Palbociclib-vista

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PALBOCICLIB-VISTA

Composition:

Active substance: palbociclib;

1 tablet contains 75 mg, 100 mg, or 125 mg of palbociclib;

Excipients: microcrystalline cellulose (type 102), colloidal anhydrous silicon dioxide, crospovidone (type A), copovidone, magnesium stearate, succinic acid, microcrystalline cellulose (type 200), crospovidone (type B), sodium stearyl fumarate, tablet coating:

for 75 mg tablets — Opadry 03K140024 pink (titanium dioxide (E 171), triacetin, red iron oxide (E172));

for 100 mg tablets — Opadry 03K240007 red (titanium dioxide (E 171), triacetin, red iron oxide (E172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

75 mg tablets: round, biconvex, film-coated tablets of pink color, 9 mm in diameter, with an embossing «L» on one side and no marking on the other side;

100 mg tablets: oval, biconvex, film-coated tablets of red color, 15 mm in length and 7 mm in width, with an embossing «I» on one side and no marking on the other side;

125 mg tablets: oval, biconvex, film-coated tablets of pink color, 16 mm in length and 8 mm in width, with an embossing «H» on one side and no marking on the other side.

Pharmacotherapeutic group

Antineoplastic agents. Protein kinase inhibitors. ATC code: L01EF01.

Pharmacological Properties

Mechanism of Action

Palbociclib is a highly selective, reversible inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin D1 and CDK4/6 are components of multiple downstream signaling pathways that drive cell proliferation.

Pharmacodynamics

By inhibiting CDK4/6, palbociclib reduces cell proliferation by blocking the transition of cells from the G1 phase to the S phase of the cell cycle. Testing of palbociclib in breast cancer cell lines with defined molecular profiles demonstrated high activity against luminal breast cancer, particularly ER-positive breast cancer. In tested cell lines, loss of retinoblastoma (Rb) was associated with loss of palbociclib activity. However, further investigation using fresh tumor samples revealed no correlation between RB1 expression and tumor response. No causal relationship was observed when studying response to palbociclib treatment in vivo in patient-derived xenograft tumor models (PDX models). Available clinical data are presented below (see Clinical Efficacy and Safety).

Cardiac Electrophysiology

The effect of palbociclib on the heart rate-corrected QT interval (QTc) was evaluated using time-matched electrocardiograms (ECGs), assessing changes from baseline along with corresponding pharmacokinetic data in 77 patients with advanced breast cancer. Palbociclib did not cause a clinically significant increase in QTc when administered at the recommended dose of 125 mg once daily (3/1 schedule).

Clinical Efficacy and Safety

Phase 3 Randomized PALOMA-2 Study: Palbociclib in Combination with Letrozole

The efficacy of palbociclib in combination with letrozole was compared to letrozole with placebo in an international, randomized, double-blind, placebo-controlled, multicenter, parallel-group study conducted in postmenopausal women with ER-positive, HER2-negative locally advanced breast cancer that was not amenable to surgical or radiation therapy with curative intent, or in women with metastatic breast cancer who had not received prior systemic therapy for advanced disease.

A total of 666 postmenopausal women were randomized 2:1 to receive either palbociclib plus letrozole or placebo plus letrozole, stratified by disease site (visceral vs. non-visceral), disease-free interval from the end of (neo)adjuvant therapy to recurrence (de novo metastases ≤12 months vs. de novo metastases >12 months), and prior (neo)adjuvant anticancer therapy (with or without prior hormonal therapy). Patients with progressive symptomatic visceral disease at risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitic carcinomatosis, or liver involvement >50%) were not eligible for the study.

Patients continued their assigned treatment until objective disease progression, worsening of symptoms, unacceptable toxicity, death, or withdrawal of consent. Cross-over between treatment groups was not permitted.

Patients were well balanced across baseline demographic and prognostic characteristics between the palbociclib plus letrozole and placebo plus letrozole groups. The median age of patients included in this study was 62 years (range 28–89). Of these, 48.3% had received chemotherapy and 56.3% had received antihormonal therapy as part of (neo)adjuvant treatment prior to diagnosis of advanced breast cancer, while 37.2% had received no prior systemic therapy as part of (neo)adjuvant treatment. The majority of patients (97.4%) had metastatic disease at baseline, 23.6% had bone-only disease, and 49.2% had visceral disease.

