Vinorelbine (Monograph)

Brand name: Navelbine
Drug class: Antineoplastic Agents
- Vinca Alkaloids
- Antimitotic Agents
VA class: AN900
Chemical name: 3′,4′-Didehydro-4′-deoxy-C′-norvincaleukoblastine [R-(R*, R*)]-2,3-dihydroxybutane dioate (1:2)
Molecular formula: C₄₅H₅₄N₄O₈•2C₄H₆O₆

Introduction

Antineoplastic agent; semisynthetic vinca alkaloid.

Uses for Vinorelbine

Non-Small Cell Lung Cancer

Used alone or in combination with cisplatin as first-line therapy in ambulatory patients for the palliative treatment of unresectable, advanced non-small cell lung cancer (NSCLC).

Used alone or in combination with cisplatin in patients with Stage IV NSCLC.

Use in combination with cisplatin is preferred treatment of advanced NSCLC in patients with good performance status because of improved response and survival.

Used in combination with cisplatin in patients with Stage III NSCLC.

Use in combination with cisplatin is being investigated for adjuvant treatment of completely resected NSCLC^{† [off-label]}.

Breast Cancer

Use in combination with trastuzumab is being investigated for the treatment of HER2-overexpressing metastatic breast cancer^{† [off-label]}.

Has been used as first-line or salvage therapy for metastatic breast cancer in combination with various other agents^{† [off-label]}, including anthracyclines (e.g., doxorubicin), fluoropyrimidines (e.g., fluorouracil, capecitabine), mitoxantrone, cisplatin, taxanes (e.g., docetaxel, paclitaxel), ifosfamide, or gemcitabine.

Has been used as monotherapy in first-line or salvage (e.g., second-line or subsequent) treatment of metastatic breast cancer^{† [off-label]}.

Cervical Cancer

Use in the treatment of metastatic or recurrent cervical cancer^{† [off-label]} is being investigated.

Use in combination with other antineoplastic agents (e.g., cisplatin) is being evaluated in patients with metastatic or recurrent cervical cancer^†.

Adult Soft Tissue Sarcomas

Has been used in the treatment of adult soft tissue sarcomas^†.

Esophageal Cancer

Has been used in the treatment of esophageal cancer^†.

Related/similar drugs

Opdivo, methotrexate, Keytruda, Avastin, pembrolizumab, cisplatin, Tagrisso

Vinorelbine Dosage and Administration

General

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.

• Handle drug with caution and avoid exposure (e.g., use gloves) during handling and preparation of IV solution. If skin or mucosal contact occurs, immediately and thoroughly wash skin or mucosa with soap and water.

• Avoid contact of the drug with the eyes since severe irritation may occur; immediately wash eyes thoroughly with water.

Administration

IV Administration

For solution and drug compatibilty information, see Compatibility under Stability.

Administer IV only by individuals experienced in the administration of the drug.

Very irritating; do not administer IM, sub-Q, or intrathecally. Intrathecal administration of other vinca alkaloids has resulted in death. (See Boxed Warning.)

Management of patients mistakenly receiving intrathecal vinorelbine is a medical emergency. (See Intrathecal Administration under Cautions.)

Administer by IV injection, usually at weekly intervals. Inject the diluted injection concentrate into a free-flowing IV infusion or a large central vein.

Has been administered as a continuous IV infusion^†.

Extravasation

Extremely important to ensure that needle or catheter is securely within vein to avoid extravasation. If extravasation occurs, discontinue injection immediately and administer remainder of dose through another vein.

Dilution

Dilute injection concentrate prior to injection 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.

Rate of Administration

Administer over 6–10 minutes into the side port closest to the IV bag of a free-flowing IV infusion or into a large central vein. Follow by flushing with at least 75–125 mL of 0.9% sodium chloride injection or 5% dextrose injection over a period of 10 minutes.

Dispensing Precautions

When dispensing, must label syringe holding the individual dose with the statement: “Warning: For IV use only. Fatal if given intrathecally.”

Dosage

Available as vinorelbine tartrate; dosage expressed in terms of vinorelbine.

Adults

Non-small Cell Lung Cancer

Monotherapy

IV

Initially, 30 mg/m² once weekly until disease progression or dose-limiting toxicity occurs.

Combination Therapy

IV

Vinorelbine 25 mg/m² once weekly in combination with cisplatin 100 mg/m² every 4 weeks.

Alternatively, vinorelbine 30 mg/m² once weekly in combination with cisplatin (120 mg/m² on days 1 and 29 and then once every 6 weeks).

Breast Cancer†

First-line or Salvage (second-line or subsequent) Monotherapy

IV

Initially, 20–30 mg/m² (infused over 20–60 minutes) weekly.

