Vinorelbine Injection - Sientific Information
|Manufacture:||Fresenius Kabi USA, LLC|
|Condition:||Metastatic Breast Cancer (Breast Cancer, Metastatic), Non-Small Cell Lung Cancer|
|Class:||Antineoplastic detoxifying agents, Mitotic inhibitors|
|Form:||Liquid solution, Intravenous (IV)|
|Ingredients:||Vinorelbine tartrate, Water for Injection, Sodium Hydroxide|
|Proper name||Vinorelbine Tartrate|
|Molecular formula||C45H54N4O8 • 2C4H6O6|
|Molecular mass||Vinorelbine Tartrate: 1079.12 Vinorelbine: 778.9|
|Chemical Abstracts Service [Reg. No.]||
125317–39–7 (Vinorelbine Ditartrate)
105661–0702 (Vinorelbine Tartrate)
|Physicochemical Properties||Vinorelbine tartrate is a white to yellow or light brown amorphous powder having a melting point of 210 °C with decomposition. It is freely soluble in water, soluble in alcohol, slightly soluble in methylene chloride, insoluble in chloroform. pH is 3.5, pKa1 and pKa2 are 5.8 and 8.2, respectively.|
Advanced Non-Small Cell Lung Cancer (NSCLC)
Data from two controlled clinical studies (612 + 211 patients), as well as additional data from more than 100 patients enrolled in two uncontrolled clinical trials, support the use of vinorelbine in patients with advanced non- small cell lung cancer (NSCLC). One randomized, three-arm trial in 612 Stage III or IV NSCLC patients compared treatment with single-agent vinorelbine (30 mg/m2/week), vinorelbine (30 mg/m2/week) plus cisplatin (120 mg/m2 days 1 and 29, then every six weeks), and vindesine (3 mg/m2/week for 7 weeks, then every other week) plus cisplatin (120 mg/m2 days 1 and 29, then every 6 weeks). Vinorelbine, as a single agent, was well-tolerated and resulted in a median survival of 31 weeks and a response rate of 14%. The combination of vinorelbine plus cisplatin produced a median survival of 40 weeks and a response rate of 28%. The results achieved with vinorelbine as a single agent were comparable to those seen with vindesine plus cisplatin (median survival 32 weeks and response rate of 19%), but significantly less severe nausea, vomiting, and neurotoxicity were observed in patients treated with single-agent vinorelbine. In the subgroup of patients with Stage IV disease, vinorelbine plus cisplatin produced longer survival than vindesine plus cisplatin (36 weeks vs. 27 weeks).
The results with single-agent vinorelbine noted in the above trial were confirmed in a second randomized, two-arm study (211 patients) which compared treatment with single-agent vinorelbine (30 mg/m2 weekly) to a control drug, 5-fluorouracil (5FU) (425 mg/m2 i.v. bolus) plus leucovorin (LV) (20 mg/m2 i.v. bolus) administered five consecutive days every four weeks. Compared to 5FU/LV, vinorelbine improved survival. The median survival for patients treated with vinorelbine was 30 weeks versus 22 weeks for 5FU⁄LV. The median survival for similar patients given best supportive care is reported to range from 9 to 21 weeks. The one year survival rates were 24% (±4%S.E.) for vinorelbine and 16± (± 5% S.E.) for 5FU⁄LV, using the Kaplan-Meier product-limit estimates. The response rates for vinorelbine and 5FU⁄LV were 14% and 5%respectively.
In an uncontrolled study in 78 patients with inoperable NSCLC treated with single-agent vinorelbine (30 mg⁄m2⁄ week), the median survival was 33 weeks. The response rate was 33±. A Phase I⁄II dose-ranging study of vinorelbine (20, 25, or 30 mg⁄m2 week) plus cisplatin (120 mg⁄m2 days 1 and 29, then every 6 weeks) in 32 patients with NSCLC demonstrated a median survival of 44 weeks. There were no responses at the lowest dose level; the response rate was 33% in the 21 patients treated at the two highest dose levels.
