ATC Class:L01CA04

VA Class:AN900

AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• Vinorelbine Tartrate

Chemical Name:

• 3',4'-Didehydro-4'-deoxy- C '-norvincaleukoblastine [ R -( R *, R *)]-2,3-dihydroxybutane dioate (1:2)

Molecular Formula:

• C₄₅H₅₄N₄O₈•2C₄H₆O₆

Vinorelbine, a semisynthetic vinca alkaloid, is an antineoplastic agent.1,4,21

Non-small Cell Lung Cancer

Adjuvant Therapy

Cisplatin-containing chemotherapy, such as cisplatin in combination with vinorelbine, is used for the adjuvant treatment of completely resected non-small cell lung cancer†.91

The use of cisplatin-containing adjuvant therapy prolongs survival in patients with completely resected non-small cell lung cancer.110 (Also see Uses: Non-small Cell Lung Cancer in Cisplatin 10:00.) In the International Adjuvant Lung Cancer Trial (IALT), 1867 patients with completely resected stage I, II, or III non-small cell lung cancer were assigned to receive either adjuvant chemotherapy (cisplatin with etoposide, or cisplatin with a vinca alkaloid) or observation.110 At 5 years, the rate of survival was higher among patients receiving cisplatin-based adjuvant therapy (44.5%) than among those assigned to observation (40.4%).110 Subset analysis of pooled abstracted data from 11 randomized trials including this one indicates that adjuvant therapy with cisplatin-based therapy prolongs survival in patients with completely resected non-small cell lung cancer.124

Vinorelbine is used in combination with cisplatin as adjuvant therapy for completely resected non-small cell lung cancer.125,127 In a randomized trial (National Cancer Institute of Canada and Intergroup JBR10 study) involving 482 patients with completely resected stage IB or stage II non-small cell lung cancer, overall survival (94 versus 73 months) and relapse-free survival were prolonged in patients receiving adjuvant therapy with vinorelbine and cisplatin compared with those assigned to observation.125 Retrospective analysis of the data from this clinical trial showed that, despite receiving lower dose intensities of both drugs, patients older than 65 years experienced a survival benefit similar to that observed for all patients receiving adjuvant therapy with vinorelbine and cisplatin for non-small cell lung cancer.126 In the Adjuvant Navelbine International Trialist Association (ANITA) trial, which involved 840 patients with stage IB, II, or IIIA non-small cell lung cancer, median survival was prolonged (66 versus 44 months) in patients receiving adjuvant therapy with vinorelbine and cisplatin compared with those assigned to observation.127

Analysis of pooled data for individual patients from 5 large randomized trials, including the IALT, JBR10, and ANITA studies, indicates that adjuvant treatment with cisplatin-based therapy prolongs survival in patients with completely resected non-small cell lung cancer.128 Subgroup analysis showed that survival benefit varies according to stage of disease; cisplatin-based adjuvant chemotherapy prolongs survival in patients with stage II or III disease, may benefit some patients with stage IB disease, and may not benefit patients with stage IA disease.128

Therapy for Metastatic Disease

Depending on the stage of disease and the performance status of the patient, vinorelbine is used either alone or in combination with cisplatin as first-line therapy in ambulatory patients for the palliative treatment of unresectable, advanced (stage III or IV) non-small cell lung cancer.1,19,91

Although the drug is active alone in this cancer,1,11,12,19 use of vinorelbine in combination with cisplatin is preferred for the treatment of advanced non-small cell lung cancer in patients with good performance status because of improved response and survival.1,12,19,99,112 In the American Society of Clinical Oncology (ASCO) practice guidelines for the treatment of unresectable non-small cell lung cancer (NSCLC), an expert panel recommended 2-drug combination chemotherapy for patients with good performance status (ECOG/Zubrod performance status 0 or 1); for patients with ECOG/Zubrod performance status 2, or for geriatric patients, single-agent chemotherapy, such as vinorelbine alone, may be used.99 A European Experts Panel that convened in April 2003 also stated that single-agent therapy may be used in patients with advanced NSCLC and ECOG performance status 2.118 In patients with stage IV disease, quality-of-life considerations may prompt monotherapy with vinorelbine, and the manufacturer states that such monotherapy can be used for stage IV but not stage III non-small cell lung cancer.1,20

Age alone should not deter the use of chemotherapy for the treatment of advanced non-small cell lung cancer in geriatric patients.99,114,116 Data from a randomized trial demonstrate a survival benefit among geriatric patients (70 years of age or older) receiving single-agent therapy with vinorelbine compared with those receiving supportive care alone.113 Subgroup analysis of a phase III randomized trial according to age and performance status indicates that among patients receiving cisplatin-based combination chemotherapy for advanced non-small cell lung cancer, fit older patients (i.e., 70 years of age or older with ECOG performance status of 0 or 1) had similar outcomes for response rate and survival as younger patients; older patients were more likely to have concomitant disease and had a higher incidence rate of certain drug-related toxicities.114 Results of a large randomized trial among geriatric patients (70 years of age or older) with advanced non-small cell lung cancer showed that combination therapy with vinorelbine and gemcitabine did not improve survival and caused greater toxicity than single-agent therapy with either vinorelbine or gemcitabine.115 Systemic therapy should be offered to geriatric patients with advanced non-small cell lung cancer; further study is needed to determine optimal therapy with single agents or combination regimens for such patients.116

The combination of cisplatin with vinorelbine currently is a preferred regimen for the treatment of advanced non-small cell lung cancer.19,91,92,99

In a randomized trial involving 612 patients with advanced non-small cell lung cancer, similar results were noted for response rate, median survival, and time to disease progression between 3 platinum-based regimens; adverse effects occurring more frequently in each group included neutropenia and nausea/vomiting in patients receiving vinorelbine and cisplatin, thrombocytopenia in those receiving gemcitabine and cisplatin, and peripheral neuropathy and alopecia in those receiving paclitaxel followed by carboplatin.117 In another randomized trial, response rates, median survival, and 1- and 2-year survival rates were similar in patients receiving either cisplatin and vinorelbine or carboplatin and paclitaxel for advanced non-small cell lung cancer; grade 3 or 4 leukopenia and neutropenia and grade 3 nausea and vomiting were more frequent in patients receiving vinorelbine and cisplatin whereas grade 3 peripheral neuropathy occurred more frequently in patients receiving paclitaxel and carboplatin.100

In a randomized study, 432 patients with stage IIIb or IV non-small cell lung cancer receiving vinorelbine 25 mg/m² once weekly and cisplatin 100 mg/m² once every 4 weeks had a longer median survival (8 versus 6 months) and higher survival rate at 1 year (38 versus 22%) than those receiving cisplatin 100 mg/m² once every 4 weeks.1,92 Objective response rates of 19 and 8% were observed in patients receiving vinorelbine and cisplatin versus cisplatin alone.1 The incidence and severity of granulocytopenia was substantially higher in patients receiving combination therapy with vinorelbine and cisplatin than in those receiving cisplatin alone.92 Granulocyte-colony stimulating factor was administered in approximately one-third of patients receiving combination therapy to reduce the severity of myelosuppression associated with vinorelbine.92 All patients in the study had a WHO performance status of 0 or 1, and none had received prior chemotherapy.1,92