The primary endpoint of the study was progression-free survival (PFS), assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by investigator assessment. Secondary efficacy endpoints included objective response rate, clinical benefit rate, safety, and change in quality of life.

As of the data cutoff date of February 26, 2016, the study met its primary objective of demonstrating improved progression-free survival. The observed hazard ratio was 0.576 (95% confidence interval [CI]: 0.46, 0.72) in favor of palbociclib plus letrozole, with a one-sided stratified log-rank p-value <0.000001. After an additional 15 months of follow-up (data cutoff date: May 31, 2017), an updated analysis of the primary and secondary endpoints was performed. A total of 405 PFS events were recorded: 245 events (55.2%) in the palbociclib plus letrozole group and 160 events (72.1%) in the comparator group.

Efficacy results based on the initial and updated analyses, including data from the PALOMA-2 study, as assessed by investigators and an independent review committee, are presented in Table 1.

Table 1
Efficacy results based on initial and updated analyses from the PALOMA-2 study, according to investigator assessment and independent review

N – number of patients; CI – confidence interval; NE – not estimable; OR – objective response; CRR – clinical response rate; PFS – progression-free survival.

*Secondary efficacy endpoints based on confirmed and unconfirmed responses according to RECIST 1.1.

A series of subgroup analyses of PFS based on prognostic factors and baseline characteristics were conducted to assess the internal consistency of the treatment effect. A reduction in the risk of disease progression or death in favor of the palbociclib plus letrozole arm was observed across all individual patient subgroups defined by stratification factors and baseline characteristics, as demonstrated by the results of the primary and updated analyses.

As of the data cutoff date of May 31, 2017, this risk reduction in favor of the palbociclib plus letrozole arm continued to be observed in the following subgroups:

(1) patients with visceral metastases (HR 0.62 [95% CI: 0.47; 0.81], median PFS [mPFS] 19.3 months versus 12.3 months) or without visceral metastases (HR 0.50 [95% CI: 0.37; 0.67], mPFS 35.9 months versus 17.0 months); and (2) patients with bone-only disease (HR 0.41 [95% CI: 0.26; 0.63], mPFS 36.2 months versus 11.2 months) or patients with non-bone disease (HR 0.62 [95% CI: 0.50; 0.78], mPFS 24.2 months versus 14.5 months). Similarly, a reduction in the risk of disease progression or death in the palbociclib plus letrozole arm was observed in 512 patients whose tumor tested positive for Rb protein expression by immunohistochemistry (IHC) (HR 0.543 [95% CI: 0.433; 0.681], mPFS 27.4 months versus 13.7 months). For the 51 patients with absence of Rb expression confirmed by IHC, the difference between the palbociclib plus letrozole and placebo plus letrozole treatment groups was not statistically significant (HR 0.868 [95% CI: 0.424; 1.777], mPFS 23.2 months versus 18.5 months).

Additional efficacy measures (objective response and time to first tumor response [TTR]), evaluated in subgroups of patients with or without visceral disease, as of the data cutoff date of May 31, 2017, are presented in Table 2.

Table 2

Efficacy results from the PALOMA-2 study in patients with visceral and non-visceral disease (Intent-to-Treat population, as of data cutoff date May 31, 2017)

N – number of patients; CI – confidence interval; OR – objective response based on confirmed and unconfirmed responses according to RECIST 1.1; TTF – time to first tumor response.

At the time of the updated analysis, the median time from randomization to initiation of second subsequent therapy was 38.8 months in the palbociclib in combination with letrozole group and 28.8 months in the placebo plus letrozole group, HR 0.73 (95% CI: 0.58; 0.91).

Final overall survival (OS) results from the PALOMA-2 study are presented in Table 3.

After a median follow-up time of 90 months, the final OS results were not statistically significant.

Table 3

PALOMA-2 (Intent-to-Treat patients) – Final Overall Survival Results

CI – confidence interval.

* Not statistically significant.

† Two-sided p-value by stratified log-rank test with stratification by disease location (visceral or non-visceral metastases) within each randomization group.

Phase 3 randomized PALOMA-3 study: palbociclib in combination with fulvestrant

The efficacy of palbociclib in combination with fulvestrant compared to fulvestrant with placebo was evaluated in an international, randomized, double-blind, multicenter, parallel-group study conducted in pre/perimenopausal and postmenopausal women with HR-positive, HER2-negative locally advanced breast cancer that was not amenable to surgical or radiation therapy with curative intent, or in women with metastatic breast cancer regardless of menopausal status, whose disease had progressed on or after prior hormonal therapy administered in the (neo)adjuvant setting or for metastatic disease.