Advanced Breast Cancer
Data from one randomized, controlled clinical study (179 patients) and three uncontrolled studies (302 patients) support the effectiveness of vinorelbine in patients with advanced breast cancer. The randomized, controlled trial compared vinorelbine (30 mg⁄m2⁄week) to intravenous melphalan (25 mg⁄m2⁄every 4 weeks) in patients who had progressed on one or two prior chemotherapy regimens for advanced disease, with one regimen containing an anthracycline. Patients who relapsed during or within 6 months of treatment with an anthracycline-containing adjuvant chemotherapy regimen were also eligible. Melphalan was chosen as a Phase II comparator because of the lack of a commonly accepted standard treatment in this patient population. Treatment with vinorelbine resulted in significantly longer time to disease progression, time to treatment failure, and survival compared to melphalan. Median time to disease progression was 12 weeks for the vinorelbine patients and 8 weeks for the melphalan arm (p < 0.001). Median time to treatment failure was 11 weeks and 8 weeks respectively, for the vinorelbine and melphalan groups (p < 0.001). The median survival was 35 weeks for the group receiving vinorelbine and 31 weeks for the melphalan arm (p = 0.03). The 1-year survival rates were 36% and 22% respectively, for the vinorelbine and melphalan groups. Although the proportion of patients who responded to vinorelbine (16%) was greater than those responding to melphalan (9%), the difference was not significant (p = 0.42). However, when objective responses and stabilization were combined, the difference approached significance in favour of vinorelbine (47% vs. 28%, p = 0.06). Disease–related symptoms improved or remained stable compared to baseline in the majority of patients in both groups.
An uncontrolled study conducted in the U.S. was designed to determine the safety and efficacy of vinorelbine (30 mg/m2/week) used as first-line or second-line therapy in the treatment of patients with advanced breast cancer. Patients were not previously treated with an anthracycline-containing regimen. The overall response rate was 35% for 60 first-line patients and 32% for 47 second-line patients. There were 9 (15%) complete responses and 12 (20%) partial responses among the first-line patients. The median duration of response was 34 weeks for both first- and second–line patients. There were 3 (6%) complete responses and 12 (26%) partial responses among second-line patients. The estimated median duration of complete response for first– and second–line patients combined exceeds 1 year.
A total of 195 patients were treated with single-agent vinorelbine (30 mg/m2 /week) in two European Phase II clinical trials. The patients in both trials had no previous cytotoxic therapy for advanced breast cancer. In one trial, the objective response rate was 41% in 145 evaluable patients. In the other trial, an objective response rate of 50% was observed in 50 evaluable patients.
Vinorelbine was a potent inhibitor of tumour cell growth with broad spectrum activity comparable to vincristine (VCR) and vinblastine (VLB). Vinorelbine was shown to participate in both multi–level drug resistance (MDR) and non–MDR forms of resistance. In combination studies, an additive effect was noted when cells were exposed sequentially to vinorelbine and then to cisplatin, while synergy was observed with a simultaneous combination of vinorelbine and paclitaxel.
Vinorelbine demonstrated antitumour activity in both murine and human tumour xenograft models that have been previously shown to be sensitive to either VLB or VCR. Vinorelbine was active by the intraperitoneal (i.p.), oral (p.o.) and intravenous (i.v.) routes on several administration schedules against i.p., i.v., and subcutaneous (s.c.) implants of various murine tumours. Vinorelbine when administered i.v. was also active against s.c. implants of lung, mammary and stomach human tumour xenografts in nude mice. Vinorelbine plus either etoposide or cisplatin provided a significant advantage in increased life span (ILS) over that of comparably dosed single agents.
In cultured mouse embryos, vinorelbine was active against all classes of mitotic microtubules (the antitumour target), while it was least active against axonal microtubules (the neurotoxic target). At pharmacologic concentrations in cell -free systems, vinorelbine was much less effective than VLB or VCR at inducing spiralization of microtubules (a potential toxicity endpoint). Vinorelbine, VLB, and VCR were equipotent in inhibiting assembly regardless of isotubulins or microtubule associated proteins (MAPS).
Cell Cycle Arrest
At physiologic concentrations, vinorelbine was similar to other vinca alkaloids in its effect on tumour cell cycle kinetics, producing mitotic arrest (block in M phase without altering G2 phase) and polyploidy. Polyploid cells are usually non-viable and this probably plays a role in the mechanism of antitumour activity.
Neuropharmacological Effect in Mice and Rats
Neuropharmacologically, vinorelbine presented the same hypothermic, and acute neurotoxicity profile expected of the vinca alkaloids. Mice treated intravenously with vinorelbine experienced only slight hypothermia, which, although statistically significant, was within standard pharmacological limits. No characteristic signs that typically accompany hypothermia (e.g., ptosis, piloerection, or tremors) were noted in the vinorelbine-treated animals. Vinorelbine produced neurotoxic effects in rats after acute i.v. administration, similar to those that occurred with VCR. However, unlike VCR, vinorelbine did not produce limb paralysis. And, although mortalities occurred after both i.v. vinorelbine and VCR administration, a 10-fold greater dose of vinorelbine than VCR was required to produce the same effect.