In a randomized study of 612 patients with stage III or IV non-small cell lung cancer who had not received prior chemotherapy, higher response rates and longer survival times (albeit modestly improved) were observed in patients receiving vinorelbine and cisplatin compared with those receiving either vinorelbine alone or vindesine and cisplatin.1,12 All patients in this study had a WHO performance status of 0, 1, or 2.1,12 Patients were randomized to receive single-agent vinorelbine 30 mg/m² once weekly; vinorelbine 30 mg/m² once weekly and cisplatin 120 mg/m²on days 1 and 29 and then once every 6 weeks; or vindesine 3 mg/m² once weekly for 7 weeks and then once every other week and cisplatin 120 mg/m² on days 1 and 29 then once every 6 weeks.1,12,20 Median survival times of 9.2, 7.4, or 7.2 months were observed in patients with advanced non-small cell lung cancer receiving vinorelbine and cisplatin, vindesine and cisplatin, or vinorelbine alone, respectively.1 Survival at 1 year was 35% in patients receiving vinorelbine and cisplatin, 27% in those receiving vindesine and cisplatin, and 30% in those receiving single-agent therapy with vinorelbine.1 The overall objective response rate (all partial responses) was 28% (based on intention-to-treat analysis) in patients receiving vinorelbine and cisplatin, 19% in those receiving vindesine and cisplatin, and 14% in those receiving vinorelbine alone.1,12,20

Follow-up at 5 years indicates that survival is prolonged for patients receiving vinorelbine and cisplatin compared with either vindesine and cisplatin or vinorelbine alone.112 However, subgroup analysis suggests that this survival benefit is obtained only among patients with a WHO performance status of 0 or 1.112 Among patients with nonresectable non-small cell lung cancer who have a WHO performance status of 2, single-agent therapy with vinorelbine may be appropriate.112

In a clinical trial in which 211 patients with stage IV non-small cell lung cancer were randomized on a 2:1 basis to receive vinorelbine 30 mg/m² once weekly or fluorouracil 425 mg/m² IV plus leucovorin 20 mg/m² IV daily for 5 days every 4 weeks, respectively, median survival time was 30 weeks for patients receiving vinorelbine compared with 22 weeks for those receiving fluorouracil with leucovorin.1,20,80 Combination therapy with fluorouracil and leucovorin was chosen as a control treatment because this regimen has a tolerable safety profile and its activity in non-small cell lung cancer is unknown.1,80 Because the median survival time in patients with non-small cell lung cancer who received the control treatment was comparable to that usually observed in patients with untreated disease, it appears that combination therapy with fluorouracil and leucovorin did not have a detrimental effect.1,80 All patients in the study had a Karnofsky performance status of 70 or higher and none had received prior chemotherapy.1,80 Survival at 1 year was 24% in patients receiving vinorelbine and 16% in patients receiving fluorouracil with leucovorin.1,20,80 Overall objective response rates (all partial responses) were 12 and 3% for vinorelbine and fluorouracil with leucovorin, respectively.1,20,80 Measurements of quality of life assessing role functioning, physical functioning, symptom distress, and global quality of life were similar in patients receiving either vinorelbine or combination therapy with fluorouracil and leucovorin.80

Breast Cancer

Vinorelbine and Trastuzumab for HER2-positive Metastatic Breast Cancer

Combination therapy with vinorelbine and trastuzumab is being investigated as an active regimen for the treatment of HER2-overexpressing metastatic breast cancer†.19,104,105,106

Monotherapy for Metastatic Breast Cancer

Vinorelbine is used as monotherapy in the first-line or salvage (e.g., second-line or subsequent) treatment of metastatic breast cancer†.19,106

First-line vinorelbine monotherapy produced a median objective response rate (complete and partial responses) of 44% (range: 35-52%) in women with advanced disease.3,9,20,21,22,23,24,25,27,28,30,44,49,50,51,52,53,58 The median duration of response and the median time to treatment failure were 8.5 (range: 4.3-9)3,9,20,21,22,23,24,25,27,28,30 and 5 (range: 4.4-6)3,20,23,25,28,30 months, respectively. Patients treated with vinorelbine had a median survival of 16 (range: 9.9-24) months.3,9,20,23,24,28,30,44

Salvage (second-line or subsequent) chemotherapy with vinorelbine alone also has been employed in the treatment of metastatic breast cancer.22 When administered as salvage therapy, vinorelbine monotherapy produced a median objective response in 28% (range: 16-37%) of patients with advanced/ metastatic breast cancer that failed to respond to a previous cytotoxic chemotherapy regimen.9,20,21,22,23,26,31,32,33,34,35,44,49,50,51,52,53,58,61 The drug produced a median duration of response, time to treatment failure, and survival of 5 (range: 3.5-8.5),9,20,21,22,23,26,31,32,34,35,44,41 3.8 (range: 3-4.5),9,20,23,31,32,33,61 and 11.7 (range: 7-24)23,31,33,35,44 months, respectively. Objective responses to vinorelbine have been observed in patients with metastatic breast cancer refractory to anthracyclines33,108 or taxanes.107,108

In a randomized, active-control trial involving women with anthracycline-refractory metastatic breast cancer, vinorelbine's antitumor activity appeared superior to that of melphalan.33 Vinorelbine and melphalan produced objective responses in 16 and 9% of patients, respectively.33 Differences favoring vinorelbine were noted for median time to disease progression and treatment failure, median survival, and 1-year survival rates.33 The median time to disease progression and treatment failure was 3 or 2 months for patients receiving vinorelbine or melphalan, respectively, the median survival rate was 8.8 or 7.8 months, respectively, and the 1-year survival rate was 35.7 or 21.7%, respectively.33

Vinorelbine has been administered in various regimens for the treatment of metastatic breast cancer, such as a short IV infusion once weekly,24,28 or a continuous IV infusion of up to 5 days in duration.44,72 The use of oral† vinorelbine (currently not commercially available in the US) also is being investigated in the treatment of metastatic breast cancer.54,55,56,57,109

Cervical Cancer

Vinorelbine is being investigated as an active agent in the treatment of metastatic or recurrent cervical cancer†.19,97,98 An objective response rate of 18% was reported in a small uncontrolled study of patients receiving vinorelbine as a single agent for advanced or recurrent squamous cell carcinoma of the cervix.97 The combination of vinorelbine with other antineoplastic agents (e.g., cisplatin) is being evaluated in patients with metastatic or recurrent cervical cancer.98 (See Uses: Cervical Cancer in Cisplatin 10:00 for an overview of therapy for cervical cancer.)

Other Uses

Vinorelbine also is used in the treatment of adult soft tissue sarcomas† and esophageal cancer†.19

Administration

Vinorelbine is administered only by IV injection into a free-flowing IV infusion or a large central vein, usually over a period of 6-10 minutes followed by flushing of the vein with a compatible IV solution, by individuals experienced in administration of the drug.1,3,9,20,73 The IV needle or catheter must be properly positioned before vinorelbine is injected.1 Improper administration of vinorelbine may result in extravasation of the drug causing local tissue necrosis and/or thrombophlebitis.1 Although vinorelbine also has been infused IV over 20-60 minutes via a peripheral vein or by rapid IV injection over 1-2 minutes, such methods of administration are not recommended because of the high rate of adverse local effects (e.g., phlebitis, erythema, venous discoloration, ulceration, pain) associated with this infusion rate and reports of severe back pain associated with rapid injection.73 Continuous IV infusions† of vinorelbine have been well tolerated,44,72,73 but additional study is needed to establish the role of such infusion in treating various cancers.44,73

Vinorelbine tartrate is very irritating and must not be given IM, subcutaneously, or intrathecally. Intrathecal administration of other vinca alkaloids (i.e., vinblastine, vincristine) has resulted in death. 1 When dispensed, the syringe containing the individual dose prepared for administration to the patient must be labeled with the statement: “Warning: For IV use only. Fatal if given intrathecally.”1 The syringe must be enclosed in an overwrap (e.g., plastic bag or similar wrap with typed label) bearing the statements: “Do not remove covering until moment of injection. Fatal if given intrathecally. For IV use only.”130

