine with tubulin and to determine the clinical relevance of this activity ^{03}.

Distribution:

Preclinical tissue distribution studies in mice, rats, and monkeys showed that radiolabeled vinorelbine was widely distributed in the body after intravenous administration ^{04}. High amounts of radioactivity were localized in the spleen, liver, kidneys, lungs, and thymus; moderate amounts in the heart and muscles; and minimal amounts in fat, the brain, and bone marrow ^{{03} {04}}.

In human hepatocytes, the degree of cellular accumulation of the vinca alkaloids increases with increasing lipophilicity of the compound ^{04}. Since vinorelbine is one of the most lipid-soluble vinca alkaloids, there is rapid uptake and extensive distribution in cells ^{04}. Measurements in human lung tissue show that vinorelbine has up to a 300-fold greater concentration in lung tissue than in serum ^{04}.

Protein binding:

Vinorelbine is highly bound to platelets and lymphocytes ^{{01} {04}}, and is also bound to alpha ₁-acid glycoprotein, albumin, and lipoproteins ^{04}. In one study in 24 cancer patients, serum binding of vinorelbine ranged from 79.6 to 91.2% ^{04}. The fraction of unbound vinorelbine averaged 0.135 (range 0.088 to 0.204) ^{{03} {04}}. Because of high binding to platelets, the fraction bound in blood was 98.3% ^{04}. Concurrent administration of other anticancer agents is unlikely to cause displacement of vinorelbine from its binding sites in serum ^{04}. In control serum, vinorelbine binding (85.2%) was not significantly different from binding in the presence of 5-fluorouracil (87.4%), doxorubicin (85%), or cisplatin (85.6%) ^{04}.

Biotransformation:

Hepatic ^{{01} {02} {04}}. Metabolism of vinorelbine was initially suggested by in vitro studies that used human hepatic subcellular fractions and identified two metabolites ^{04}. Radiochromatography of urine and fecal samples found at least three unidentified vinorelbine metabolites after intravenous and oral administration of the agent to cancer patients ^{04}. An HPLC method was developed for the measurement of two likely vinorelbine metabolites, vinorelbine N-oxide and deacetylvinorelbine ^{04}. Although vinorelbine N-oxide appears to be inactive, evidence indicates that deacetylvinorelbine possesses pharmacologic activity similar to that of vinorelbine ^{04}. However, this finding may have minimal clinical significance, since a pharmacokinetics study in 20 patients who received intravenous vinorelbine revealed no vinorelbine N-oxide in serum or urine and no deacetylvinorelbine in serum ^{04}. A small amount of deacetylvinorelbine, however, was found in urine ^{04}.

Half-life:

There is a prolonged terminal phase due to relatively slow efflux of vinorelbine from peripheral compartments, which results in a long terminal-phase half-life, with average value ranging from 27.7 to 43.6 hours ^{{01} {04}}.

Elimination:
    Preclinical animal studies indicated that vinorelbine and its metabolites are excreted in the bile ^{04}. Significant amounts of vinorelbine and metabolites were found in the feces of all species studied and in the bile of cannulated rats after intravenous administration of vinorelbine ^{04}. Researchers used an HPLC method to study the biliary excretion of vinorelbine in micropigs following administration of doses comparable to those used in humans and found that 25.8% of the vinorelbine dose was excreted unchanged in the bile ^{04}. Low amounts of deacetylvinorelbine (< 5%) were found, and treatment of urine with beta-glucuronidase did not indicate glucuronidation of vinorelbine ^{04}. Most likely, biliary excretion also occurs in humans, since, as mentioned above, a large percentage of radiolabeled vinorelbine administered intravenously is eliminated in the feces ^{04}.


Precautions to Consider

Carcinogenicity

Carcinogenicity studies with vinorelbine have not been done ^{01}.

Mutagenicity

In vivo studies found that vinorelbine affected chromosome number and possibly structure (polyploidy in bone marrow cells from Chinese hamsters and a positive micronucleus test in mice) ^{{01} {21}}. Results of the Ames mutagenicity test were negative ^{01} and results were inconclusive in the mouse lymphoma TK Locus assay ^{01}.