Cardiovascular/Respiratory Effect in Dogs
Cardiovascular and respiratory studies of i.v. vinorelbine in anaesthetized dogs indicate that vinorelbine (along with two other vinca alkaloids studied) has no effect on hemodynamics, respiratory function, or the incidence of cardiac arrhythmias.
Gastrointestinal Effects in Mice and Rats
Possible gastrointestinal (GI) effects of vinorelbine were explored using models of GI transit, GI tolerance, and gastric secretion. In mice, i.v. treatment with vinorelbine had no effect on the GI transit time in a standard charcoal meal test. In mice and rats, i.v. vinorelbine showed excellent GI tolerance, with no evidence of ulcers or bleeding in the esophagus, stomach or intestine. Vinorelbine was found to inhibit gastric secretion after i.v. administration in rats. This effect, however, occurred at one half the LD50 dose.
Urinary System Effects in Rats
Studies with vinorelbine on renal function indicate a moderate diuretic effect in rats after i.v. administration. Additionally, a pronounced increase in electrolyte elimination occurred. And, although there was evidence of hemolyzed blood in the urine after high i.v. doses of vinorelbine, examination of the kidneys and bladder revealed no histologic changes.
Hemobiologic Effects in Rats
Hemobiologic studies with vinorelbine showed a platelet antiaggregating property in vitro, but only at the very high concentration of 1.0 mM, which at minimum is 1,000-fold the therapeutic plasma concentration.
In vitro studies have shown that vinorelbine is rapidly and highly distributed into cells. Studies of vinorelbine binding to human blood constituents revealed high binding to platelets and lymphocytes. The free fraction was ∼ 0.11 in pooled human plasma over a concentration range of 234 to 1,169 ng/mL. The binding to plasma constituents in cancer patients ranged from 79.6% to 91.2%. Vinorelbine binding was not altered in the presence of cisplatin, 5-fluorouracil, or doxorubicin.
Absorption and Disposition
In all animal species studied (mouse, rat, dog, monkey), vinorelbine plasma concentration declined in a multi- exponential manner with an initial rapid decay followed by a slower terminal phase. Half-life values, after intravenous administration, were 7.3 hours in the mouse and 9.5 hours in the rat. Half-lives were considerably longer in the dog (ranging from 13 to 42 hours after various oral doses) and the monkey (16.6 to 35.5 hours after various oral and intravenous doses). Plasma clearances, estimated after intravenous administration in the rat and monkey, were 2 L/h/kg and 0.54 L/h/kg, respectively. Vinorelbine was shown to be rapidly absorbed after oral administration in all species studied with Tmax values ranging from 1 to 2 hours after administration. The bioavailability of radioactivity in the mouse was 25% following a radiolabelled dose, while absorption of radioactivity was essentially complete after oral administration to the monkey. Absolute bioavailability in the rat, determined using immunoassay methodology, was found to be 16%.
In tissue distribution studies of radiolabelled vinorelbine, radioactivity was widely distributed throughout the animals studied (mouse, rat, and monkey) with the highest amounts of radioactivity typically found in organs of elimination such as liver and kidneys. Minimal amounts of radioactivity were found in the heart and brain tissue.
Elimination and Metabolism
Vinorelbine was primarily eliminated in the feces in all species studied (mouse, rat, and monkey). Typically, 50% to 80% of an administered dose was recovered, regardless of the route of administration. A small percentage of the dose was excreted in the urine (1% to 19%, usually < 10%) and the majority of the amount excreted was recovered as unchanged drug. Evidence for substantial metabolism exists, and excretion via the bile appears to be a significant pathway for metabolites and parent drug. Three metabolites were isolated from perfused rat liver preparations, but not in sufficient quantity for identification. In vivo isolation and identification of metabolites was hindered because of the low quantities of metabolites present in animals administered non toxic doses and the inadequate sensitivity of analytical methodology.
Single-dose lethality values calculated from the results of mouse and rat studies are listed below. The combined male/female value is given, as no sex differences were apparent.
|Species/Strain||Route||LD10 (mg/kg)||LD10 (mg/kg)||LD90 (mg/kg)|
Ataxia, convulsions and respiratory difficulty were noted almost immediately after dosing in animals treated intravenously at the highest doses. Deaths occurred as early as 15 minutes postdose. Clinical signs seen in animals treated by all three routes included lethargy and piloerection in mice and rats and diarrhea, chromodacryorrhea, edema of the muzzle, and prostration in rats. Swollen abdomens and evidence of peritonitis were noted in some animals treated by the intraperitoneal route. Deaths occurred from day 1 to as late as 16 and 29 days postdose in mice and rats respectively.
