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Navelbine

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Navelbine

SIDE EFFECTS

The following serious adverse reactions, which may include fatalities, are discussed in greater detail in other sections of the label:

Clinical Trials Experience

Because clinical trials are conducted under varying designs and in different patient populations, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.

Single Agent

The data below reflect exposure to NAVELBINE as a single agent administered at a dose of 30 mg/m² on a weekly basis to 365 patients enrolled in 3 controlled studies for metastatic NSCLC and advanced breast cancer. The population included 143 previously untreated metastatic NSCLC patients (Study 3) who received a median of 8 doses of NAVELBINE. The patients were aged 32 to 79 (median 61 years), 71% were male, 91% Caucasian, 48% had adenocarcinoma histology. The data also reflect exposure to NAVELBINE in 222 patients with previously treated advanced breast cancer who received a median of 10 doses of NAVELBINE. NAVELBINE is not indicated for the treatment of breast cancer.

Selected adverse reactions reported in these studies are provided in Tables 1 and 2. The most common adverse reactions ( ≥ 20%) of single agent NAVELBINE were leukopenia, neutropenia, anemia, Aspartate aminotransferase (AST) elevation, nausea, vomiting, constipation, asthenia, injection site reaction, and peripheral neuropathy. The most common ( ≥ 5%) Grade 3 or 4 adverse reactions were neutropenia, leukopenia, anemia, increased total bilirubin, AST elevation, injection site reaction and asthenia. Approximately 49% of NSCLC patients treated with Navelbine experienced at least one dose reduction due to an adverse reaction. Thirteen percent of patients discontinued NAVELBINE due to adverse reactions. The most frequent adverse reactions leading to NAVELBINE discontinuation were asthenia, dyspnea, nausea, constipation, anorexia, myasthenia and fever.

Table 1: Hematologic Adverse Reactions Experienced in > 5% of Patients Receiving NAVELBINE*†

    All patients
(n=365)
NSCLC
(n= 143)
Laboratory Hematologic
Neutropenia < 2,000 cells/mm³ 90% 80%
< 500 cells/mm³ 36% 29%
Leukopenia < 4,000 cells/mm³ 92% 81%
< 1,000 cells/mm³ 15% 12%
Thrombocytopenia < 100,000 cells/mm³ 5% 4%
Anaemia < 11 g/dl 83% 77%
< 8 g/dl 9% 1%
Hospitalizations due to neutropenic complications 9% 8%
*Grade based on modified criteria from the National Cancer Institute version 1.
†Patients with NSCLC had not received prior chemotherapy. The majority of the remaining patients had received prior chemotherapy.

Table 2: Non-hematologic Adverse Reactions Experienced in ≥ 5% of Patients Receiving NAVELBINE*†

  All grades Grades 3+4
All Patients NSCLC All Patients NSCLC
Laboratory
Hepatic
  AST increased (n=346) 67% 54% 6% 3%
  bilirubin increased (n=351) 13% 9% 7% 5%
Clinical
  Nausea 44% 34% 2% 1%
  Asthenia 36% 27% 7% 5%
  Constipation 35% 29% 3% 2%
  Injection site reaction 28% 38% 2% 5%
  Injection site pain 16% 13% 2% 1%
  Neuropathy peripheral} 25% 20% < 2% 1%
  Vomiting 20% 15% 2% 1%
  Diarrhea 17% 13% 1% 1%
  Alopecia 12% 12% <1% 1%
  Phlebitis 7% 10% <1% 1%
  Dyspnea 7% 3% 3% 2%
* Grade based on modified criteria from the National Cancer Institute version 1.
‡ Incidence of paresthesia plus hypesthesia.
†Patients with NSCLC had not received prior chemotherapy. The majority of the remaining patients had received prior chemotherapy.

Myelosuppression: In clinical trials, Grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 69%, 9% and 1%, respectively of patients receiving single-agent NAVELBINE. Neutropenia is the major dose-limiting toxicity.

Neurotoxicity: neurotoxicity was most commonly manifested as constipation, paresthesia, hypersthesia, and hyporeflexia. Grade 3 and 4 neuropathy was observed in 1% of the patients receiving single-agent NAVELBINE.