In addition to the use of the warning labels and overwrap, other protective measures to prevent inadvertent intrathecal administration of vinorelbine or other vinca alkaloids include: administering diluted vinca alkaloid solutions in minibags, preparing the medication at the time of administration, attaching a unique filter, dispensing the vinca alkaloid separately from all other medications, dispensing the vinca alkaloid directly to the individual who is administering the drug, conducting an independent check of the dose and route of administration for the drug both at the time of preparation and prior to administration of the drug, and administering the vinca alkaloid in a separate room from rooms where other medications are administered.130

Management of patients mistakenly receiving intrathecal vinorelbine is a medical emergency.73 Currently, there are no reports of patients mistakenly receiving intrathecal administration of vinorelbine.73 Unfortunately, the prognosis to date for patients inadvertently administered vincristine, another vinca alkaloid, intrathecally generally has been poor despite immediate efforts at removing spinal fluid and flushing with lactated Ringer's injection as well as other solutions, with such efforts failing to prevent ascending paralysis and death in almost all cases.93,94 In one case, progression of paralysis was stopped in an adult patient when the following treatment was initiated immediately after inadvertent intrathecal injection of vincristine.93 Such treatment consisted of immediate removal of as much CSF as safely possible via lumbar access, followed by flushing of the subarachnoid space with lactated Ringer's solution infused continuously at a rate of 150 mL/hour through a catheter in a cerebral lateral ventricle and removal of fluid through a lumbar access.93 As soon as available, fresh frozen plasma (25 mL) diluted in 1 L of lactated Ringer's solution was infused through the cerebral ventricular catheter at a rate of 75 mL/hour with removal of fluid through the lumbar access.93 The rate of infusion was adjusted to maintain a CSF protein concentration of 150 mg/dL.93 Glutamic acid was administered in a dose of 10 g given IV over 24 hours, followed by 500 mg orally 3 times daily for 1 month or until stabilization of neurologic status.93,94 The role of glutamic acid in this treatment is uncertain.93 There currently is no experience with this or any other treatment protocol in patients who mistakenly receive vinorelbine intrathecally.73

Leakage of vinorelbine into surrounding tissue during IV administration of the drug can cause considerable irritation, local tissue necrosis, and/or thrombophlebitis.1 If extravasation occurs, the injection should be discontinued immediately, and any remaining portion of the dose should then be administered into another vein.1 The manufacturer states that there are no established guidelines for the treatment of extravasation injuries caused by vinorelbine and that institutional guidelines for extravasation injuries may be used.1 (See Cautions: Local Effects.)

Vinorelbine for injection concentrate must be diluted prior to injection into a free-flowing IV infusion or a large central vein. 1,3,9,20 The manufacturer recommends diluting the concentrate in a syringe with 5% dextrose injection or 0.9% sodium chloride injection to a final vinorelbine concentration of 1.5-3 mg/mL or in an IV bag with 5% dextrose injection, 0.9% sodium chloride injection, 0.45% sodium chloride injection, 5% dextrose and 0.45% sodium chloride injection, Ringer's injection, or lactated Ringer's injection to a final vinorelbine concentration of 0.5-2 mg/mL.1 The diluted solution of vinorelbine should then be administered over a period of 6-10 minutes into the side port closest to the IV bag of a free-flowing IV infusion or into a large central vein followed by flushing with at least 75-125 mL of 0.9% sodium chloride injection or 5% dextrose injection over a period of 10 minutes.1,3,9

Caution should be exercised in handling and preparing solutions of vinorelbine.1 Because skin reactions may occur with accidental exposure to vinorelbine, the manufacturer recommends the use of latex gloves when handling the drug.1 If vinorelbine tartrate injection or a solution of the drug comes in contact with the skin or mucosa, the affected area should be washed immediately and thoroughly with soap and water.1 Care must be taken to avoid contact of vinorelbine tartrate solutions with the eyes since severe irritation of the eye has been reported with accidental exposure to another vinca alkaloid;1 if contact occurs, the eye should be flushed thoroughly with water immediately.1

Vinorelbine tartrate injection or solutions of the drug should be inspected visually for particulate matter and/or discoloration prior to administration.1

Dosage

Dosage of vinorelbine tartrate is expressed in terms of the base.1

Adjustment of vinorelbine dosage in geriatric patients solely on the basis of age is not necessary.1,20

Non-small Cell Lung Cancer

Combination Therapy

For the treatment of non-small cell lung cancer in adults, IV vinorelbine 25 mg/m² once weekly may be administered in combination with IV cisplatin 100 mg/m² given once every 4 weeks.1 Dosage reductions for both vinorelbine and cisplatin typically were required (see Dosage Modification for Toxicity and Contraindications for Continued Therapy: Hematologic Toxicity).1 Another regimen for the treatment of non-small lung cancer in adults is IV vinorelbine 30 mg/m² administered once weekly in combination with cisplatin (120 mg/m² given on days 1 and 29 and then once every 6 weeks).1

In a dose-ranging study, 32 patients with non-small cell lung cancer receiving vinorelbine 20, 25, or 30 mg/m² weekly plus cisplatin 120 mg/m² on days 1 and 29 then once every 6 weeks had a median survival of 10 months.1 No responses were observed in patients receiving the 20 mg/m²dose;1 a response rate of 33% was observed in patients receiving a vinorelbine dose of either 25 or 30 mg/m².1

According to ASCO practice guidelines, patients with unresectable stage III non-small cell lung cancer (NSCLC) who are candidates for combined chemotherapy and radiation should receive 2 to 4 cycles of initial platinum-based chemotherapy; no more than 4 cycles of chemotherapy are recommended.99 In patients with stage IV NSCLC, a maximum of 4 cycles of first-line chemotherapy should be administered if the disease is not responding to treatment, and a maximum of 6 cycles of chemotherapy should be administered if the disease responds to treatment.99

Monotherapy

For the treatment of non-small cell lung cancer in adults, the manufacturer reports a usual initial dosage of single-agent vinorelbine of 30 mg/m² IV administered once weekly.1

In clinical studies, dosages of vinorelbine have ranged from 15-30 mg/m² IV once weekly.9,11,12,80,85,92

The optimum duration of vinorelbine therapy in patients with non-small cell lung cancer has not been determined, and in clinical trials, patients were treated with single-agent vinorelbine until the occurrence of either dose-limiting toxicity or progression of disease.1 According to ASCO practice guidelines, for patients with stage IV NSCLC, a maximum of 4 cycles of first-line chemotherapy should be administered if the disease is not responding to treatment, and a maximum of 6 cycles of chemotherapy should be administered if the disease responds to treatment.99

Breast Cancer

When used as first-line or salvage (second-line or subsequent) monotherapy in the treatment of advanced/ metastatic breast cancer†, vinorelbine has been infused IV over 20-60 minutes at initial doses of 20-30 mg/m² per week.3,5,9,20,21,22,23,24,25,26,27,28,30,31,32,33,34,35 The drug also has been administered at 30 mg/m² per week as a direct IV injection over 3-5 minutes30 or as a rapid IV dose.3,20,34 However, because of better local tolerance, the manufacturer currently recommends that vinorelbine usually be infused IV over 6-10 minutes.73 (See Dosage and Administration: Administration.) During the course of therapy, the dosing regimen generally was modified (e.g., dosing was delayed or doses were reduced) because of vinorelbine-induced toxicity.3,5,20,21,22,23,24,25,27,28,30,31,32,33,34,35,52