Lethality studies using daily doses for 5 days were conducted in mice (i.v.) and rats (oral). The 5-day cumulative mg/kg values calculated were as follows
|Species/Strain||Route||LD10 (mg/kg)||LD50 (mg/kg)||LD90 (mg/kg)|
Mortality occurred from day 6 to 23 in mice and day 4 to 21 in rats, with clinical signs first noted on days 5 or 6. Piloerection, muzzle or facial edema, and subdued behaviour were seen in both species. In addition, skin paleness was noted in mice and diarrhea, chromorhinorrhea, and vaginal bleeding were seen in rats. Thus single and cumulative intravenous 5-dose LD50s in mice were essentially the same (36 and 40 mg/kg) and the cumulative oral 5-dose LD50n rats was the same as the intravenous single-dose LD50 in rats (14 and 14.1 mg/kg).
The beagle dog was the most susceptible of any species tested in single dose studies. An oral dose of 2.0 mg/kg and an intravenous dose of 1.0 mg/kg were lethal. Toxic effects included leukopenia, enteritis, elevated liver enzymes with or without histopathological evidence of hepatic necrosis or biliary hyperplasia, bone marrow hypoplasia and lymphoid depletion of spleen/lymph nodes. The lowest dose where one or more toxic effects were recorded was 0.5 mg/kg (oral and i.v.).
Acute toxic effects in rhesus and cynomolgus monkeys were observed after oral doses of 36 mg/kg (only dose tested) and 20 mg/kg (lowest dose) respectively and were similar to those seen in beagle dogs.
|Species/ Strain||No. per Group||Route||Dose (mg/kg)||Frequency||Duration||Drug-Related Findings (Lowest Dose where Effect Noted)|
|Rat/ Sprague- Dawleya||5 M, 5 F||i.v.||1.0, 2.0, 5.0||1 x wk||9 wk||1.0 Decreased WBC/RBC, elevated liver enzymes, infections, injection site irritation
2.0 Decreased body weight
|Dog/ Beagle||2 M, 2 F||i.v.||0.25, 0.50, 0.75||1 x wk||13 wk||0.25 Injection site irritation
0.50 Decreased WBC, thymic involution, injection site irritation
0.75 Mortality, decreased RBC, increased hepatic enzymes, decreased body weight, infections
|Monkey/ Rhesus||1 M, 1 F||i.v.||0.75, 1.0, 1.50, 2.0||1 x wk||29 - 39 wk||0.75 Decreased WBC/RBC, injection site irritation
1.50 Enteritis, decreased body weight
2.00 Bone marrow hypoplasia
|1 M, 1 F||i.v.||1.0||2 x wk||5 wk||Decreased WBC/RBC, decreased body weight, thymic involution|
|1 M, 1 F||i.v.||0.20 - 0.80 escalating||5 x wk, off 2 wks (1 cycle)||15 cycles||Mortality, decreased WBC/RBC, thymic involution and bone marrow hypoplasia following completion of the dosage regimen|
|1 M, 1 F||i.v.||doseb 2.0 - 4.0 cyclicc||1 x wk||4 wk||Mortality, enteritis, decreased WBC/RBC, decreased body weight, bone marrow hypoplasia|
|Rat/ Sprague- Dawleyaa||6 M, 0 F||Oral||5.0, 10.0||2 x wk||4 wk||5.0 Decreased RBC 10.0 Mortality, decreased WBC, increased hepatic enzymes, decreased body weight, infections 15.0 Mortality, decreased RBC, increased hepatic enzymes, decreased body weight, infections 20.0 Decreased WBC|
|6 M, 0 F||Oral||15.0, 20.0||1 x wk||4 wk|
|Rat/ Sprague- Dawleyaa||10 M, 10 F||Oral||1.0, 2.0, 4.0||daily||42 days||2.0 Increased hepatic enzymes
4.0 Mortality, decreased WBC/RBC, reduced body weight, thymic involution, bone marrow hypoplasia
|10 M, 10 F||Oral||7.0, 14.0||1 x wk||6 wk||7.0 Decreased WBC/RBCd
14.0 Mortality, increased hepatic enzymes, reduced body weight, thymic involution, bone marrow hypoplasia
|Monkey/ Rhesus||1 M, 1 F||Oral||4.0 - 70.0 escalatinge||1 x wk||13 wk||Enteritis, decreased WBC/RBC, increased hepatic enzymes, thymic involution, bone marrow hypoplasia|
|Monkey/ Rhesus||2 M or 2 F||Oral||4.0, 10.0||1 x wk||13 wk||4.0 Decreased WBC, increased hepatic enzymes|
a As noted in previous studies, affected rats showed signs of piloerection, decreased activity and muzzle swelling.
b 0.20 mg/kg (3 cycles), 0.40 mg/kg (6 cycles), 0.60 mg/kg (3 cycles), 0.80 mg/kg (3 cycles).
c 4.0 mg/kg for 3 weeks followed by 2.0 mg/kg for 1 week (3.0 mg/kg for 4 weeks after washout in 1 animal).
d Splenic extramedullary hematopoiesis – 7 mg/kg once weekly dose only.
e 4.0 mg/kg escalating to 6.0, 8.0, 10.0, 12.0, 14.0, 20.0, 30.0, 40.0, 40.0, 50.0, 70.0, 70.0 (weeks 2 - 13).