Pregnancy/Reproduction
Fertility—
Studies in rats given either 9 mg per square meter of body surface area (mg/m ²) (approximately one third the human dose) once a week or 4.2 mg/m ² (approximately one seventh the human dose) every other day, prior to and during mating, found no significant effect on fertility ^{01}. However, studies in male rats given 2.1 and 7.2 mg/m ² (approximately one fifteenth and one fourth the human dose, respectively) biweekly for 13 or 26 weeks found decreased spermatogenesis and prostate/seminal vesicle secretion ^{01}.

Pregnancy—
Studies have not been done in humans ^{{01} {02}}.

Vinorelbine has been shown to be embryotoxic and/or fetotoxic in animals ^{{01} {02} {21}}; nonmaternotoxic doses of vinorelbine caused a reduction in fetal weight and a delay in ossification ^{01}. However, vinorelbine has not been shown to be teratogenic ^{21}. Women of childbearing potential should be informed about the potential hazard to the fetus if they become pregnant during vinorelbine therapy ^{01}. They should also be advised to avoid becoming pregnant during vinorelbine therapy ^{01}.

FDA Pregnancy Category D ^{01}.

Breast-feeding

It is not known whether vinorelbine is distributed into breast milk ^{{01} {02}}. However, because of vinorelbine's potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued in women receiving vinorelbine therapy ^{{01} {02}}.

Pediatrics

Appropriate studies on the relationship of age to the effects of vinorelbine have not been performed in the pediatric population. Safety and efficacy in children have not been established ^{{01} {02}}.


Geriatrics


Approximately one third of the patients enrolled in the North American clinical trials of vinorelbine were over the age of 65 years ^{05}. Although this subset of patients did experience a slight increase in grades 3 and 4 leukopenia and granulocytopenia compared with patients under 65 years of age, the overall safety profile and antitumor efficacy were not significantly different for the older people ^{05}. Furthermore, examination of pharmacokinetic parameters from the clinical trials did not suggest any differences in drug metabolism in older patients ^{05}. As a result, no specific dosage adjustments are recommended for geriatric patients ^{05}. The safety profile of vinorelbine suggests that vinorelbine may be particularly well suited to elderly patients, as this patient population is typically intolerant of severe side effects ^{{05} {06}}.


Dental

The leukopenic and thrombocytopenic effects of vinorelbine may result in an increased incidence of certain microbial infections of the mouth, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Blood dyscrasia–causing medications (see Appendix II )    (leukopenic effects of vinorelbine may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of vinorelbine, if necessary, should be based on blood count ^{25})


» Bone marrow depressants, other (see Appendix II ) or
Radiation therapy    (concurrent use may increase the bone marrow depressant effect of these medications and radiation therapy ^{25})


Cisplatin    (although the pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin, the incidence of toxicities, specifically granulocytopenia, with the combination of vinorelbine and cisplatin is significantly higher than with single-agent vinorelbine ^{{01} {02}})


» Mitomycin    (acute pulmonary reactions have been reported with vinorelbine used in conjunction with mitomycin; vinorelbine should be administered with caution in combination with mitomycin ^{{01} {02}})


» Paclitaxel    (concomitant or sequential use may result in neuropathy; routine monitoring for symptoms of neuropathy is recommended ^{{01} {27}})


Vaccines, killed virus    (because normal defense mechanisms may be suppressed by vinorelbine therapy, the patient's antibody response to the vaccine may be decreased ^{25}. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year ^{25})


» Vaccines, live virus    (because normal defense mechanisms may be suppressed by vinorelbine therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the vinorelbine therapy ^{25}. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year ^{25}. Patients with leukemia in remission should not receive live virus vaccine until at least 3 months after their last chemotherapy ^{{25} {26}}. Immunization with oral poliovirus vaccine should also be postponed in persons in close contact with the patient, especially family members ^{{25} {26}})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase and
Aspartate aminotransferase (AST [SGOT])    (values may be increased ^{{06} {07}})


Bilirubin, serum    (concentrations may be increased ^{{06} {07}})


Note: Transient increases in alanine aminotransferase and aspartate aminotransferase values were reported in approximately 50% of patients, but patients with elevated liver enzymes values were typically asymptomatic and did not require discontinuation of therapy ^{06}. A somewhat greater effect was observed on total bilirubin concentrations, with 6% of patients developing concentrations of grade 3 or 4 severity ^{06}. Although vinorelbine treatment may have contributed to these increases in bilirubin concentrations, these abnormalities also may be related to disease progression in the liver ^{06}.