Dosage Modification for Toxicity and Contraindications for Continued Therapy

Hematologic Toxicity

Vinorelbine therapy should not be administered to patients with baseline granulocyte counts less than 1000 cells/ mm³.1 In patients with a granulocyte count less than 1000 cells/ mm³, the granulocyte count should be repeated in 1 week.1 If it is necessary to withhold vinorelbine doses for 3 consecutive weeks because of persistence of a granulocyte count less than 1000 cells/ mm³, therapy with the drug should be discontinued.1 In patients with a granulocyte count of 1000-1499 cells/ mm³, the vinorelbine dose should be reduced to 50% of the starting dose.1

In patients who have experienced fever and/or sepsis because of granulocytopenia during vinorelbine therapy or in patients in whom the vinorelbine dose has been withheld for 2 consecutive weeks because of granulocytopenia, subsequent doses of vinorelbine should be reduced to 75% of the starting dose in patients with a granulocyte count of at least 1500 cells/ mm³and to 37.5% of the starting dose in those with a granulocyte count of 1000-1499 cells/ mm³.1 The vinorelbine dose should be withheld if the granulocyte count is less than 1000 cells/mm³, and the granulocyte count should be repeated in 1 week.1 If it is necessary to withhold vinorelbine doses for 3 consecutive weeks because of persistence of a granulocyte count less than 1000 cells/mm³, therapy with the drug should be discontinued.1

Among patients receiving combination therapy with vinorelbine and cisplatin, blood counts should be checked weekly and dosage of vinorelbine and/or cisplatin should be reduced according to hematologic toxicity.1 In a large randomized trial, most patients required a 50% dose reduction of vinorelbine at day 15 of each cycle and a 50% dose reduction of cisplatin by cycle 3.1

In patients with concurrent hematologic toxicity and hepatic impairment, vinorelbine dosage should be adjusted to the lower dosage advised by these guidelines.1 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Hepatic Toxicity

Dosage of vinorelbine should be reduced in patients who develop hyperbilirubinemia.1 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.) In patients with concurrent hepatic impairment and hematologic toxicity, vinorelbine dosage should be adjusted to the lower dosage advised by these guidelines.1

Renal Toxicity

Reduction of vinorelbine dosage in patients with renal impairment does not appear to be necessary.1 When vinorelbine is used in combination with cisplatin, appropriate dosage reductions for cisplatin should be made in patients with renal impairment.1

Neurologic Toxicity

If manifestations of moderate or severe (grade 2 or higher) neurotoxicity occur in patients receiving vinorelbine, therapy with the drug should be discontinued immediately.1

Dosage in Renal and Hepatic Impairment

The effect of renal and/or hepatic impairment on the disposition of vinorelbine has not been fully established.1 Reduction of vinorelbine dosage in patients with renal impairment does not appear to be necessary.1

Because the drug is extensively metabolized in the liver, doses of vinorelbine should be reduced and the drug should be administered with caution in patients with hepatic impairment.1 In patients with total serum bilirubin concentration of 2 mg/dL or less, no dosage reduction is required.1 In patients with total serum bilirubin concentration of 2.1-3 mg/dL, vinorelbine dose should be reduced to 50% of the starting dose.1 In patients with total serum bilirubin concentration exceeding 3 mg/dL, vinorelbine dose should be reduced to 25% of the starting dose.1 In patients with concurrent hepatic impairment and hematologic toxicity, vinorelbine dosage should be adjusted to the lower dosage advised by these guidelines.1

A similar pattern of adverse effects is observed in patients receiving vinorelbine as a single agent or in combination therapy.1 Unless otherwise noted, incidence data for adverse effects are derived from data for 365 patients (222 patients with advanced breast cancer, 143 patients with non-small cell lung cancer) receiving vinorelbine as a single agent in 3 clinical studies.1 The dosing schedule in each study was vinorelbine 30 mg/m² once weekly.1

Hematologic Effects and Infectious Complications

The major and dose-limiting adverse effect of vinorelbine is myelosuppression,1 manifested principally by granulocytopenia1,80,92 and leukopenia.1 The incidence of myelosuppression does not appear to be influenced by age or prior exposure to chemotherapy.1 Granulocyte counts less than 2000 and 500/mm³ occurred in 90 and 36% of patients, respectively.1 Leukopenia (less than 4000/mm³) occurred in 92% of patients, and was severe (less than 1000 cells/mm³) in 15% of patients.1 Leukopenia occurred at a similar rate in patients receiving vinorelbine and cisplatin in randomized trials (88 or 94%), but the rate of grade 3 or 4 leukopenia was higher (about 60%).1 Hospitalization for granulocytopenic complications (e.g., fever,1 sepsis,1 infection,24,25,27,28,30,33,80 pneumonia1,33 ) occurred in 9% of patients.1 Hospitalization for documented sepsis was reported in about 4% of patients receiving vinorelbine either alone or with cisplatin.1 Septic death occurred in approximately 1% of patients.1,92

The manufacturer states that, although the pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin, the incidence of granulocytopenia is higher when vinorelbine is used in combination with cisplatin than when it is used as a single agent.1 In a clinical trial in which patients were randomized to receive single-agent vinorelbine or vinorelbine plus cisplatin, grade 3 or 4 granulocytopenia occurred more frequently with the combination (79%) than with single-agent vinorelbine (53%).1 In another randomized trial, grade 3 or 4 granulocytopenia occurred more frequently in those receiving vinorelbine and cisplatin (82%) than in those receiving cisplatin alone (5%); fever and/or sepsis related to granulocytopenia occurred in 11% of patients receiving combination therapy compared with 0% of patients receiving cisplatin alone, and 4 patients receiving vinorelbine and cisplatin died of granulocytopenia-related sepsis.1 In the same study, death from febrile neutropenia occurred in 3 patients receiving vinorelbine and cisplatin.1 Infection (unspecified type) was reported in 11% of patients receiving vinorelbine and cisplatin compared with less than 1% of those receiving cisplatin alone, and severe infection occurred in 6% of patients receiving combination therapy.1 Respiratory infection was reported in patients receiving vinorelbine and cisplatin (10%) or cisplatin alone (3%).1

Vinorelbine-induced myelosuppression generally is reversible and does not appear to increase with cumulative exposure.1,5,21,22,44 Granulocyte nadirs generally occur between 7-10 days after dosing, and granulocyte count recovery usually occurs within the following 7-14 days.1,5,21,23,26 However, granulocytopenia may require dosage adjustment,1,5,26 treatment delay,1,5,26,44 or drug discontinuance.1,31 Among patients with non-small cell lung cancer receiving vinorelbine and cisplatin who experienced grade 3 or 4 granulocytopenia (1000/mm³ or less) following the first course of therapy or who developed neutropenic fever between cycles of therapy, the use of granulocyte colony-stimulating factor (G-CSF) was permitted.1 At 24 hours following completion of chemotherapy, G-CSF 5 mcg/kg daily was initiated and continued until the total granulocyte count exceeded 1000/mm³ on 2 successive determinations; G-CSF was not administered on the day of treatment.1 Some data suggest that the addition of filgrastim to vinorelbine therapy may reduce the duration and severity of granulocytopenia and/or allow dose intensification.61,65

Anemia1,80,92 (hemoglobin less than 11 g/dL) was reported in 83% of patients, and was severe (hemoglobin less than 8 g/dL) in 9% of patients.1 Whole blood and/or packed red blood cells were administered to 18% of patients who received vinorelbine.1 Among patients with non-small cell lung cancer in a randomized trial, grade 3 or 4 anemia occurred more frequently in those receiving vinorelbine and cisplatin (24%) than in those receiving cisplatin alone (8%).1

