CABAZITAXEL EVER PHARMA

(cabazitaxel) injection is an antineoplastic agent belonging to the taxane class that is for intravenous use.

It is prepared by semi-synthesis with a precursor extracted from yew needles.

The chemical name of cabazitaxel is (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3-[(tertbutoxycarbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate – propan-2-one (1:1).

Cabazitaxel has the following structural formula

Cabazitaxel is a white to almost-white powder with a molecular formula of C 45 H 57 NO 14 C 3 H 6 O and a molecular weight of 894.01 (for the acetone solvate) / 835.93 (for the solvent free).

It is lipophilic, practically insoluble in water and soluble in alcohol.

JEVTANA (cabazitaxel) injection 60 mg/1.5 mL is a sterile, non-pyrogenic, clear yellow to brownish-yellow viscous solution and is available in single-dose vials containing 60 mg cabazitaxel (anhydrous and solvent free) and 1.56 g polysorbate 80 (citric acid monohydrate is used to adjust the pH of the polysorbate 80 between 3.3 to 3.8).

Each mL contains 40 mg cabazitaxel (anhydrous) and 1.04 g polysorbate 80.

DILUENT for

JEVTANA is a clear, colorless, sterile, and non-pyrogenic solution containing 13% (w/w) ethanol in water for injection, approximately 5.7 mL.

JEVTANA requires two dilutions prior to intravenous infusion.

JEVTANA injection should be diluted only with the supplied DILUENT for JEVTANA, followed by dilution in either 0.9% sodium chloride solution or 5% dextrose solution.

in combination with prednisone or prednisolone is indicated for the treatment of adult patients with castration-resistant metastatic prostate cancer previously treated with docetaxel.

Cabazitaxel is a microtubule inhibitor.

Cabazitaxel binds to tubulin and promotes its assembly into microtubules while simultaneously inhibiting disassembly.

This leads to the stabilization of microtubules, which results in the inhibition of mitotic and interphase cellular functions. 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of cabazitaxel following a single dose of 25 mg/m 2 administered by intravenous infusion on QTc interval was evaluated in 94 patients with solid tumors.

No large changes in the mean

QT interval (i.e., >20 ms) from baseline based on Fridericia correction method were detected.

However, a small increase in the mean QTc interval (i.e., <10 ms) cannot be excluded due to study design limitations. 12.3 Pharmacokinetics A population pharmacokinetic analysis was conducted in 170 patients with solid tumors at doses ranging from to 30 mg/m 2 weekly or every three weeks.

Based on the population pharmacokinetic analysis, after an intravenous dose of cabazitaxel 25 mg/m 2 every three weeks, the mean C max in patients with metastatic prostate cancer was 226 ng/mL (CV 107%) and was reached at the end of the one-hour infusion (T max ).

The mean

AUC in patients with metastatic prostate cancer was 991 ng ∙ h/mL (CV 34%).

No major deviation from the dose proportionality was observed from to 30 mg/m in patients with advanced solid tumors.

The volume of distribution (V ss ) was 4,864 L (2,643 L/m for a patient with a median BSA of 1.84 m 2 ) at steady state.

In vitro, the binding of cabazitaxel to human serum proteins was 89% to 92% and was not saturable up to 50,000 ng/mL, which covers the maximum concentration observed in clinical trials.

Cabazitaxel is mainly bound to human serum albumin (82%) and lipoproteins (88% for HDL, 70% for LDL, and 56% for VLDL).

The in vitro blood-to-plasma concentration ratio in human blood ranged from 0.90 to 0.99, indicating that cabazitaxel was equally distributed between blood and plasma.

Cabazitaxel is extensively metabolized in the liver (>95%), mainly by the CYP3A4/5 isoenzyme (80% to 90%), and to a lesser extent by CYP2C8.

Cabazitaxel is the main circulating moiety in human plasma.

Seven metabolites were detected in plasma (including the 3 active metabolites issued from O-demethylation), with the main one accounting for 5% of cabazitaxel exposure.

Around 20 metabolites of cabazitaxel are excreted into human urine and feces.

After a one-hour intravenous infusion [ 14 C]-cabazitaxel 25 mg/m 2, approximately 80% of the administered dose was eliminated within 2 weeks.

Cabazitaxel is mainly excreted in the feces as numerous metabolites (76% of the dose); while renal excretion of cabazitaxel and metabolites account for 3.7% of the dose (2.3% as unchanged drug in urine).

Based on the population pharmacokinetic analysis, cabazitaxel has a plasma clearance of 48.5 L/h (CV 39%; 26.4 L/h/m for a patient with a median BSA of 1.84 m 2 ) in patients with metastatic prostate cancer.