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression    (administration of vinorelbine is not recommended if pretreatment granulocyte counts are less than 1000 cells per cubic millimeter ^{01}; as with other vinca alkaloids, vinorelbine should not be used in patients who have drug-induced severe granulocytopenia or severe thrombocytopenia ^{02})


» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster    (risk of severe generalized disease)


» Infection^{01}
» Sensitivity to vinorelbine^{01}{02}
» Tumor cell infiltration of the bone marrow
» Caution should be used also in patients with inadequate bone marrow reserves due to previous cytotoxic drug or radiation therapy.

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Alanine aminotransferase (ALT [SGPT]) values, and
Alkaline phosphatase values, serum and
Aspartate aminotransferase (AST [SGOT]) values, and
Bilirubin concentrations, serum    (recommended prior to initiation of therapy and at periodic intervals during therapy ^{{06} {07}})


» Leukocyte count, total and differential    (determinations and review recommended on the day of treatment prior to administering each dose of vinorelbine ^{01})




Side/Adverse Effects

Note: Extensive clinical experience has been obtained with the antineoplastic agent vinorelbine in Europe and elsewhere ^{06}. This experience has been supplemented by more clinical trials of patients with advanced non–small cell lung cancer or breast cancer conducted in North America ^{06}. Data from these trials indicate that vinorelbine is safe and well tolerated in the outpatient population ^{{06} {19}}. Granulocytopenia is the dose-limiting toxicity ^{{01} {02} {03} {06} {07}}. Although the incidence of this condition is high among vinorelbine-treated patients, it is uncommonly associated with severe complications ^{{06} {19}}. Elevations in alkaline phosphatase values are seen in the majority of patients, but this effect may be due in part to liver and bone metastases ^{06}. Nonhematologic toxicities are mostly mild or moderate ^{06}. Injection site reactions have been noted in some patients, but improved administration techniques may help reduce the incidence of the effect ^{06}. Gastrointestinal and respiratory effects are seldom severe and usually respond to treatment ^{06}. Drug-associated neurotoxicity occurs less often with vinorelbine than with other commonly used vinca alkaloid compounds ^{06}. Overall, vinorelbine is associated with few severe toxicities, which, for the most part, are easily managed ^{06}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Anemia ^{{01}{02}{06}{07}}(unusual tiredness or weakness)
    
asthenia (loss of strength and energy ^{{01} {02}})
    
granulocytopenia or leukopenia ^{{07}{09}{12}{17}}(fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination ; sore throat)
    
injection site reactions ^{{01} {01}{02}{06}}(redness, increased warmth, pain, or discoloration of vein at place of injection)

Note: Asthenia is one of the most common adverse effects of vinorelbine, occurring in one third of patients ^{03}. The fatigue is generally mild or moderate but increases with repeated administration ^{03}.
Injection site reactions are common with vinorelbine treatment, although, in one study, only approximately 2% of patients experienced severe reactions ^{06}. Like other vinca alkaloids, vinorelbine is a vesicant that can cause extravasation injuries as well as local effects at the injection site ^{06}. The occurrence and severity of venous irritation appear to be reduced when vinorelbine is administered as a 6- to 10-minute infusion with a free-flowing intravenous fluid to ensure proper flushing of veins ^{03}. Phlebitis occurs in approximately 6% of patients ^{06}; however, the frequency of phlebitis was notably greater in clinical trials in which vinorelbine was administered over a period of 1 hour ^{03}.
The most notable toxicity associated with vinorelbine treatment is hematologic ^{06}. Granulocytopenia is the dose-limiting toxicity, with grade 3 or 4 granulocytopenia occurring in 64% of treated patients ^{06}. Nadir of granulocyte counts occurs 7 to 10 days after a dose; recovery usually occurs within the following 7 to 14 days ^{01}. White blood cell counts are also severely affected; grade 3 or 4 leukopenia was reported in 50% of vinorelbine-treated patients ^{06}. A lesser effect was observed in red blood cells, as indicated by hemoglobin concentrations; only 9% of patients reached grade 3 or 4 toxicity ^{06}. Although anemia was fairly common among vinorelbine-treated patients, it was rarely severe, and transfusions were required rarely ^{06}. Platelets are relatively unaffected ^{06}.