Thrombocytopenia (less than 100,000/mm³) developed less frequently than granulocytopenia, neutropenia, or anemia, occurring in 5% of patients; severe thrombocytopenia (less than 50,000/mm³) was reported in 1% of patients.1 In randomized trials, grade 3 or 4 thrombocytopenia was reported in 6% of those receiving vinorelbine and cisplatin compared with 2% of those receiving cisplatin alone, and in 4% of those receiving vinorelbine and cisplatin compared with 0% of those receiving vinorelbine alone.1

Nervous System Effects

Peripheral neuropathy, manifested by paresthesia and hypesthesia,1,80,86 occurred in 25% of patients, and was grade 3 or 4 in 1% and less than 1% of patients, respectively.1 Painful paresthesia with marked motor loss on the plantar surfaces has been reported rarely.25 Peripheral neuropathy may be related to cumulative dose44,86 and is generally reversible upon drug discontinuance.1,21,31,44,86

In a randomized trial, the incidence of grade 3 or 4 peripheral numbness was higher in patients receiving vinorelbine and cisplatin than in those receiving cisplatin alone (2 versus 1%); paresthesias occurred in 17% of patients receiving combination therapy versus 10% of those receiving cisplatin alone.1 In another randomized study, the incidence of neurotoxicity (including peripheral neuropathy and constipation) was similar in patients receiving combination therapy with cisplatin and vinorelbine compared with those receiving single-agent vinorelbine (44%).1

Loss of deep tendon reflexes occurred in less than 5% of patients.1 Myasthenia also has been reported.23 Adverse peripheral nervous system effects, including muscle weakness and gait disturbance, have been observed in patients with and without prior symptoms.1 Patients with preexisting neuropathy, regardless of etiology, or previous or concomitant exposure to neurotoxic agents (e.g., paclitaxel) may be at increased risk for adverse nervous system effects when receiving vinorelbine.1,5,79,86 (See Cautions: Precautions and Contraindications.)

Asthenia was reported in 36% of patients, and was grade 3 in 7% of patients.1 Fatigue occurred in 27% of patients receiving vinorelbine.1 Fatigue is usually mild to moderate in severity, although the frequency and severity tend to increase with dose1,21 or repeated drug administration.21 Malaise, fatigue, or lethargy was reported in 67% of patients receiving vinorelbine and cisplatin versus 49% of those receiving cisplatin alone.1 Dizziness,23 hyperalgesia,25 confusion,57 disorientation,57 hyporeflexia,86 insomnia,23 headache,1 generalized pain,23,75,80 pain in tumor-containing tissue,1,21 and back pain1,21 also have been reported. In a randomized trial, dizziness/vertigo was reported in patients receiving vinorelbine and cisplatin (9%) or cisplatin alone (3%).1

Vestibular and auditory deficits have been reported in patients receiving vinorelbine, principally in those receiving cisplatin concomitantly.1 Taste alterations occurred at a similar rate among patients receiving vinorelbine and cisplatin versus cisplatin alone (17 versus 15%) in a randomized trial.1

Respiratory Effects

Cases of interstitial pulmonary changes and acute respiratory distress syndrome (ARDS), most of which were fatal, have been reported in patients receiving vinorelbine as monotherapy.1 The mean time to onset of symptoms was 1 week (range: 3-8 days) after vinorelbine administration.1 Patients who experience an increase in baseline pulmonary manifestations or the onset of new manifestations (e.g., dyspnea, cough, hypoxia) should undergo prompt evaluation.1

Acute shortness of breath and severe bronchospasm have been reported infrequently following the administration of vinorelbine and other vinca alkaloids, usually when administered in combination with mitomycin.1 These adverse pulmonary events may require treatment with supplemental oxygen, bronchodilators, and/or corticosteroids, particularly in patients with preexisting pulmonary dysfunction.1

Dyspnea1,23,26,80,83 was reported in 7% of patients, and was severe (grade 3 or 4) in 3% of patients.1 Shortness of breath1,21 was reported in 3% of patients, and was severe in 2% of patients.1 (See Cautions: Precautions and Contraindications.) Interstitial pulmonary changes,1 hypoxia,23 and pneumonia1,31 also have been reported. Adverse respiratory effects associated with hypersensitivity to vinorelbine also have been reported.9,21,61 Acute pulmonary reactions to vinorelbine usually resemble an allergic reaction and respond to bronchodilators.21 Subacute pulmonary reactions generally occur within 1 hour after vinorelbine administration and manifest as cough, dyspnea, hypoxemia, and interstitial infiltration.21 These reactions usually respond to corticosteroid administration.21

GI Effects

A fatal case of neutropenic enterocolitis (typhlitis) occurred in a patient following a single dose of vinorelbine.123

Severe constipation (grade 3 or 4), paralytic ileus, and intestinal obstruction, necrosis, and perforation have been reported in patients receiving vinorelbine.1 In some cases, these events have been fatal.1

Nausea was reported in 44% of patients receiving vinorelbine, and was grade 3 in 2% of patients.1 Antiemetic agents generally were not administered prophylactically in clinical trials, and serotonin type 3 (5-HT₃) receptor antagonists generally are not required for management of nausea and vomiting.1,21 Vomiting was reported in 20% of patients, and was grade 3 in 2% of patients.1 Nausea and vomiting usually occur within 24 hours of vinorelbine dosing.25 Nausea or vomiting each was reported at a similar rate (about 60%) in patients receiving vinorelbine and cisplatin or cisplatin alone in a randomized trial.1 In another randomized trial, grade 3 or 4 nausea and/or vomiting occurred more frequently in patients receiving vinorelbine and cisplatin (30%) than in those receiving vinorelbine alone (2%).1

Constipation occurred in 35% of patients receiving vinorelbine, and was severe in 3% of patients.1 Constipation may cause treatment delay.31 Grade 3 or 4 constipation and/or paralytic ileus was reported in 3% of patients receiving vinorelbine and cisplatin and in 1% of patients receiving cisplatin.1 Diarrhea was reported in 17% of patients, and was grade 3 in 1% of patients.1 Similar or higher rates of diarrhea (17 or 25%) were reported in patients receiving vinorelbine and cisplatin in randomized trials.1 Anorexia occurred at a similar rate in patients receiving vinorelbine and cisplatin (46%) or cisplatin alone (37%);1 anorexia has been reported in patients receiving vinorelbine alone.44,57,80 Stomatitis also has been reported in patients receiving vinorelbine.1,80 Vomiting, diarrhea, anorexia, and stomatitis usually were mild or moderate in severity.1,80 In a randomized clinical trial, severe nausea and vomiting was reported in 30% of patients receiving vinorelbine concomitantly with cisplatin, compared with less than 2% of patients receiving single-agent vinorelbine.1 Duration of vinorelbine treatment, previous therapy with emetogenic agents, prior abdominal irradiation, and/or pathology of the abdominal cavity may increase the incidence and severity of GI adverse effects.5

Dysphagia,1 mucositis,1,44,61,76,85 dyspepsia,23 epigastralgia,75 pancreatitis,1,77,82 esophagitis85 or radiation recall esophagitis,1 and abdominal pain1,23 also have been reported in patients receiving vinorelbine.1 Ischemic colitis occurred in a patient receiving vinorelbine and cisplatin.119

Cardiovascular Effects

Fatal cardiovascular effects have been reported rarely when vinorelbine was used with cisplatin.1

In a randomized trial, 2 deaths related to myocardial ischemia and one death from massive stroke occurred in patients receiving vinorelbine and cisplatin.1

Chest pain1,9,21,28,44,75,80 was reported in 5% of patients receiving vinorelbine in clinical trials.1 Most patients experiencing chest pain had a history of cardiovascular disease or tumor within the chest.1,9 Myocardial ischemia81 and infarction,1,21,81 and cardiogenic shock87 have been reported rarely.1 Flushing,1 hypertension,1 hypotension,1 vasodilation,1 tachycardia,1 and pulmonary edema1,87,129 also have been reported.