Following a one-hour intravenous infusion, plasma concentrations of cabazitaxel can be described by a three-compartment pharmacokinetic model with α-, β-, and γ.

• half-lives of 4 minutes, 2 hours, and 95 hours, respectively.

Cabazitaxel is minimally excreted via the kidney.

A population pharmacokinetic analysis carried out in 170 patients including 14 patients with moderate renal impairment (30 mL/min ≤CL CR <50 mL/min) and 59 patients with mild renal impairment (50 mL/min ≤CL CR <80 mL/min) showed that mild to moderate renal impairment did not have meaningful effects on the pharmacokinetics of cabazitaxel.

This was confirmed by a dedicated comparative pharmacokinetic study in patients with solid tumors with normal renal function (n=8, CL CR >80 mL/min/1.73 m 2 ), or moderate (n=8, 30 mL/min/1.73 m 2 ≤CL CR <50 mL/min/1.73 m 2 ) and severe (n=9, CL CR <30 mL/min/1.73 m 2 ) renal impairment, who received several cycles of cabazitaxel in single IV infusion up to 25 mg/m 2.

Limited pharmacokinetic data were available in patients with end-stage renal disease (n=2, CL CR <15 mL/min/1.73 m 2 ).

Cabazitaxel is extensively metabolized in the liver.

A dedicated study in 43 cancer patients with hepatic impairment showed no influence of mild (total bilirubin >1 to ≤1.5 × ULN or AST >1.5 × ULN) or moderate (total bilirubin >1.5 to ≤3.0 × ULN) hepatic impairment on cabazitaxel pharmacokinetics.

The maximum tolerated dose (MTD) of cabazitaxel was and 15 mg/m 2, respectively.

In 3 patients with severe hepatic impairment (total bilirubin >3 × ULN), a 39% decrease in clearance was observed when compared to patients with mild hepatic impairment (ratio=0.61, 90% CI: 0.36–1.05), indicating some effect of severe hepatic impairment on cabazitaxel pharmacokinetics.

MTD of cabazitaxel in patients with severe hepatic impairment was not established.

Based on safety and tolerability data, cabazitaxel dose should be maintained at 20 mg/m in patients with mild hepatic impairment and reduced to 15 mg/m in patients with moderate hepatic impairment.

Cabazitaxel is contraindicated in patients with severe hepatic impairment.

Drug Interactions A drug interaction study of JEVTANA in 23 patients with advanced cancers has shown that repeated administration of ketoconazole (400 mg orally once daily), a strong CYP3A inhibitor, increased the exposure to cabazitaxel (5 mg/m 2 intravenous) by 25%.

A drug interaction study of

JEVTANA in 13 patients with advanced cancers has shown that repeated administration of aprepitant (125 or 80 mg once daily), a moderate CYP3A inhibitor, did not modify the exposure to cabazitaxel (15 mg/m 2 intravenous).

JEVTANA in 21 patients with advanced cancers has shown that repeated administration of rifampin (600 mg once daily), a strong CYP3A inducer, decreased the exposure to cabazitaxel (15 mg/m 2 intravenous) by 17%.

JEVTANA in 11 patients with advanced cancers has shown that cabazitaxel (25 mg/m 2 administered as a single 1-hour infusion) did not modify the exposure to midazolam, a probe substrate of CYP3A.

Prednisone or prednisolone administered at 10 mg daily did not affect the pharmacokinetics of cabazitaxel.

Based on in vitro studies, the potential for cabazitaxel to inhibit drugs that are substrates of other CYP isoenzymes (1A2, -2B6, -2C9, -2C8, -2C19, -2E1, -2D6, and CYP3A4/5) is low.

In addition, cabazitaxel did not induce CYP isozymes (-1A, -2C9 and -3A) in vitro.

In vitro, cabazitaxel did not inhibit the multidrug-resistance protein 1 (MRP1), 2 (MRP2) or organic cation transporter (OCT1).

In vitro, cabazitaxel inhibited P-gp, BRCP, and organic anion transporting polypeptides (OATP1B1, OATP1B3).

However, the in vivo risk of cabazitaxel inhibiting MRPs, OCT1, P-gp, BCRP, OATP1B1 or OATP1B3 is low at the dose of 25 mg/m 2.

In vitro, cabazitaxel is a substrate of P-gp, but not a substrate of MRP1, MRP2, BCRP, OCT1, OATP1B1 or OATP1B3.

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There is no known antidote for

JEVTANA overdose.

Overdose has resulted from improper preparation.

Read the entire section Dosage and

Administration carefully before mixing or diluting.