Incidence less frequent
    
Chest pain ^{{01} {03}}
    
neuropathy, peripheral, mild to moderate, including paresthesia and hypesthesia ^{{01} {03} {12} {16}} (numbness or tingling in fingers and toes)
    
pulmonary reactions ^{03}(shortness of breath)
    
stomatitis ^{01} (sores in mouth and on lips )

Note: Chest pain has been reported in 5% of patients receiving vinorelbine therapy ^{03}. The majority of patients reporting chest pain have either a history of cardiovascular disease or a tumor within the chest ^{03}. One report describes a fatal myocardial infarction in a patient with a previous infarction who received two courses of vinorelbine ^{03}. It is unclear what role vinorelbine played in the patient's myocardial infarction ^{03}. Cardiovascular toxicity has been rarely reported with vincristine and vinblastine ^{03}. The pathogenesis of cardiovascular toxicity is postulated to involve transitory coronary artery spasm ^{03}.
Shortness of breath has been noted in 5% of patients; 2% of these patients described severe shortness of breath ^{03}. As with other vinca alkaloids, vinorelbine can produce both acute and subacute pulmonary reactions ^{03}. The acute reaction resembles an allergic reaction and responds to bronchodilators ^{03}. Subacute pulmonary reactions generally occur within 1 hour after drug administration and are characterized by cough, dyspnea, hypoxemia, and interstitial infiltration ^{03}. Subacute pulmonary reactions typically respond to corticosteroid therapy ^{03}.
The neurotoxic effects of vinorelbine, such as peripheral neuropathy, seem to be reversible on discontinuation of vinorelbine ^{{01} {03}}. The addition of cisplatin does not appear to increase the neurotoxic effects of vinorelbine ^{03}. However, prior treatment with paclitaxel may result in cumulative neurotoxicity ^{03}.


Incidence rare
    
Hemorrhagic cystitis ( blood in urine; painful urination)—reported in less than 1% of patients ^{03}
    
pancreatitis ^{58}(bloating ; chills; constipation ; darkened urine; fast heartbeat; indigestion; loss of appetite; nausea; pains in stomach; vomiting; yellow eyes or skin)^{01}
    
skin rash —reported in 4% of patients ^{03}
    
thrombocytopenia ^{01} ( unusual bleeding or bruising; black, tarry stools; blood in urine or stools ; pinpoint red spots on skin)

Note: Grades 3 and 4 thrombocytopenia have been reported in less than 1% of patients ^{02}; however, in one study no grade 3 or 4 thrombocytopenia was observed in vinorelbine recipients ^{09}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Anorexia (loss of appetite ^{{01} {03}})
    
constipation ^{{01} {16}}
    
nausea and vomiting ^{{01} {02} {12} {17}}

Note: Prophylactic antiemetic therapy has not been used routinely in clinical trials of vinorelbine ^{03}. Nausea and vomiting occur in approximately 40% and 20% of patients, respectively ^{03}. Vinorelbine-associated nausea and vomiting are typically mild to moderate and appear to respond to conventional antiemetic therapy; serotonin-receptor antagonists are not generally required ^{03}.


Incidence less frequent
    
Diarrhea ^{01}
    
jaw pain ^{01}
    
joint or muscle pain ^{01}



Those not indicating need for medical attention
Incidence more frequent
    
Alopecia ^{01}{02}{03}(loss of hair)

Note: Vinorelbine has caused alopecia in about 10% of patients, manifested as a gradual thinning of hair ^{03}. Few patients suffer total hair loss ^{03}. Alopecia appears to occur with cumulative toxicity of vinorelbine ^{03}.






Overdose
For specific information on the agents used in the managment of vinorelbine overdose, see:    • Filgrastim and/or Sargramostim in Colony Stimulating Factors (Systemic) monograph.


For more information on the management of overdose, contact a Poison Control Center (see Poison Control Center Listing )

Clinical effects of vinorelbine overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and chronic effects
    
Bone marrow suppression ^{01}{02}(fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination; sore throat; unusual bleeding or bruising; unusual tiredness or weakness)
    
esophagitis^{01} (chest pain; heartburn; vomiting)
    
neurotoxicity, peripheral ^{01}{02}(numbness or tingling in fingers and toes)
    
paralytic ileus^{01} (abdominal pain, mild; constipation; nausea; vomiting)
    
stomatitis^{{01} {01}}(sores in mouth and on lips)


Note: Bone marrow aplasia, sepsis, paresis, and fatalities have been reported following overdose ^{01}.