Alternatively, 30 mg/m² weekly as a direct IV injection over 3–5 minutes or as a rapid IV dose. However, manufacturers recommend to infuse over 6–10 minutes to improve local tolerance.

Adjust doses (e.g., delay or reduce doses) throughout therapy to minimize potential toxicity.

Dosage Modification for Toxicity

Hematologic Toxicity

Granulocyte counts should be ≥1000/mm³ prior to administration.

Perform CBC with differential before administration of each dose; consider withholding next dose in patients with granulocytopenia or infectious complications.

Adjust dosage according to hematologic toxicity.

Hepatic Toxicity

Adjust dosage according to hepatic toxicity.

Reduce dosage in patients who develop hyperbilirubinemia based on total bilirubin levels.

Adjust dosage to lower end of dosage range for patients with concurrent hepatic impairment and hematologic toxicity.

Neurologic Toxicity

If manifestations of moderate or severe (grade 2 or higher) neurotoxicity occur, discontinue therapy immediately.

Prescribing Limits

Adults

Non-small Cell Lung Cancer

IV

Stage III NSCLC: Maximum 4 cycles of chemotherapy.

Stage IV NSCLC: Maximum 4 cycles if disease not responding to treatment; maximum 6 cycles of chemotherapy if disease responds to treatment.

Special Populations

Hepatic Impairment

Adjust dosage to lower end of dosage range for patients with concurrent hepatic impairment and hematologic toxicity.

Reduce dosage in patients who develop hyperbilirubinemia. (See Hepatic Toxicity under Dosage and Administration.)

Renal Impairment

No dosage adjustments required in patients with renal impairment.

Cautions for Vinorelbine

Contraindications

• Patients with pretreatment granulocyte counts <1000/mm³.

Warnings/Precautions

Warnings

Intrathecal Administration

Fatal if administered intrathecally; management of patients mistakenly receiving intrathecal vinorelbine is a medical emergency.

Prognosis to date for patients inadvertently receiving another vinca alkaloid generally has been poor despite immediate efforts to remove spinal fluid and flush with lactated Ringer’s injection and other solutions, with such efforts failing to prevent ascending paralysis and death in almost all cases.

In one adult patient, progression of paralysis was stopped when treatment was initiated immediately after inadvertent intrathecal injection of vincristine.

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.

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. The rate of infusion was adjusted to maintain a CSF protein concentration of 150 mg/dL. 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. The role of glutamic acid in this treatment is uncertain.

Hematologic Effects

Granulocytopenia usually is the dose-limiting factor in therapy. Nadir in granulocyte count generally occurs 7–10 days after administration and recovery usually occurs within another 7–14 days.

Perform CBC with differential before administration of each dose.

Do not administer if granulocyte counts <1000/mm³.

Carefully monitor patients with severe granulocytopenia for evidence of infection and/or fever. (See Hematologic Toxicity under Dosage and Administration.)

Respiratory Effects

Acute shortness of breath and severe bronchospasm have occurred rarely; most frequently when mitomycin was administered concomitantly. May require treatment with supplemental oxygen, bronchodilators, and/or corticosteroids, particularly with preexisting pulmonary dysfunction.

Fatal interstitial pulmonary changes and acute respiratory distress syndrome (ARDS) have been reported. Mean time to onset of symptoms was 1 week (range: 3–8 days). Evaluate promptly patients with preexisting pulmonary dysfunction or new onset of dyspnea, cough, hypoxia, or other symptoms.

GI Effects

GI effects (some fatal), including severe constipation (grade 3 or 4), paralytic ileus, intestinal obstruction, necrosis, and/or perforation reported.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals. Avoid pregnancy during therapy. If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.

Major Toxicities

Hepatic Toxicity

Adjust dosage according to hepatic toxicity. (See Hepatic Toxicity under Dosage and Administration.)

General Precautions

Administer only under constant supervision by clinicians experienced in therapy with chemotherapeutic agents.

Pattern of adverse effects appears to be similar in patients receiving monotherapy or combination therapy with vinorelbine.

Most drug-related adverse effects are reversible. If severe adverse effects occur, reduce dosage or discontinue therapy. Reinstitute therapy with caution; possible recurrence of toxicity.

Compromised Bone Marrow Reserve

Use with extreme caution in patients whose bone marrow reserve may have been compromised by prior chemotherapy or radiation therapy, or whose marrow function is recovering from previous cytotoxic therapy.

Nervous System Effects

Monitor patients with preexisting neuropathy, regardless of etiology, for new or worsening signs and symptoms, while receiving the drug.