Complications of overdose include exacerbation of adverse reactions such as bone marrow suppression and gastrointestinal disorders.

Overdose has led to fatal outcome.

In case of overdose, the patient should be kept in a specialized unit where vital signs, chemistry and particular functions can be closely monitored.

Patients should receive therapeutic

G-CSF as soon as possible after discovery of overdose.

Other appropriate symptomatic measures should be taken, as needed.

is contraindicated in patients with: neutrophil counts of ≤1,500/mm 3 history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80 severe hepatic impairment (total bilirubin >3 × ULN) Neutrophil counts of ≤1,500/mm 3 History of severe hypersensitivity to JEVTANA or polysorbate 80 Severe hepatic impairment (Total Bilirubin >3 × ULN).

JEVTANA 20 mg/m 2 administered every three weeks as a one-hour intravenous infusion in combination with oral prednisone 10 mg administered daily throughout JEVTANA treatment.

A dose of 25 mg/m 2 can be used in select patients at the discretion of the treating healthcare provider.

JEVTANA requires two dilutions prior to administration.

Use the entire contents of the accompanying diluent to achieve a concentration of 10 mg/mL JEVTANA.

PVC equipment should not be used.

Administer intravenously 30 minutes before each dose of JEVTANA: Antihistamine (dexchlorpheniramine 5 mg or diphenhydramine 25 mg or equivalent antihistamine) Corticosteroid (dexamethasone 8 mg or equivalent steroid) H 2 antagonist Antiemetic prophylaxis (oral or intravenous) is recommended as needed.

See full prescribing information 2.1 Dosing Information The recommended dose of JEVTANA is based on calculation of the Body Surface Area (BSA), and is 20 mg/m 2 administered as a one-hour intravenous infusion every three weeks in combination with oral prednisone 10 mg administered daily throughout JEVTANA treatment.

Primary prophylaxis with

G-CSF is recommended in patients with high-risk clinical features.

Consider primary prophylaxis with

G-CSF in all patients receiving a dose of 25 mg/m 2.

Premedicate at least 30 minutes prior to each dose of JEVTANA with the following intravenous medications to reduce the risk and/or severity of hypersensitivity: antihistamine (dexchlorpheniramine 5 mg, or diphenhydramine 25 mg or equivalent antihistamine), corticosteroid (dexamethasone 8 mg or equivalent steroid), H 2 antagonist.

Antiemetic prophylaxis is recommended and can be given orally or intravenously as needed.

JEVTANA injection single-dose vial requires two dilutions prior to administration. 2.2 Dose Modifications for Adverse Reactions Reduce or discontinue JEVTANA dosing for adverse reactions as described in Table 1.

Table 1: Recommended Dosage Modifications for Adverse Reactions in Patients Treated with JEVTANA Toxicity Dosage Modification Prolonged grade ≥3 neutropenia (greater than 1 week) despite appropriate medication including granulocyte-colony stimulating factor (G-CSF) Delay treatment until neutrophil count is >1,500 cells/mm 3, then reduce dosage of JEVTANA by one dose level.

G-CSF for secondary prophylaxis.

Febrile neutropenia or neutropenic infection

Delay treatment until improvement or resolution, and until neutrophil count is >1,500 cells/mm 3, then reduce dosage of JEVTANA by one dose level.

Grade ≥3 diarrhea or persisting diarrhea despite appropriate medication, fluid and electrolytes replacement Delay treatment until improvement or resolution, then reduce dosage of JEVTANA by one dose level.

Grade 2 peripheral neuropathy Delay treatment until improvement or resolution, then reduce dosage of JEVTANA by one dose level.

Grade ≥3 peripheral neuropathy Discontinue JEVTANA.

Patients at a 20 mg/m 2 dose who require dose reduction should decrease dosage of JEVTANA to 15 mg/m 2.

Patients at a 25 mg/m 2 dose who require dose reduction should decrease dosage of JEVTANA to 20 mg/m 2.

One additional dose reduction to 15 mg/m 2 may be considered. 2.3 Dose Modifications for Hepatic Impairment Mild hepatic impairment (total bilirubin >1 to ≤1.5 × Upper Limit of Normal (ULN) or AST >1.5 × ULN): Administer JEVTANA at a dose of 20 mg/m 2.

Moderate hepatic impairment (total bilirubin >1.5 to ≤3 × ULN and AST = any): Administer JEVTANA at a dose of 15 mg/m 2 based on tolerability data in these patients; however, the efficacy of this dose is unknown.