Thromboembolic adverse effects, including pulmonary embolus and deep venous thrombosis, have been reported in patients receiving vinorelbine, principally in those who were seriously ill and debilitated with known predisposing risk factors for these adverse effects.1 In a randomized trial, phlebitis/thrombosis/embolism occurred in 10% of those receiving vinorelbine and cisplatin versus less than 1% of those receiving cisplatin alone; these adverse effects were grade 3 or 4 in severity in 3% of those receiving combination therapy versus less than 1% of those receiving cisplatin alone.1 Central venous catheter thrombosis has been reported in patients receiving vinorelbine by continuous IV infusion.44

Hepatic Effects

Fatal hepatic failure has been reported in a patient receiving vinorelbine and gemcitabine.120

Increased serum AST (SGOT) concentrations1,9,21,23,26,80 occurred in 67%, and increased serum total bilirubin concentrations1,9,21,23,26,80 occurred in 13% of patients.1 Increased serum ALT (SGPT) concentrations21,23,80 and increased serum alkaline phosphatase concentrations23 also have been reported. Transient elevations in hepatic enzymes generally were not associated with clinical symptoms.1,21,26,80 However, vinorelbine should be used with caution in patients with hepatic insufficiency, and dosage adjustment may be required.1,9 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Dermatologic Effects

Alopecia, manifested as a gradual thinning of hair,21 was reported in 12% of patients1 and was reversible.9 Total hair loss was uncommon.21 In a randomized trial, alopecia occurred more frequently in patients receiving vinorelbine and cisplatin (34%) than in those receiving cisplatin alone (14%); in another randomized trial, the incidence of alopecia was higher among patients receiving vinorelbine and cisplatin than in those receiving vinorelbine alone (51 versus 30%), including grade 3 or 4 alopecia (8 versus 2%).1 Radiation recall dermatitis1 has been reported.

Hand-foot syndrome,76 generally manifested as bilateral erythema of both the hands and feet, which responds to corticosteroids, has been reported in patients receiving vinorelbine by prolonged (96-hour) IV infusion; the mechanism of the reaction is unclear, but it appears to be dose related.76 In vitro, vinorelbine has been shown to stimulate histamine release from mast cells.88

Local Effects

Vinorelbine is a moderate vesicant.1 Injection site reactions and injection site pain occurred in 28 and 16% of patients, respectively.1 Injection site reactions, including reactions secondary to extravasation, usually were mild and were characterized by erythema, pain at the injection site, and vein discoloration; 5% were severe.1 Among patients receiving vinorelbine and cisplatin in randomized trials, injection site reactions occurred in 17% and were severe in up to 2% of patients.1 In clinical practice, injection site reactions also have been characterized by localized rash, urticaria, blister formation, and skin sloughing.1

The incidence of injection site reactions may be dose related,80 and delayed onset of injection site reactions also has been reported.1 Chemical phlebitis along the vein proximal to the injection site was reported in 10% of patients receiving vinorelbine.1

The incidence of adverse local reactions appears to be lower when vinorelbine is administered over 6-10 minutes rather than 20 minutes,5,20,21,80,95 and when the veins are flushed with 75-125 mL of IV fluid after the infusion is completed.20,21 The incidence of adverse local reactions also may be decreased by flushing the vein with 100 mL of fluid before administering vinorelbine and then flushing with an additional 400 mL of fluid following completion of the vinorelbine infusion.73,95 Dexamethasone has been added to the IV fluid used to flush the vein following completion of the vinorelbine infusion to help prevent adverse local reactions.73,96 Treatment of injection site reactions has included silver sulfadiazine, local hyaluronidase injection, warm compresses, and central venous catheter placement.80

Supravenous hyperpigmentation at the infusion site9 and a localized necrotizing epidermal reaction9,21 each have been reported rarely.9

Renal Effects

Elevated serum creatinine concentration was reported in a randomized trial in 13% of patients receiving vinorelbine as a single agent versus 46% of patients receiving vinorelbine and cisplatin; in another randomized trial, elevated serum creatinine concentration occurred at a similar rate among patients receiving vinorelbine and cisplatin (37%) or cisplatin alone (28%).1

Musculoskeletal Effects

Jaw pain,1,9,21,23,61 myalgia,1,23,25,61,71,80 and arthralgia1,80 each have been reported in less than 5% of patients receiving vinorelbine.1 In a randomized trial, myalgia/arthralgia was reported in 12% of patients receiving vinorelbine and cisplatin versus 3% of patients receiving cisplatin alone.1 Myalgias generally are controlled with nonopioid analgesics but may require treatment delay until symptoms are relieved.25

Sensitivity Reactions

Rash1,21,80 has been reported in less than 5% of patients receiving vinorelbine.1 Systemic allergic reactions,1,24 including anaphylaxis, pruritus, urticaria, and angioedema also have been reported.1 Drug fever44 has been reported in patients receiving high doses of vinorelbine as a continuous infusion.44

Other Effects

Hemorrhagic cystitis1,21,80 and the syndrome of inappropriate ADH secretion1,21 each were reported in less than 1% of patients receiving vinorelbine.1 Electrolyte abnormalities, including hyponatremia with or without the syndrome of inappropriate ADH secretion, have been reported in seriously ill and debilitated patients receiving vinorelbine.1 Weight loss has been reported in 34% of patients receiving vinorelbine and cisplatin and in 21% of those receiving cisplatin alone in a randomized trial.1 Fever without infection occurred more frequently in patients receiving vinorelbine and cisplatin than in those receiving cisplatin alone (20 versus 4%).1 Hearing loss or impairment occurred at a similar rate (18%) among patients receiving either vinorelbine and cisplatin or cisplatin alone in a randomized trial; in another randomized trial, ototoxicity occurred in 10% of patients receiving vinorelbine and cisplatin versus 1% of patients receiving vinorelbine alone.1

Precautions and Contraindications

Vinorelbine is a toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without evidence of toxicity.1 The drug must be used only under constant supervision by clinicians experienced in therapy with cytotoxic agents and only when the potential benefits of vinorelbine therapy are thought to outweigh the possible risks.1 Most adverse effects of vinorelbine are reversible.1 When severe adverse effects occur during vinorelbine therapy, the drug should be discontinued or dosage reduced and appropriate measures initiated.1 Vinorelbine should be reinstituted with caution, if at all, with adequate consideration of further need for the drug, and with awareness of possible recurrence of toxicity.1 (See Dosage and Administration: Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy.)

Administration of vinorelbine is contraindicated in patients with baseline granulocyte counts less than 1000 cells/mm³,1 and the drug should be administered with extreme caution in patients whose bone marrow reserve may have been compromised by prior irradiation or chemotherapy, or in patients whose marrow function is recovering from the effects of previous chemotherapy.1 To monitor the occurrence of vinorelbine-induced myelosuppression, mainly granulocytopenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts with differentials be performed before administration of each vinorelbine dose and following discontinuance of therapy with the drug.1 Vinorelbine therapy should be withheld in patients with granulocyte counts less than 1000 cells/mm³.1 Patients with severe vinorelbine-induced granulocytopenia should be monitored carefully for evidence of infection and/or fever.1 For further instructions regarding monitoring and dosage adjustment according to hematologic toxicity, see Dosage Modification for Toxicity: Hematologic Toxicity in Dosage and Administration: Dosage.