Treatment of overdose
There are no known antidotes for the treatment of vinorelbine overdosage ^{{01} {02}}. Therefore, treatment of overdose is supportive and may include appropriate blood transfusions, antibiotics, and administration of colony stimulating factors (filgrastim [rG-CSF] or sargramostim [rGM-CSF]) ^{{01} {02}}.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Vinorelbine (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to vinorelbine

Pregnancy—Advisability of using contraception; telling physician immediately if pregnancy is suspected





Breast-feeding—Not recommended because of the risk of serious side effects
Other medications, especially bone marrow depressants, mitomycin, or previous cytotoxic or radiation therapy
Other medical problems, especially bone marrow depression; chickenpox; herpes zoster; or tumor cell infiltration of the bone marrow

Proper use of this medication
Caution in taking combination therapy; taking each medication at the right time

Importance of ample fluid intake and subsequent increase in urine output to aid in excretion of uric acid

Possible nausea and vomiting; importance of continuing medication despite stomach upset

» Proper dosing

Precautions while using this medication
» Importance of close monitoring by physician

» Possibility of local tissue injury if infiltration of intravenous solution occurs; telling physician or nurse right away about redness, swelling, or pain at site of injection

» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding other persons who have taken oral poliovirus vaccine or wearing a protective mask that covers nose and mouth

Caution if bone marrow depression occurs
» Avoiding exposure to persons with infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occurs

» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur

Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done

Not touching eyes or inside of nose unless hands washed immediately before

Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters

Avoiding contact sports or other situations where bruising or injury could occur


Side/adverse effects
Signs of potential side effects, especially anemia, asthenia, granulocytopenia or leukopenia, injection site reaction, chest pain, pancreatitis, peripheral neuropathy, pulmonary reactions, stomatitis, hemorrhagic cystitis, skin rash, and thrombocytopenia


General Dosing Information
Patients receiving vinorelbine should be under the supervision of a physician experienced in cancer chemotherapy ^{01}. Patients and/or family members should be instructed to report any side/adverse effects immediately ^{17}.

Clinical trials have demonstrated that vinorelbine is an effective chemotherapeutic agent in the treatment of patients with advanced non–small cell lung cancer (NSCLC) ^{{11} {12} {19} {20} {22}}. Vinorelbine has also been shown to increase survival without compromising quality of life (QOL) in several randomized, controlled trials ^{{05} {19}}. A summary of preliminary QOL findings for two vinorelbine (randomized and single-arm) trials in patients with NSCLC shows that symptoms status was as good or better for patients receiving vinorelbine as for those receiving 5-fluorouracil/leucovorin in the randomized study ^{23}.

Although vinorelbine is effective as monotherapy, a higher overall response rate and median duration of survival are seen when it is combined with cisplatin ^{{12} {14} {19} {20} {22}}. Data from some clinical studies indicate that vinorelbine plus cisplatin is superior to vindesine plus cisplatin and to vinorelbine alone ^{20}.

Patients with renal insufficiency do not require dosage adjustments ^{05}. However, in patients with hepatic insufficiency, the dosage of vinorelbine should be adjusted on the basis of degree of hyperbilirubinemia ^{05}.

Vinorelbine should be administered intravenously ^{01}. Intrathecal administration of other vinca alkaloids has resulted in death ^{01}.

It is very important that the intravenous needle or catheter be positioned properly before any vinorelbine is injected ^{{01} {02}}. Leakage into surrounding tissue during intravenous administration of vinorelbine may cause considerable irritation, local tissue necrosis, and/or thrombophlebitis ^{{01} {02}}. If extravasation occurs, the injection should be discontinued immediately ^{{01} {02} {17}}, and any remaining portion of the dose should then be introduced into another vein ^{{01} {02}}. Local injection of hyaluronidase and the application of moderate heat to the area of leakage has been reported to help disperse the agent and minimize discomfort associated with the extravasation of other vinca alkaloids ^{02}.

Although venous irritation is a problem associated with peripherally administered vinorelbine, it does not necessitate central line placement ^{18}. Incidence of this problem can be reduced with a shorter duration of administration ^{18}. Vinorelbine should be diluted in either a syringe or intravenous bag and administered by intravenous injection, over a period of 6 to 10 minutes ^{{01} {05} {17} {18}}. However, if a central line is to be considered for patients receiving vinorelbine, the following can be used as a guide ^{18}:    • If the patient has poor venous access, early placement of a central line should be considered ^{18}.
   • If the patient has reasonable venous access, treatment should be started with peripheral administration (especially until therapeutic response is determined) ^{18}. Placement of a central line should be considered only if difficulty in venous access is encountered ^{18}.