Severe hepatic impairment (total bilirubin >3 × ULN): JEVTANA is contraindicated in patients with severe hepatic impairment. 2.4 Dose Modifications for Use with Strong CYP3A Inhibitors Concomitant drugs that are strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase plasma concentrations of cabazitaxel.

Avoid the coadministration of

JEVTANA with these drugs.

If patients require coadministration of a strong CYP3A inhibitor, consider a 25% JEVTANA dose reduction. 2.5 Preparation and Administration JEVTANA is a hazardous anticancer drug.

Follow applicable special handling and disposal procedures.

If JEVTANA first diluted solution, or second (final) dilution for intravenous infusion should come into contact with the skin or mucous, immediately and thoroughly wash with soap and water.

Do not use

PVC infusion containers or polyurethane infusions sets for preparation and administration of JEVTANA infusion solution.

JEVTANA should not be mixed with any other drugs.

Read this entire section carefully before mixing and diluting.

Follow the preparation instructions provided below, as improper preparation may lead to overdose.

Both the JEVTANA injection and the diluent vials contain an overfill to compensate for liquid loss during preparation.

This overfill ensures that after dilution with the entire contents of the accompanying diluent, there is an initial diluted solution containing 10 mg/mL JEVTANA.

Inspect the

JEVTANA injection and supplied diluent vials.

JEVTANA injection is a clear yellow to brownish-yellow viscous solution.

Step 1 – first dilution Each vial of JEVTANA (cabazitaxel) 60 mg/1.5 mL must first be mixed with the entire contents of supplied diluent.

Once reconstituted, the resultant solution contains 10 mg/mL of JEVTANA.

When transferring the diluent, direct the needle onto the inside wall of JEVTANA vial and inject slowly to limit foaming.

Remove the syringe and needle and gently mix the initial diluted solution by repeated inversions for at least 45 seconds to assure full mixing of the drug and diluent.

Do not shake.

Let the solution stand for a few minutes to allow any foam to dissipate, and check that the solution is homogeneous and contains no visible particulate matter.

It is not required that all foam dissipate prior to continuing the preparation process.

The resulting initial diluted

JEVTANA solution (cabazitaxel 10 mg/mL) requires further dilution before administration.

The second dilution should be done immediately (within 30 minutes) to obtain the final infusion as detailed in Step 2.

Step 2 – second (final) dilution Withdraw the recommended dose from the JEVTANA solution containing 10 mg/mL as prepared in Step 1 using a calibrated syringe and further dilute into a sterile 250 mL PVC-free container of either 0.9% sodium chloride solution or 5% dextrose solution for infusion.

If a dose greater than 65 mg of JEVTANA is required, use a larger volume of the infusion vehicle so that a concentration of 0.26 mg/mL JEVTANA is not exceeded.

The concentration of the

JEVTANA final infusion solution should be between 0.10 mg/mL and 0.26 mg/mL.

Remove the syringe and thoroughly mix the final infusion solution by gently inverting the bag or bottle.

As the final infusion solution is supersaturated, it may crystallize over time.

Do not use if this occurs and discard.

Fully prepared

JEVTANA infusion solution (in either 0.9% sodium chloride solution or 5% dextrose solution) should be used within 8 hours at ambient temperature (including the one-hour infusion), or for a total of 24 hours (including the one-hour infusion) under the refrigerated conditions.

Discard any unused portion.

Inspect visually for particulate matter, any crystals and discoloration prior to administration.

If the

JEVTANA first diluted solution or second (final) infusion solution is not clear or appears to have precipitation, it should be discarded.

Use an in-line filter of 0.22 micrometer nominal pore size (also referred to as 0.2 micrometer) during administration.

The final

JEVTANA infusion solution should be administered intravenously as a one-hour infusion at room temperature.

JEVTANA is supplied as a kit, NDC 0024-5824-11, that contains the following: One single-dose vial of JEVTANA (cabazitaxel) injection: a clear yellow to brownish-yellow viscous solution of 60 mg/1.5 mL in a clear glass vial with a grey rubber closure, aluminum cap, and light green plastic flip-off cap (JEVTANA vial NDC 0024-5823-15).

One single-dose vial of Diluent for

JEVTANA: a clear colorless solution of 13% (w/w) ethanol in water for injection in a clear glass vial with a grey rubber closure, gold-color aluminum cap, and colorless plastic flip-off cap (diluent vial NDC 0024-5822-01). 16.2 Storage JEVTANA injection and Diluent for JEVTANA: Store at 25°C (77°F); excursions permitted between 15°C–30°C (59°F–86°F).

Do not refrigerate. 16.3 Handling and Disposal JEVTANA is a hazardous anticancer drug.

Follow applicable special handling and disposable procedures.