Injection site reactions: Injection site reactions, including erythema, pain at injection site, and vein discoloration, occurred in approximately one third of patients; 5% were severe. Phlebitis (chemical phlebitis) along the vein proximal to the site of injection was reported in 10% of patients.

Cardiovascular toxicity: Chest pain occurred in 5% of patients; myocardial infarction occurred in less than 0.1% of patients.

Pulmonary Toxicity and Respiratory Failure: Dyspnea (shortness of breath) was reported in 3% of patients; it was severe in 2%. Interstitial pulmonary changes were documented.

Other: Hemorrhagic cystitis and the syndrome of inappropriate ADH secretion were each reported in < 1% of patients.

In Combination with Cisplatin

Table 3 presents the incidence of selected adverse reactions, occurring in ≥ 10% of NAVELBINE treated patients reported in a randomized trial comparing the combination of NAVELBINE 25 mg/m² administered every week of each 28-day cycle and cisplatin 100 mg/m² administered on day 1 of each 28-day cycle versus cisplatin alone at the same dose and schedule in patients with previously untreated NSCLC (Study 1).

Patients randomized to NAVELBINE plus cisplatin received a median of 3 cycles of treatment and those randomized to cisplatin alone received a median of 2 cycles of treatment. Thirty-Five percent of the eligible patients in the combination arm required treatment discontinuation due to an adverse reaction compared to 19% in the cisplatin alone arm. The incidence of Grade 3 and 4 neutropenia was significantly higher in the NAVELBINE plus cisplatin arm (82%) compared to the cisplatin alone arm (5%). Four patients in the NAVELBINE plus cisplatin arm died of neutropenic sepsis. Seven additional deaths were reported in the combination arm: 2 from cardiac ischemia, 1 cerebrovascular accident, 1 multisystem failure due to an overdose of NAVELBINE, and 3 from febrile neutropenia.

Table 3: Adverse Reactions Experienced by ≥ 10% of Patients on NAVELBINE plus Cisplatin versus Single-Agent Cisplatin*

Laboratory NAVELBINE 25mg/m² plus Cisplatin 100 mg/m² (n=212) Cisplatin 100mg/m² (n=210)
All Grades Grades 3+4 All Grades Grades 3+4
Hematologic
  Neutropenia 89% 82% 26% 5%
  Anemia  89% 24% 72% < 8%
  Leukopenia 88% 58% 31% < 1%
  Thrombocytopenia 29% 5% 21% < 2%
  Febrile neutropenia N/A* 11% N/A* 0%
Renal
  Blood creatinine increased 37% 4% 28% < 5%
Clinical
  Malaise/Fatigue/Lethargy 67% 12% 49% 8%
  Vomiting 60% 13% 60% 14%
  Nausea 58% 14% 57% 12%
  Decreased apetite 46% 0% 37% 0%
  Constipation 35% 3% 16% 1%
  Alopecia 34% 0% 14% 0%
  Weight decreased 34% 1% 21% < 1%
  Fever without infection 20% 2% 4% 0%
  Hearing impaired 18% 4% 18% < 4%
  Injection site reaction 17% < 1% 1% 0%
  Diarrhea 17% < 3% 11% < 2%
  Paraesthesia 17% < 1% 10% < 1%
  Taste alterations 17% 0% 15% 0%
  Peripheral numbness 11% 2% 7% < 1%
  Myalgia/Arthralgia 12% < 1% 3% < 1%
  Phlebitis/Thrombosis/Embolism 10% 3% <1% < 1%
  Weakness 12% < 3% 7% 2%
  Infection 11% < 6% <1% < 1%
  Respiratory tract infection 10% < 5% 3% 3%
*Graded according to the standard SWOG criteria version 1.
*Categorical toxicity grade not specified

Table 4 presents the incidence of selected adverse reactions, occurring in ≥ 10% of NAVELBINE treated patients reported in a randomized trial of NAVELBINE plus cisplatin, vindesine plus cisplatin and NAVELBINE alone in patients with stage III or IV NSCLC who had not received prior chemotherapy. A total of 604 patients received either NAVELBINE 30 mg/m² every week plus cisplatin 120 mg/m² on Day 1 and Day 29, then every 6 weeks thereafter (N=207), vindesine 3 mg/m² for 6 weeks, then every other week thereafter plus cisplatin 120 mg/m² on Days 1 and Day 29, then every 6 weeks thereafter (N=193) or NAVELBINE 30mg/m² every week (N=204).