Vinorelbine was shown to be mutagenic in a mouse micronucleus assay and an in vivo cytogenetics study in which bone marrow cells from treated Chinese hamsters were examined. The effect seen, polyploidy, is one that the Ames and mouse lymphoma mutagenesis assays do not detect and these assays were negative or equivocal with vinorelbine.
Reproduction and Teratology
No deleterious effects on maternal or fetal parameters were seen in an intravenous rat fertility/reproduction study in which males were treated once weekly for 9 weeks and females once weekly for 4 weeks with a dose of 1.5 mg/kg vinorelbine.
Vinorelbine was found to be embryotoxic when given to mice once during gestation at 1 to 5 mg/kg intravenously but not at 0.5 mg/kg.
The in vitro hemolysis and protein flocculation test with human blood revealed a 10 mg/mL solution of vinorelbine to be unlikely to exert any hemolytic or protein flocculation problems when used clinically. An acute study of 17-deacetyl-vinorelbine sulfate (a vinorelbine degradation product) resulted in a LD50 of 23.0 mg/kg. Clinical signs of toxicity included subdued behaviour, prostration, piloerection and clonic convulsions. In a mouse micronucleus mutagenicity study, 17–deacetyl-vinorelbine sulfate produced an increase in the incidence in micronuclei in mice sampled 24 or 48 hours postdose. Bromo-12-vinorelbine sulfate (a vinorelbine process impurity) was negative in the same assay.
|Species||No./ Group||Route||Dose (mg/kg) and Frequency||Drug–Related Findings|
|Mouse||10 F||i.v.||0.5, 1.0, 3.0, 5.0
One dose on day 9 of gestation
|Embryotoxicity at doses 1.0 – 5.0 mg/kg. Fetotoxicity (delayed ossification) at 1.0 mg/kg.|
|Rat||25 F||i.v.||0.10, 0.26, 0.70
Every 3 days for 2 weeks and then through mating and until gestation day 7
|Decreased weight gain and enlarged spleens in dams receiving 0.70 mg/kg. External and/or visceral abnormalities were observed in 4 fetuses at the 0.10 mg/kg dose level. Skeletal abnormalities were observed in all dose groups.|
|Rat||35 F||i.v.||0.10, 0.22, 0.50
Dosed on gestational days 7, 10, 13 and 16
|A low incidence of skeletal abnormalities were observed in F1 fetuses in the 0.50 mg/kg dose group.|
|Rat||25 F||i.v.||0.10, 0.32, 1.0
Dosed every 3 days starting at day 17 o gestation and continuing until day 21 o lactation
|Decreased weight gain was observed in female neonates during suckling and in male neonates up to 7 weeks of age at the 1.00 mg/kg dose only. No other deleterious effects observed.|
|Rabbit||6 F||i.v.||0.10, 0.25, 0.50, 0.7
Dosed on gestation days 6, 12 and 18
|Decreased mean fetal weight and increased number of small fetuses, increased incidence of blood in fetal cochleas and discoloration of fetal lens observed in the 0.75 mg/kg dose group.|
|Rabbit||6 F||i.v.||0.10, 0.25, 0.50, 0.75
Dosed on gestation days 6, 9, 12, 15 and 18
|Reduced fetal weight was observed in the 0.25 and 0.50 mg/kg dose groups. Embryotoxicity was observed at doses of 0.50 and 0.75 mg/kg. Vinorelbine was maternally lethal at 0.75 mg/kg when given for 5 but not 3 days. No terata was seen at any dose level.|
|Rabbit||15 F||i.v.||0.22, 0.40, 0.70
Dosed on gestation days 6, 9, 12, 15, 18
0.70 Dosed on gestation days 7, 10, 13, 16
0.70 Dosed on gestation days 8, 11, 14, 17
|Vinorelbine was severely maternally toxic at the 0.70 mg/kg dose level and resulted in maternal clinical signs, reduced body weight and food intake, abortions, and deaths with an increased incidence of external and visceral anomalies in the few live fetuses remaining.|