A total of 521 pre/perimenopausal and postmenopausal women with disease progression within 12 months of or after completion of adjuvant hormonal therapy, or within 1 month of or after completion of prior hormonal therapy for advanced disease, were randomized in a 2:1 ratio to receive either palbociclib plus fulvestrant or placebo plus fulvestrant. Patients were stratified by documented sensitivity to prior hormonal therapy, menopausal status at study entry (pre/perimenopausal or postmenopausal), and presence of visceral metastases. Pre/perimenopausal women received the GnRH agonist goserelin. Patients with progressive metastatic symptomatic visceral disease at risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitic carcinomatosis, or liver involvement >50%) were not eligible for the study.

Patients continued their assigned treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first. Crossover between treatment groups was not permitted.

Patients were well balanced across baseline demographic and prognostic characteristics between the palbociclib plus fulvestrant and placebo plus fulvestrant groups. The median age of enrolled patients was 57 years (range: 29 to 88). The majority of study participants were of White race, had documented sensitivity to prior hormonal therapy, and were postmenopausal. Approximately 20% of patients were pre/perimenopausal. All patients had received prior systemic therapy, and most patients in each treatment group had received prior chemotherapy for their initial diagnosis. More than half of the patients (62%) had an ECOG PS of 0, 60% had visceral metastases, and 60% had received more than one prior hormonal therapy for their initial diagnosis.

The primary endpoint of the study was progression-free survival (PFS), as defined by RECIST 1.1 criteria, assessed by the investigator. Additional PFS analyses were based on independent central radiological review. Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), safety, and time to deterioration (TTD) of symptoms based on pain intensity as a key endpoint.

The study met its primary endpoint of prolonged PFS as assessed by the investigator at an interim analysis based on 82% of the planned PFS events; results exceeded the predefined Haybittle-Peto efficacy boundary (α = 0.00135), demonstrating a statistically significant improvement in progression-free survival and a clinically meaningful treatment effect.

Further details on efficacy are provided in Table 4.

After additional follow-up (median follow-up of 45 months), a final OS analysis was performed based on 310 events (60% of randomized patients). The difference in median OS between the palbociclib plus fulvestrant group and the placebo plus fulvestrant group was 6.9 months; this result was not statistically significant according to the pre-specified (one-sided) significance level of 0.0235. In the placebo plus fulvestrant group, 15.5% of randomized patients received palbociclib or other CDK4/6 inhibitors as subsequent therapy after disease progression.

Results for PFS as assessed by the investigator and final OS data from the PALOMA-3 study are presented in Table 4.

Table 4
Efficacy results from the PALOMA-3 study (investigator assessment, Intent-to-Treat population)

PFS - progression-free survival; CI - confidence interval; N - number of patients; OR - objective response.

Secondary efficacy endpoints based on confirmed and unconfirmed responses according to RECIST 1.1.

* Not statistically significant.

† One-sided p-value derived from the log-rank test, stratified by presence of visceral metastases and sensitivity to prior endocrine therapy at randomization.

A reduction in the risk of disease progression or death was observed in favor of the palbociclib plus fulvestrant group across all prespecified patient subgroups defined by stratification factors and baseline characteristics. The effect was evident in pre/perimenopausal women (HR 0.46 [95% CI: 0.28; 0.75]) and postmenopausal women (HR 0.52 [95% CI: 0.40; 0.66]), as well as in patients with visceral metastases (HR 0.50 [95% CI: 0.38; 0.65]) and those without visceral metastases (HR 0.48 [95% CI: 0.33; 0.71]). Benefit was also observed regardless of prior lines of therapy for metastatic disease: 0 (HR 0.59 [95% CI: 0.37; 0.93]), 1 (HR 0.46 [95% CI: 0.32; 0.64]), 2 (HR 0.48 [95% CI: 0.30; 0.76]), or ≥3 lines (HR 0.59 [95% CI: 0.28; 1.22]). Additional efficacy measures (OR and PFS), evaluated in subgroups of patients with or without visceral disease, are shown in Table 5.