Prophylactic colony-stimulating factors have not been used routinely with vinorelbine.1 However, as clinically indicated, such hematopoietic agents may be used at recommended doses no sooner than 24 hours following completion of the administration of cytotoxic chemotherapy.1 Growth factors should not be administered in the 24-hour period preceding the administration of chemotherapy.1 Hematopoietic agents also may be indicated for the treatment of vinorelbine overdosage.1

Patients should be informed that the major acute toxicities of vinorelbine are related to bone marrow toxicity, particularly granulocytopenia with increased susceptibility to infection, and should be advised to report fever or chills immediately.1 Patients also should be advised to contact their clinician if they experience increased shortness of breath, cough, or other new respiratory symptoms, or if they experience abdominal pain or constipation.1

Administration of vinorelbine to patients who have received prior radiation therapy may result in radiation recall reactions, such as dermatitis and esophagitis.1

Patients who have experienced neuropathy with previous drug therapy (e.g., paclitaxel-associated neuropathy) should be monitored for symptoms of neuropathy while receiving vinorelbine.1,74 Patients with a previous or preexisting neuropathy, regardless of etiology, as well as those receiving combination therapy with vinorelbine and paclitaxel, either concomitantly or sequentially, should be monitored for new or worsening signs and symptoms of neuropathy while receiving vinorelbine.1 For further instructions regarding dosage adjustment according to neurologic toxicity, see Dosage Modification for Toxicity: Neurologic Toxicity in Dosage and Administration: Dosage.

Acute shortness of breath and severe bronchospasm have been reported infrequently following the administration of vinorelbine and other vinca alkaloids, most commonly when these agents were used in combination with mitomycin.1 If a patient develops these adverse effects during administration of vinorelbine, appropriate therapy (e.g., supplemental oxygen, bronchodilators, corticosteroids) may be required, particularly in patients with preexisting pulmonary dysfunction.1

Because severe irritation of the eye has been reported with accidental exposure to another vinca alkaloid, the manufacturer states that care must be taken to avoid contamination of the eyes with concentrations of vinorelbine used clinically.1 If ocular exposure occurs, the eye(s) should be thoroughly flushed with water immediately.1

There is no evidence that the toxicity of vinorelbine is greater in patients with elevated serum hepatic enzyme concentrations, and no data are available regarding the use of the drug in patients with severe baseline cholestasis.1 Because vinorelbine is metabolized mainly in the liver and clinical experience with the drug in patients with severe liver disease is limited, vinorelbine should be administered with caution in patients with severe hepatic injury or impairment, and dosage reduction may be necessary.1 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Pediatric Precautions

Safety and efficacy of vinorelbine in children younger than 18 years of age have not been established.1,20 No meaningful clinical activity was demonstrated among 46 pediatric patients receiving vinorelbine (at dosages similar to those used in adults) for recurrent solid malignant tumors, including rhabdomyosarcoma/undifferentiated sarcoma, neuroblastoma, and CNS tumors; children experienced similar toxicities as adults.1

Geriatric Precautions

When the total number of patients studied in North American clinical trials of vinorelbine is considered, approximately one-third were 65 years of age or older.1 Although no overall differences in efficacy or safety were observed between geriatric and younger patients,1 and other clinical experience revealed no evidence of age-related differences,1,55,75,85 the possibility that some geriatric patients may exhibit increased sensitivity to the drug cannot be ruled out.1

Mutagenicity and Carcinogenicity

In in vivo studies, vinorelbine has been shown to cause chromosomal damage (polyploidy in bone marrow cells from Chinese hamsters and positive results of the micronucleus test in mice).1 The drug was not mutagenic in the Ames test, and results of the mouse lymphoma TK locus assay were inconclusive.1

Studies to determine the carcinogenic potential of vinorelbine have not been performed to date.1

Pregnancy, Fertility, and Lactation

Pregnancy

Vinorelbine can cause fetal toxicity when administered to pregnant women,1 but potential benefits from use of the drug may be acceptable in certain conditions despite the possible risks to the fetus.89,90 Vinorelbine has been shown to be embryotoxic and/or fetotoxic in mice and rabbits at single doses of 9 and 5.5 mg/m², respectively (one-third and one-sixth the usual human dose).1 At doses that were not toxic to the pregnant animal, fetal weight was reduced and ossification was delayed.1 Vinorelbine and fluorouracil were administered to 3 women with breast cancer during the second or third trimester of pregnancy.84 The infants were delivered at 34, 37, and 41 weeks' gestation and no chemotherapy-related adverse effects were observed except for anemia in one infant, which occurred 21 days after delivery.84 There are no adequate and controlled studies to date using vinorelbine in pregnant women.1 Vinorelbine should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective.1,89,90 When vinorelbine is administered during pregnancy or the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.1 Women of childbearing potential should be advised to avoid becoming pregnant while receiving the drug.1

Fertility

Vinorelbine did not affect fertility when administered to rats on either a once-weekly (9 mg/m², approximately one-third the usual human dose) or alternate-day (4.2 mg/m², approximately one-seventh the usual human dose) schedule preceding and during mating.1 However, studies in rats using biweekly (i.e., once every 2 weeks) administration of vinorelbine for 13 or 26 weeks at doses of 2.1 and 7.2 mg/m² (approximately one-fifteenth and one-fourth the usual human dose, respectively) showed decreased spermatogenesis and prostate/seminal vesicle secretion.1,73

Lactation

It is not known whether vinorelbine is distributed in milk.1 Because many drugs are distributed in milk and because of the potential for serious adverse reactions to vinorelbine in nursing infants, nursing should be discontinued during vinorelbine therapy.1

Antineoplastic Agents

Acute pulmonary reactions have been reported in patients receiving vinorelbine or other vinca alkaloids (vinblastine, vincristine) in combination with mitomycin.1 (See Cautions: Respiratory Effects.) A higher incidence of grade 3 and 4 granulocytopenia has been reported in patients receiving combination therapy with vinorelbine and cisplatin than in those receiving vinorelbine alone.1 (See Cautions: Hematologic Effects and Infectious Complications.) Concomitant administration of vinorelbine and paclitaxel may be associated with an increased risk of neuropathy.1 (See Cautions: Nervous System Effects.)

Drugs Affecting Hepatic Microsomal Enzymes

Metabolism of vinca alkaloids is mediated by the cytochrome P-450 (CYP) isoenzyme CYP3A, and inhibitors of this isoenzyme may impair the metabolism of vinca alkaloids.1 Caution is advised since concomitant administration of vinorelbine and inhibitors of isoenzyme CYP3A may cause earlier onset and/or increased severity of adverse effects.1

Death occurred in a patient following chemotherapy with vinorelbine and cisplatin; an interaction between vinorelbine and itraconazole was cited as possible cause.121

Concomitant use of itraconazole, a potent inhibitor of CYP3A, and another vinca alkaloid, vincristine, has been associated with earlier onset and/or increased severity of adverse neuromuscular effects, probably related to inhibition of vincristine metabolism.101 In vitro studies demonstrate that voriconazole is a less potent inhibitor of CYP3A4 than ketoconazole or itraconazole.102 Because concomitant use of voriconazole or other azole antifungal agents may increase plasma concentrations of vinca alkaloids, such as vinorelbine, and lead to neurotoxicity, dosage reduction of vinorelbine should be considered.102