Patients randomized to NAVELBINE plus cisplatin received a median of 15 weeks of treatment, vindesine plus cisplatin 12 weeks and NAVELBINE received 13 weeks. Study discontinuation due to an adverse reaction was required in 27, 22 and 10% of the patients randomized to NAVELBINE plus cisplatin, vindesine plus cisplatin and cisplatin alone arms, respectively. Grade 3 and 4 neutropenia was significantly greater in the NAVELBINE plus cisplatin arm (78%) compared to vindesine plus cisplatin (48%) and NAVELBINE alone (53%). Neurotoxicity, including peripheral neuropathy and constipation was reported in 44% (Grades 34, 7%) of the patients receiving NAVELBINE plus cisplatin, 58% (Grades 3-4, 17%) of the patients receiving vindesine and cisplatin and 44% (Grades 3-4, 8.5%) of the patients receiving NAVELBINE alone.

Table 4: Adverse Reactions Experienced by ≥ 10 % of Patients from a Comparative Trial of NAVELBINE Plus Cisplatin versus Vindesine Plus Cisplatin versus Single-Agent NAVELBINE*

  NAVELBINE/ Cisplatinf† Vindesine/ Cisplatin‡ NAVELBINE§
All Grades Grades 3+4 All Grades Grades 3+ 4 All Grades Grades 3+4
Laboratory
Hematologic
  Neutropenia 95% 78% 79% 48% 85% 53%
  Leukopenia 94% 57% 82% 27% 83% 32%
  Thrombocytopenia 15% 4% 10% 3.5% 3% 0%
Renal
  Blood creatinine increased| 46% N/A 37% N/A 13% N/A
Clinical
  Nausea/Vomiting 74% 30% 72% 25% 31% 2%
  Alopecia 51% 7.5% 56% 14% 30% 2%
  Neurotoxicity¶ 44% 7% 58% 17% 44% 8.5%
  Diarrhoea 25% 1.5% 24% 1% 12% 0.5%
  Injection site reaction 17% 2.5% 7% 0% 22% 2%
  Ototoxicity 10% 2% 14% 1% 1% 0%
* Grade based on criteria from the World Health Organization (WHO).
† n=194 to 207; all patients receiving NAVELBINE/ cisplatin with laboratory and non-laboratory data.
‡ n=173 to 192; all patients receiving vindesine/ cisplatin with laboratory and non-laboratory data.
§ n=165 to 201; all patients receiving NAVELBINE with laboratory and non-laboratory data.
Categorical toxicity grade not specified.
¶ Neurotoxicity includes peripheral neuropathy and constipation.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of NAVELBINE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Infections and infestations: pneumonia

Immune system disorders: anaphylactic reaction, pruritus, urticaria, angioedema

Nervous system disorders: loss of deep tendon reflexes, muscular weakness, gait disturbance, headache

Ear and labyrinth disorders: vestibular disorder, hearing impaired

Cardiac disorders: tachycardia

Respiratory disorders: pulmonary edema

Vascular disorders: pulmonary embolism, deep vein thrombosis, hypertension, hypotension, flushing, vasodilatation

Gastrointestinal disorders: mucosal inflammation, dysphagia, pancreatitis

Skin disorders: generalized cutaneous reactions (rash)

Musculoskeletal and connective tissue disorders: jaw pain, myalgia, arthralgia

General disorders and administration site conditions: injection site rash, urticaria, blistering, sloughing of skin

Injury, poisoning and procedural complications: radiation recall phenomenon, dermatitis, esophagitis

Laboratory abnormalities: electrolyte imbalance including hyponatremia

Other: tumor pain, back pain, abdominal pain

Read the Navelbine (vinorelbine tartrate) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

CYP3A Inhibitors

Exercise caution in patients concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily. Concurrent administration of NAVELBINE with an inhibitor of this metabolic pathway may cause an earlier onset and/or an increased severity of adverse reactions.

Read the Navelbine Drug Interactions Center for a complete guide to possible interactions

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

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