Table 5

Efficacy results from the PALOMA-3 study by visceral and non-visceral disease status (Intent-to-Treat patients)

N – number of patients; CI – confidence interval; OR – objective response based on confirmed and unconfirmed responses according to RECIST 1.1; TTR – time to first tumor response.

Symptoms reported by patients were assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and its breast cancer module (EORTC QLQ-BR23). A total of 335 patients in the palbociclib plus fulvestrant group and 166 patients in the fulvestrant monotherapy group completed the questionnaire at baseline and at least once during a post-baseline visit.

Time to deterioration was predefined as the time between baseline pain score and the first occurrence of an increase of ≥10 points compared to baseline on the pain symptom scale. Addition of palbociclib to fulvestrant treatment significantly delayed the time to worsening of pain symptoms compared to placebo plus fulvestrant (median 8.0 months vs. 2.8 months; HR 0.64 [95% CI: 0.49; 0.85]; p <0.001).

Pharmacokinetics

The pharmacokinetics of palbociclib have been characterized in patients with solid tumors, including patients with advanced breast cancer, and in healthy volunteers.

Absorption

Mean Cmax of palbociclib is generally reached within 4–12 hours (time to maximum concentration [Tmax]) after oral administration. The mean absolute bioavailability of palbociclib following a single 125 mg oral dose is 46%. Following doses in the range of 25 mg to 225 mg, the area under the pharmacokinetic curve (AUC) and Cmax increased proportionally with dose. Steady state was achieved within 8 days of once-daily administration of palbociclib. With repeated once-daily dosing, palbociclib accumulates with a mean accumulation ratio of 2.4 (range 1.5–4.2).

Effect of food

The AUCinf and Cmax of palbociclib increased by 22% and 26%, respectively, when palbociclib was administered with a high-fat, high-calorie meal (approximately 800–1000 calories, with 150, 250, and 500–600 calories from protein, carbohydrates, and fat, respectively), and by 9% and 10%, respectively, when palbociclib tablets were administered with a standard-calorie meal low in fat (approximately 500–700 calories, with 75–100, 250–350, and 175–245 calories from protein, carbohydrates, and fat, respectively), compared to administration under fasting conditions. Based on these results, palbociclib tablets may be administered independently of food intake.

Distribution

In vitro protein binding of palbociclib to human plasma proteins is approximately 85%, independent of drug concentration. The mean unbound fraction (fu) of palbociclib in human plasma in vivo gradually increased with worsening hepatic function. No clear trend in changes in the mean fu of palbociclib in human plasma in vivo was observed with worsening renal function. In vitro, accumulation of palbociclib in human hepatocytes occurred primarily via passive diffusion. Palbociclib is not a substrate of OATP1B1 or OATP1B3.

Metabolism

In vitro and in vivo studies demonstrated that palbociclib is metabolized in the liver in humans. After a single oral dose of [14C]-palbociclib 125 mg in humans, the primary metabolic pathways of palbociclib were oxidation and sulfonation, with minor pathways being acylation and glucuronidation. Palbociclib in plasma was the main circulating drug-derived entity.

The majority of the drug was excreted as metabolites. In feces, the main metabolite was the palbociclib sulfate conjugate, accounting for 25.8% of the administered dose. In vitro studies using human hepatocytes, liver cytosolic and S9 fractions, and recombinant sulfotransferase (SULT) enzymes demonstrated that CYP3A and SULT2A1 are primarily involved in metabolism.

Elimination

The mean geometric value of apparent total clearance (CL/F) of palbociclib was 63 L/h, and the mean geometric half-life in plasma was 28.8 hours in patients with advanced breast cancer. In 6 healthy male volunteers who received a single oral dose of [14C] palbociclib, on average 92% of the administered radioactive dose was excreted within 15 days, predominantly in feces (74% of dose), and 17% in urine. Excretion of unchanged palbociclib in feces and urine accounted for 2% and 7% of the administered dose, respectively.

In vitro, palbociclib is not an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, or 2D6, and is not an inducer of CYP1A2, 2B6, 2C8, or 3A4 at clinically relevant concentrations.

In vitro assessment indicates that palbociclib has low potential to inhibit the activity of organic anion transporter (OAT)1, OAT3, organic cation transporters (OCT)2, organic anion transporting polypeptides (OATP)1B1 and OATP1B3, and bile salt export pump (BSEP) at clinically relevant concentrations.