After vinorelbine has been infused, flushing of the vein should be continued with at least 100 mL of normal saline or 5% dextrose in water to prevent injection site reactions ^{17}. Inadequate flushing may increase the risk of phlebitis; therefore, the catheter should not be removed without flushing the vein ^{17}.

Vinorelbine has shown reduced neurotoxicity, at both the cellular and clinical levels, compared with other vinca alkaloids ^{19}. However, physicians should make clinical judgment before initiating vinorelbine treatment in patients with pre-existing neurologic disorders ^{17}. Patients who previously have received neurologic chemotherapy are at high risk for developing neurologic complications ^{17}. Patients receiving paclitaxel concomitantly with vinorelbine should be monitored for neurologic symptoms ^{{01} {27}}. It is recommended that vinorelbine be discontinued if moderate or severe neurotoxicity occurs during treatment ^{01}.

Granulocytopenia is the major dose-limiting adverse effect with vinorelbine therapy ^{{01} {02} {05}}; however, it is reversible and not cumulative over time ^{{01} {05}}. Patients who develop leukopenia (particularly granulocytopenia) should be observed carefully for signs of infection ^{01}. Prophylactic hematologic growth factors have not been used routinely with vinorelbine; however, if medically necessary, growth factors may be administered at recommended doses no earlier than 24 hours after the administration of cytotoxic chemotherapy ^{01}.

Safety considerations for handling this medication

Note: As with other toxic compounds, caution should be exercised in handling and preparing the solution of vinorelbine ^{{01} {02}}. The use of gloves is recommended since skin reactions are reported with accidental exposure ^{{01} {02}}. If the solution of vinorelbine contacts the skin or mucosa, the skin or mucosa should be washed immediately with soap and water ^{{01} {02}}. Severe irritation of the eye has been reported with accidental contamination of the eye with another vinca alkaloid ^{{01} {02}}. If this happens with vinorelbine, the affected eye should be washed with water immediately and thoroughly ^{{01} {02}}.

There is limited but increasing evidence and concern that personnel involved in preparation and administration of parenteral antineoplastics may be at some risk because of the potential mutagenicity, teratogenicity, and/or carcinogenicity of these agents, although the actual risk is unknown ^{25}. USP advisory panels recommend cautious handling both in preparation and disposal of antineoplastic agents ^{25}. Precautions that have been suggested include ^{25}:    • Use of a biologic containment cabinet during reconstitution and dilution of parenteral medications and wearing of disposable surgical gloves and masks ^{25}.
   • Use of proper technique to prevent contamination of the medication, work area, and operator during transfer between containers (including proper training of personnel in this technique) ^{25}.
   • Cautious and proper disposal of needles, syringes, vials, ampuls, and unused medication ^{25}.
A number of medical centers have developed detailed guidelines for handling of antineoplastic agents ^{25}.

For treatment of adverse effects
If shortness of breath or bronchospasm occurs during concurrent treatment with vinorelbine and mitomycin, treatment with supplemental oxygen, bronchodilators, and/or corticosteroids may be required ^{01}.


Parenteral Dosage Forms

Note: Bracketed use in the Dosage Forms section refers to category of use and/or indication that is not included in U.S. product labeling.

VINORELBINE TARTRATE INJECTION

Note: The dosing and strength of the dosage form available are expressed in terms of vinorelbine base (not the tartrate salt).


Usual adult dose
Carcinoma, lung, non–small cell or
[Carcinoma, breast ]
Intravenous (over six to ten minutes), 30 mg (base) per square meter of body surface area once a week, as a single agent ^{{01} {02}}. The same dose is used in combination therapy with cisplatin, which is given in a dose of 120 mg (base) per square meter of body surface area on Days 1 and 29, followed by one dose every six weeks ^{{01} {05}}.

Dosage adjustment is recommended according to hematologic toxicity or hepatic insufficiency, as outlined below, whichever results in a lower dose ^{01}. (If both hematologic and hepatic toxicity occur, the lower of the doses determined from the following is recommended ^{01}.)