Storage JEVTANA injection and Diluent for JEVTANA: Store at 25°C (77°F); excursions permitted between 15°C–30°C (59°F–86°F).

Do not refrigerate.

Risk Summary The safety and efficacy of JEVTANA have not been established in females.

There are no human data on the use of JEVTANA in pregnant women to inform the drug-associated risk.

In animal reproduction studies, intravenous administration of cabazitaxel in pregnant rats during organogenesis caused embryonic and fetal death at doses lower than the maximum recommended human dose.

Data Animal data

In an early embryonic developmental toxicity study in rats, cabazitaxel was administered intravenously for 15 days prior to mating through day of pregnancy, which resulted in an increase in pre-implantation loss at 0.2 mg/kg/day and an increase in early resorptions at ≥0.1 mg/kg/day (approximately 0.06 and 0.02 times the C max in patients at the recommended human dose, respectively).

In an embryo-fetal developmental toxicity study in rats, cabazitaxel caused maternal and embryo-fetal toxicity consisting of increased postimplantation loss, embryolethality, and fetal deaths when administered intravenously at a dose of 0.16 mg/kg/day (approximately 0.06 times the C max in patients at the recommended human dose).

Decreased mean fetal birthweight associated with delays in skeletal ossification was observed at doses ≥0.08 mg/kg. Cabazitaxel crossed the placenta barrier within 24 hours of a single intravenous administration of 0.08 mg/kg to pregnant rats at gestational day 17.

A dose of 0.08 mg/kg in rats resulted in a C max approximately 0.02 times that observed in patients at the recommended human dose.

Administration of cabazitaxel did not result in fetal abnormalities in rats or rabbits at exposure levels significantly lower than the expected human exposures.

The safety and effectiveness of

JEVTANA in pediatric patients have not been established.

JEVTANA was evaluated in 39 pediatric patients (ages to 18 years) receiving prophylactic G-CSF.

The maximum tolerated dose (MTD) was 30 mg/m 2 intravenously over 1 hour on Day of a 21 day cycle in pediatric patients with solid tumors based on the dose-limiting toxicity (DLT) of febrile neutropenia.

No objective responses were observed in 11 patients with refractory high grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG).

One patient had a partial response among the 9 patients with ependymoma.

Infusion related/hypersensitivity reactions were seen in 10 patients (26%).

Three patients experienced serious adverse events of anaphylactic reaction.

The incidence of infusion related/hypersensitivity reactions decreased with steroid premedication.

The most frequent treatment-emergent adverse events were similar to those reported in adults.

Based on the population pharmacokinetics analysis conducted with data from 31 pediatric patients with cancer (ages to 18 years), the clearances by body surface area were comparable to those in adults.

In the

TROPIC study, of the 371 patients with prostate cancer treated with JEVTANA every three weeks plus prednisone, 240 patients (64.7%) were 65 years of age and over, while 70 patients (18.9%) were 75 years of age and over.

No overall differences in effectiveness were observed between patients ≥65 years of age and younger patients.

Elderly patients (≥65 years of age) may be more likely to experience certain adverse reactions.

The incidence of death due to causes other than disease progression within 30 days of the last cabazitaxel dose were higher in patients who were 65 years of age or greater compared to younger patients.

The incidence of grade 3–4 neutropenia and febrile neutropenia were higher in patients who were 65 years of age or greater compared to younger patients.

The following grade 1–4 adverse reactions were reported at rates ≥5% higher in patients 65 years of age or older compared to younger patients: fatigue (40% vs 30%), neutropenia (97% vs 89%), asthenia (24% vs 15%), pyrexia (15% vs 8%), dizziness (10% vs 5%), urinary tract infection (10% vs 3%), and dehydration (7% vs 2%), respectively.

PROSELICA study, the grade 1–4 adverse reactions reported at rates of at least 5% higher in patients 65 years of age or older compared to younger patients were diarrhea (43% vs 33%), fatigue (30% vs 19%), asthenia (22% vs 13%), constipation (20% vs 13%), clinical neutropenia (13% vs 6%), febrile neutropenia (11% vs 5%), and dyspnea (10% vs 3%).

CARD study, the grade 1–4 adverse reactions reported at rates of at least 5% higher in patients 65 years of age or older compared to younger patients were decreased appetite (16% vs 7%), hypertension (5% vs 0), constipation (18% vs 7%), paresthesia (6% vs 0), stomatitis (10% vs 3%), musculoskeletal pain (5% vs 0), fatigue (31% vs 23%), asthenia (30% vs 19%), and edema peripheral (11% vs 0).

Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of cabazitaxel between patients <65 years (n=100) and older (n=70).