Caution and careful monitoring are advised during concomitant use of a vinca alkaloid and aprepitant, an antiemetic agent, which may inhibit or induce CYP3A4.103 In clinical studies, the dosage of vinorelbine was not adjusted during concomitant use of aprepitant.103

Ototoxic Drugs

Because vestibular deficits and varying degrees of permanent or temporary hearing impairment associated with damage of the eighth cranial nerve have been reported in patients receiving vinca alkaloids,1,93 vinorelbine should be used concomitantly with other potentially ototoxic drugs, such as platinum-containing antineoplastic agents, with extreme caution.1

Acute Toxicity

Manifestations

Overdosage with vinorelbine produces adverse effects that are mainly extensions of common adverse effects, including paralytic ileus, stomatitis, and esophagitis.1 Bone marrow aplasia, sepsis, and paresis also have been reported.1 Overdoses of up to 10 times the recommended dose of 30 mg/m² have been reported, and some fatalities have occurred.1 Death from multisystem failure caused by an overdose of vinorelbine has been reported in a patient receiving the drug in combination with cisplatin.1

Treatment

There is no known specific antidote for vinorelbine overdosage.1 Management of vinorelbine overdosage should consist of general supportive measures and symptomatic treatment, including blood transfusions, hematopoietic agents, and anti-infectives, when clinically indicated.1

Pharmacology

Vinorelbine is an antimicrotubule antineoplastic agent. 2,3,4,5,6,7,8,9,10,21 Microtubules are organelles that exist in a state of dynamic equilibrium with their components, tubulin dimers.8,14,15,16,17,21 They form an essential part of the mitotic spindle, participate in intracellular transport, and contribute to the cell's shape, rigidity, and motility.8,14,15,16,17

Vinorelbine and other vinca alkaloids exert their cytotoxic effects by binding to tubulin, the protein subunit of the spindle microtubules.3,5,6,7,8,9,10,21 The formation of vinorelbine-tubulin complexes prevents the polymerization of the tubulin subunits into microtubules and induces depolymerization of microtubules resulting in inhibition of microtubule assembly and cellular metaphase arrest.1,3,5,6,7,8,9,10,21

In addition to the antineoplastic effects of antimicrotubule activity, vinca alkaloids interfere with the microtubule-mediated movement of neurotransmitter substances along neuronal axons resulting in dose-limiting neurotoxicity.2,8,21 Although the depolymerizing action of vincristine, vinblastine, and vinorelbine on axonal microtubules is identical, this action occurs in vitro at higher concentrations of vinorelbine than these other vinca alkaloids, and in vitro studies suggest that vinorelbine has a higher affinity than these drugs for mitotic rather than axonal microtubules.1,2,3,4,5,8,21 In comparative clinical trials, vinorelbine was shown to be less neurotoxic than vindesine, another vinca alkaloid.9,12,21

Like other vinca alkaloids, vinorelbine reportedly also interferes with amino acid, cyclic AMP, and glutathione metabolism; calmodulin-dependent Ca²⁺-transport ATPase activity; cellular respiration; and nucleic acid and lipid biosynthesis.1,21

Pharmacokinetics

Absorption

Following IV administration, plasma concentrations of vinorelbine decline in a triphasic manner with an initial rapid decrease.1

Distribution

The initial rapid decline in plasma vinorelbine concentration following IV administration represents distribution of the drug to peripheral compartments.1 Following administration of vinorelbine 30 mg/m² IV over 15-20 minutes, a steady-state volume of distribution of 25.4-40.1 L/kg has been reported.1

Vinorelbine demonstrates high binding to human platelets and lymphocytes.1 Binding of the drug to plasma constituents in patients with cancer ranges from 79.6-91.2%, and a free fraction of approximately 0.11 was observed in pooled human plasma over a concentration range of 234-1169 ng/mL.1 The presence of cisplatin, fluorouracil, or doxorubicin does not affect vinorelbine binding.1

Elimination

The 3 phases of plasma decline of vinorelbine concentrations represent an initial rapid decline in plasma concentrations caused by distribution of the drug to peripheral compartments followed by metabolism and excretion of the drug and a prolonged terminal phase because of relatively slow efflux of drug from peripheral compartments.1 A mean terminal elimination half-life of 27.7-43.6 hours and a mean plasma clearance of 0.97-1.26 L/hour per kg have been reported for vinorelbine.1

Vinorelbine is extensively metabolized in the liver.1 The metabolism of vinca alkaloids (e.g., vinblastine, vincristine) is mediated by the cytochrome P-450 (CYP) isoenzymes in the CYP3A subfamily.1 Two metabolites of vinorelbine, vinorelbine N -oxide and deacetylvinorelbine, have been identified in human blood, plasma, and urine.1 Deacetylvinorelbine, the primary metabolite of vinorelbine in humans, has been shown to possess antitumor activity similar to the parent drug.1 However, therapeutic doses of vinorelbine result in very small, if any, quantifiable concentrations of either metabolite in blood or urine.1

Following IV administration of radiolabeled vinorelbine, approximately 46% of the administered dose was recovered in the feces and 18% in the urine.1 In another study, approximately 11% of an administered IV dose of vinorelbine was excreted unchanged in the urine.1

The effect of renal and/or hepatic impairment on the elimination of vinorelbine has not been evaluated.1 Limited data from pharmacokinetic studies indicate that the disposition of the drug in geriatric patients is similar to that observed in younger adults.1

Chemistry and Stability

Chemistry

Vinorelbine (didehydrodeoxynorvincaleukoblastine), a semisynthetic vinca alkaloid, is an antineoplastic agent.1,2,3,4,5,6,7,8,9,10,11,12,21 Like other vinca alkaloids, vinorelbine is a large dimeric asymmetric compound composed of a dihydroindole nucleus (vindoline), which is the major alkaloid present in the periwinkle ( Catharanthus roseus [Apocynaceae]), and an indole nucleus (catharanthine), which is present in low concentrations in the plant.2,4,21 However, vinorelbine differs structurally from other currently available vinca alkaloids by the presence of substitutions on the catharanthine ring, rather than the vindoline ring, of the molecule.1,2,3,4,5,9,21

Vinorelbine tartrate occurs as a white to yellow or light brown amorphous powder.1 The aqueous solubility of the drug exceeds 1000 mg/mL in distilled water.1 Commercially available vinorelbine tartrate injection occurs as a clear, colorless to pale yellow solution in water for injection and has a pH of approximately 3.5.1

Stability

Commercially available vinorelbine tartrate injection is stable until the date indicated on the package when stored unopened and refrigerated at 2-8°C and protected from light.1 Unopened vials of vinorelbine tartrate injection are stable at temperatures up to 25°C for up to 72 hours.1 Vinorelbine tartrate injection should not be frozen.1

For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

1. GlaxoSmithKline. Navelbine^® (vinorelbine tartrate) injection prescribing information. Research Triangle Park, NC; 2002 Nov.

2. Glaxo Wellcome Inc. Treatment IND protocol: Treatment IND for patients with unresectable stage III or IV NSLC and product information. Research Triangle Park, NC: 1994 Mar.

3. Glaxo Wellcome Inc. Navelbine injection product information. Research Triangle Park, NC: 1994 Mar.

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7. Binet S. In situ analysis of the action of navelbine on various types of microtubules using immunofluorescence. Semin Oncol . 1989; 16(Suppl 4):5-8. [PubMed 2652320]

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13. Burroughs Wellcome Company, Research Triangle Park, NC: Personal communication.

14. Horwitz SB. Mechanism of action of taxol. Trends Pharmacol Sci . 1992; 13:134-6. [PubMed 1350385]

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