Dosage adjustment for hematologic toxicity is:


Granulocytes 1500 cells per cubic millimeter (cells/mm ³) or more on days of treatment—
Give 30 mg (base) per square meter of body surface area ^{{01} {05}}.



Granulocytes 1000 to 1499 cells/mm ³ on days of treatment—
Give 15 mg (base) per square meter of body surface area ^{{01} {05}}.



Granulocytes less than 1000 cells/mm ³ on days of treatment—
Do not administer vinorelbine ^{{01} {05}}. Repeat granulocyte count in one week ^{{01} {05}}. If three consecutive weekly doses have to be held because of low granulocyte counts, it is recommended that vinorelbine be discontinued ^{{01} {05}}.


Note: In patients who have experienced fever and/or sepsis while granulocytopenic during vinorelbine therapy or have had two consecutive doses held because of granulocytopenia, subsequent doses should be 22.5 mg (base) per square meter of body surface area (for granulocytes greater than or equal to 1500 cells/mm ³) or 11.25 mg (base) per square meter of body surface area (for granulocytes 1000 to 1499 cells/mm ³) ^{01}.




Dosage adjustment for hepatic insufficiency is:


Total bilirubin 2 mg per deciliter (mg/dL) or less—
Give 30 mg (base) per square meter of body surface area ^{{01} {05}}.



Total bilirubin 2.1 to 3 mg/dL—
Give 15 mg (base) per square meter of body surface area ^{{01} {05}}.



Total bilirubin 3 mg/dL or more—
Give 7.5 mg (base) per square meter of body surface area ^{{01} {05}}.



[Carcinoma, cervical]¹
Patients have benefited from intravenous doses of 25 to 30 mg per square meter of body surface area, once a week, depending on white blood cell and absolute neutrophil counts.^{28}

[Carcinoma, ovarian, epithelial]¹
Patients have benefited from intravenous doses of 18 to 30 mg per square meter of body surface area, once every 7 to 21 days, depending on white blood cell and absolute neutrophil counts.^{33}


Usual pediatric dose
Safety and efficacy have not been established ^{01}.

Strength(s) usually available
U.S.—


10 mg (base) per mL (1- and 5-mL vials) (Rx) [Navelbine]

Canada—


10 mg (base) per mL (1- and 5-mL vials) (Rx) [Navelbine]^{02}

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F), in the carton ^{{01} {02}}. Protect from light ^{{01} {02}}. Protect from freezing ^{{01} {02}}.

Preparation of dosage form:
For intravenous administration via syringe, the calculated dose of vinorelbine tartrate injection is diluted to a concentration of 1.5 to 3 mg per mL (mg/mL) with either 5% dextrose injection or 0.9% sodium chloride injection ^{01}. For administration via an intravenous bag, the calculated dose of vinorelbine tartrate injection is diluted to a concentration of 0.5 to 2 mg/mL with 5% dextrose injection, 0.9% sodium chloride injection, 0.45% sodium chloride injection, 5% dextrose in 0.45% sodium chloride injection, Ringer"s injection, or lactated Ringer's injection ^{01}.

Stability:
Unopened vials of vinorelbine tartrate injection are stable for up to 72 hours at 25 °C (77 °F) ^{01}. Diluted injection is stable for up to 24 hours at 5 to 30 °C (41 to 86 °F) under normal room light when stored in polypropylene syringes or polyvinyl chloride bags ^{01}.

Incompatibilities:
Vinorelbine tartrate is not compatible with acyclovir sodium, aminophylline, amphotericin B, ampicillin sodium, cefoperazone sodium, ceforanide, cefotetan sodium, ceftriaxone sodium, fluorouracil, furosemide, ganciclovir sodium, methylprednisolone sodium succinate, mitomycin, piperacillin sodium, sodium bicarbonate, thiotepa, and sulfamethoxazole and trimethoprim when administered with these medications via Y-site injection ^{15}. Therefore, vinorelbine should not be administered simultaneously with these medications via a Y-site injection ^{15}.

Note: If accidental contamination of the eye with vinorelbine occurs, the eye should be immediately and thoroughly washed with water to prevent severe irritation ^{01}.

Developed: 08/29/1997
Revised: 01/07/2002

References

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76. Gebbia V, Testa A, Valenza R, et al. A pilot study of vinorelbine on a weekly schedule in recurrent and/or metastatic squamous cell carcinoma of the head and neck. Eur J Cancer 1993; 29A (9): 1358-9.
    