Special patient populations

Age, gender, and body weight

Based on population pharmacokinetic analysis in 183 patients with cancer (50 males and 133 females, aged 22 to 89 years, with body weight ranging from 38 to 123 kg), gender had no effect on palbociclib exposure, and age and body weight had no clinically significant effect on palbociclib exposure.

Hepatic impairment

Pharmacokinetic data from studies in patients with varying degrees of hepatic function indicate a 17% decrease in exposure to unchanged palbociclib (unchanged AUCinf) in patients with mild hepatic impairment (Child-Pugh class A), and increases of 34% and 77% in patients with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment, respectively, compared to patients with normal hepatic function. Maximum exposure to palbociclib (unbound Cmax) increased by 7%, 38%, and 72% in mild, moderate, and severe hepatic impairment, respectively, compared to patients with normal liver function. Additionally, based on population pharmacokinetic analysis in 183 patients with advanced cancer, including 40 patients with mild hepatic impairment according to National Cancer Institute (NCI) classification (total bilirubin ≤1.0 to 1.5 × ULN bilirubin at any AST level), mild hepatic impairment did not affect the pharmacokinetics of palbociclib.

Renal impairment

Pharmacokinetic data from studies in patients with varying degrees of renal function indicate increases in total palbociclib exposure (AUCinf) of 39%, 42%, and 31% in patients with mild (60 mL/min ≤ creatinine clearance < 90 mL/min), moderate (30 mL/min ≤ creatinine clearance < 60 mL/min), and severe (creatinine clearance ≤ 30 mL/min) renal impairment, respectively, compared to patients with normal renal function (creatinine clearance ≥ 90 mL/min). Maximum exposure to palbociclib (Cmax) increased by 17%, 12%, and 15% in mild, moderate, and severe renal impairment, respectively, compared to patients with normal renal function. Additionally, based on population pharmacokinetic analysis of data from 183 patients with advanced cancer, including 73 patients with mild renal impairment and 29 patients with moderate renal impairment, mild to moderate renal impairment did not affect the pharmacokinetics of palbociclib. The pharmacokinetics of palbociclib in patients requiring hemodialysis have not been studied.

Ethnicity

In a pharmacokinetic study in healthy volunteers, AUCinf and Cmax of palbociclib after a single oral dose were 30% and 35% higher, respectively, in Japanese volunteers compared to non-Asian volunteers. However, this finding was not consistently reproduced in subsequent studies in patients with breast cancer of Japanese or Asian origin receiving multiple doses of the drug. Based on integrated analyses of pharmacokinetic, safety, and efficacy data in Asian and non-Asian patient populations, dose adjustment for patients of Asian origin is not required.

Clinical Characteristics

Indications

The medicinal product PALBOCICLIB-VISTA is indicated for the treatment of hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative (HER2-negative) locally advanced or metastatic breast cancer:

• in combination with an aromatase inhibitor;
• in combination with fulvestrant in women who have previously received endocrine therapy (see section "Pharmacodynamics").

In premenopausal and perimenopausal women, endocrine therapy should be administered in combination with a gonadotropin-releasing hormone agonist (GnRHa).

Contraindications

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Use of preparations containing St. John's wort (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions

Palbociclib is primarily metabolized by the cytochrome CYP3A isoenzyme and the sulfotransferase enzyme (SULT) SULT2A1. In vivo, palbociclib is a weak inhibitor of CYP3A, and its inhibitory activity is time-dependent.

Effect of other medicinal products on the pharmacokinetics of palbociclib

Effect of CYP3A inhibitors

Repeated administration of itraconazole 200 mg daily together with a single dose of palbociclib 125 mg increased total exposure (AUCinf) and maximum concentration (Cmax) of palbociclib by approximately 87% and 34%, respectively, compared to a single dose of palbociclib 125 mg alone.

Concomitant use with strong CYP3A inhibitors should be avoided, including but not limited to: clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole, and grapefruit or grapefruit juice (see sections "Method of administration and dosage" and "Special precautions for use").

Dose adjustment is not required when using weak and moderate CYP3A inhibitors.

Effect of CYP3A inducers

Concomitant administration of multiple doses of rifampicin 600 mg and a single dose of palbociclib 125 mg resulted in a reduction of AUCinf and Cmax of palbociclib by 85% and 70%, respectively, compared to monotherapy with palbociclib 125 mg.