Eye Contamination

Avoid contamination of the eye(s) with the drug; severe irritation may occur with accidental exposure. If contamination occurs, immediately wash eye(s) with water.

Hepatic Effects

Transient elevations of liver enzymes were reported without clinical symptoms. (See Hepatic Toxicity under Dosage and Administration.)

Specific Populations

Pregnancy

Category D. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether vinorelbine is distributed into milk. Discontinue nursing or drug.

Pediatric Use

Safety and efficacy in children <18 years of age have not been established.

Limited number of pediatric patients with recurrent solid malignant tumors (e.g., rhabdomyosarcoma/undifferentiated sarcoma, neuroblastoma, CNS tumors) have received vinorelbine dosages similar to adults; no clinical efficacy reported. Toxicities were similar to adults.

Geriatric Use

No overall differences in safety and efficacy relative to younger adults. Although response in patients ≥65 years of age does not appear to differ from that in younger adults, possibility exists of greater sensitivity in some geriatric patients.

Hepatic Impairment

No evidence that vinorelbine-associated toxicity is increased in patients with elevated hepatic enzymes.

Administer with caution and reduce dosage in patients with severe hepatic impairment, since drug is metabolized by hepatic enzymes and clinical experience in severe hepatic impairment is limited. (See Hepatic Toxicity under Dosage and Administration.)

Renal Impairment

Dosage reduction in patients with renal impairment does not appear to be necessary.

Common Adverse Effects

Myelosuppression, anemia, injection site reactions (e.g., erythema, pain, chemical phlebitis, vein discoloration), fatigue, chest pain, constipation, nausea, vomiting, hypertension, malaise, paresthesia, peripheral neuropathy, loss of deep tendon reflexes, diarrhea, asthenia.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Metabolized by CYP isoenzymes, principally CYP3A.

Inhibitors of CYP3A: Potential pharmacokinetic interaction (inhibition of vinorelbine metabolism). Use concomitantly with caution.

Ototoxic Drugs

Since varying degrees of permanent or temporary hearing impairment associated with eighth cranial nerve damage have been reported in patients receiving vinca alkaloids, use concomitantly with other potentially ototoxic drugs with extreme caution. (See Specific Drugs under Interactions.)

Specific Drugs and Procedures

Vinorelbine Pharmacokinetics

Absorption

Plasma Concentrations

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

Distribution

Extent

Distributed into peripheral compartments.

Crosses the placenta in animals; not known if crosses the placenta in humans.

Not known whether vinorelbine is distributed into human milk.

Plasma Binding

High degree (79.6–91.2% in cancer patients) of binding to human platelets and lymphocytes.

Elimination

Metabolism

Extensively metabolized, mainly in the liver by CYP3A isoenzymes to vinorelbine N-oxide and deacetylvinorelbine (main metabolite with antitumor activity similar to the parent drug).

Elimination Route

Excreted, mainly as unchanged drug, in urine (11–18%) and in feces (46%).

Half-life

Mean terminal elimination half-life: 27.7–43.6 hours.

Special Populations

Effect of renal and/or hepatic impairment on the elimination of vinorelbine not evaluated.

Metabolism by CYP3A isoenzymes may be impaired in patients with hepatic impairment.

Limited data indicate that disposition of drug in geriatric patients is similar to that in younger adults.

Stability

Storage

Parenteral

Injection

2–8°C; do not freeze. ; protect from light.

Unopened vials stable at 25°C for up to 72 hours.

May store diluted solutions at normal room light (in polypropylene syringes or polyvinyl chloride bags) at 5–30°C up to 24 hours.

Compatibility

Parenteral

Solution Compatibilityb c HID

Drug Compatibility

Actions

• Mechanism of action not fully elucidated; vinorelbine and other vinca alkaloids exert their cytotoxic effects by binding to tubulin, the protein subunit of the microtubules that form the mitotic spindle.

• Formation of vinorelbine-tubulin complexes prevents the polymerization of the tubulin subunits into microtubules, induces depolymerization of microtubules resulting in inhibition of microtubule assembly and cellular metaphase arrest.

• Also interferes with amino acid, cyclic AMP, and glutathione metabolism; calmodulin-dependent calcium² +-transport ATPase activity, cellular respiration; and nucleic acid and lipid biosynthesis.

Advice to Patients

• Importance of advising patients about hematologic toxicity and increased risk of infection.

• Importance of immediately informing clinician if fever or chills occur.

• Importance of informing clinician if increased shortness of breath, cough, or other new pulmonary symptoms occur.

• Importance of informing clinician if abdominal pain or constipation occurs.

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Advise patients to avoid becoming pregnant during treatment.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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