77. Romanini A, Surbone A, Ricci S, et al. Phase II study of continuous infusion of vinorelbine in patients with locally pretreated advanced head and neck cancer. Proc Am Assoc Cancer Research 1993; 34: 205 [Abst 1222].
    

78. Canfield VA, Saxman SB, Kolodziej MA, et al. Phase II trial of vinorelbine in advanced or recurrent squamous cell carcinoma (SCC) of the head and neck. Proc Am Soc Clin Oncol 1997; 16: [Abst 1382].
    

79. Reviewers' comments on the use of vinorelbine for the treatment of recurrent, untreated/unresectable, and/or metastatic squamous cell carcinoma of the head and neck (SCHNC) ballot, 7/5/00.
    

80. Sweeney CJ, Monaco FJ, Jung SH, et al. A phase II Hoosier Oncology Group study of vinorelbine and estramustine phosphate in hormone-refractory prostate cancer. Ann Oncol 2002 Mar; 13(3): 435-40.
    

81. Morant R, Hsu Schmitz SF, Bernhard J, et al. Vinorelbine in androgen-independent metastatic prostatic carcinoma-a phase II study. Eur J Cancer 2002 Aug; 38(12): 1626-32.
    

82. Oudard S, Caty A, Humblet Y, et al. Phase II study of vinorelbine in patients with androgen-independent prostate cancer. Ann Oncol 2001 Jun; 12(6): 847-52.
    

83. Smith MR, Kaufman D, Oh W, et al. Vinorelbine and estramustine in androgen-independent metastatic prostate cancer: a phase II study. Cancer 2000 Oct 15; 89(8): 1824-8.
    

84. Koletsky AJ, Guerra M, Kruglyak E, et al. A phase II study of vinorelbine and low-dose docetaxel in patients with hormone-refractory prostate cancer (HRPC). Proc Am Soc Clin Oncol 2002; 21: [Abst 2438].
    

85. Pienta KJ, Olson KB. Treatment of Metastatic Hormone Refractory Prostate Cancer with Estramustine (Emcyt) and Vinorelbine. Proc Am Soc Clin Oncol 2001; 20: 168b [Abst 2421].
    

86. Baranwal A, Amjad M, Naidu S, et al. A Phase II Trial with Docetaxel, Vinorelbine, and G-CSF in Patients with Hormone Refractory Prostate Cancer. Proc Am Soc Clin Oncol 2001; 20: 165b [Abst 2410].
    

87. Sewak S, Chachoua A, Hamilton A, et al. Pacl-E-Vin: Triple Tubulin Targeting in a Phase I Study of Paclitaxel, Estramustine Phosphate and Vinorelbine. Proc Am Soc Clin Oncol 2001; 20: 93b [Abst 2121].
    

88. Robles C, Savaraj N, Sriratana P, et al. Phase II study of vinorelbine with low-dose prednisone in the treatment of hormone-refractory metastatic prostate cancer. Proc Am Assoc Ca Res 2001; 42: 230 [Abst 1235].
    

89. Ferraù F, Morgia G, Priolo1 D, et al. Vinorelbine (VNB) and estramustine (EMP)in hormone-refractory prostate cancer (HRPC). Ann Oncol 2000 Oct; 11(Suppl.4): 77 [Abst 339P].
    

90. Kuyu H, Acostamadiedo J, Applewhite J, et al. A phase II prospective study of Navelbine (vinorelbine), Adriamycin (doxorubicin), and prednisone- (NAP) in treatment of hormone refractory prostate cancer (HRPC). Proc Am Soc Clin Oncol 2000; 19: 375a [Abst 1482].
    

91. Garcia PB, Bolanos M, Rodriguez A, et al. Phase II study of vinorelbine (VNR) - estramustine (E) in the treatment of patients (Pts) with hormonoresistant prostate carcinoma. Proc Am Soc Clin Oncol 2000; 19: 374a [Abst 1480].
    

92. Vicario G, Scelzi E, Pastorelli D, et al. Vinorelbine and estramustine in hormone-refractory prostate cancer. Proc Am Soc Clin Oncol 2000; 19: 364a [Abst 1436].
    

93. Reviewers' consensus on the use of vinorelbine for the treatment of hormone-refractory prostate carcinoma (HRPC) ballot, 12/8/02.
    

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