Concomitant use with strong CYP3A inducers should be avoided, including: carbamazepine, enzalutamide, phenytoin, rifampicin, and St. John's wort (see sections "Contraindications" and "Special precautions for use").

Concomitant administration of the moderate CYP3A inducer modafinil 400 mg and a single dose of palbociclib 125 mg reduced AUCinf and Cmax of palbociclib by approximately 32% and 11%, respectively, compared to a single dose of palbociclib 125 mg alone. Dose adjustment is not required when used concomitantly with moderate CYP3A inducers (see section "Special precautions for use").

Effect of agents that reduce gastric acidity

When administered together fasting, a single dose of palbociclib 125 mg and multiple doses of the proton pump inhibitor (PPI) rabeprazole had no effect on the extent or rate of absorption of palbociclib compared to administration of a single dose of palbociclib 125 mg alone.

Due to the lesser effect of H2-receptor antagonists and local antacids on gastric pH compared to PPIs, their effect on palbociclib exposure is expected to be negligible.

Effect of palbociclib on the pharmacokinetics of other medicinal products

Palbociclib is a weak time-dependent inhibitor of CYP3A at a daily dose of 125 mg at steady state. Repeated co-administration of palbociclib and midazolam increased AUCinf and Cmax by 61% and 37%, respectively, compared to midazolam monotherapy.

Dose reduction of sensitive CYP3A substrates with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus) may be required, as palbociclib may increase their exposure.

Potential drug interactions between palbociclib and letrozole

Data from a clinical study in patients with breast cancer demonstrated no interaction between palbociclib and letrozole when administered concomitantly.

Effect of tamoxifen on palbociclib exposure

Data from a study in healthy male volunteers showed that palbociclib exposure following co-administration of a single dose of palbociclib with multiple doses of tamoxifen was comparable to that observed with palbociclib monotherapy.

Drug interaction between palbociclib and fulvestrant

Data from a clinical study in patients with breast cancer demonstrated that there is no clinically significant interaction between palbociclib and fulvestrant when these medicinal products are administered concomitantly.

Drug interaction between palbociclib and oral contraceptives

Drug interaction studies between palbociclib and oral contraceptives have not been conducted (see section "Use during pregnancy and breastfeeding").

In vitro transporter studies

Based on in vitro data, palbociclib is expected to inhibit the activity of P-glycoprotein (P-gp) in the intestine and breast cancer resistance protein (BCRP). Therefore, co-administration of palbociclib with medicinal products that are P-gp substrates (e.g., digoxin, dabigatran, colchicine) or BCRP substrates (e.g., pravastatin, rosuvastatin, fluvastatin, sulfasalazine) may increase their therapeutic effect and adverse reactions.

Based on in vitro study data, palbociclib may inhibit uptake by organic cation transporters OCT1, thereby increasing exposure to medicinal products that are substrates of these transporters (e.g., metformin).

Drug interaction between palbociclib and statins

Concomitant use of palbociclib with statins that are substrates of CYP3A4 and/or BCRP may increase the risk of rhabdomyolysis due to elevated plasma concentrations of statins. Cases of rhabdomyolysis, including fatal cases, have been reported following concomitant use of palbociclib with simvastatin or atorvastatin.

Special precautions

Women in the pre/perimenopausal period

Ovarian ablation or suppression with a GnRH agonist is mandatory for pre/perimenopausal women receiving palbociclib in combination with an aromatase inhibitor, due to the mechanism of action of aromatase inhibitors. Clinical trials have been conducted only with the combination of palbociclib and fulvestrant in pre/perimenopausal women in combination with a GnRH agonist.

Visceral disease

The safety and efficacy of palbociclib in patients with severe visceral disease have not been studied (see section "Pharmacodynamics").

Hematological disorders

In case of development of grade 3 or 4 neutropenia, temporary interruption of treatment, dose reduction, or delay in the start of the treatment cycle is recommended. Appropriate monitoring should be performed (see sections "Dosage and administration" and "Adverse reactions").

Interstitial lung disease (ILD)/pneumonitis

Severe, life-threatening, or fatal cases of ILD and/or pneumonitis may occur in patients receiving palbociclib in combination with endocrine therapy.

In clinical trials (PALOMA-1, PALOMA-2, PALOMA-3), ILD/pneumonitis of any severity was reported in 1.4% of patients receiving palbociclib, with 0.1% experiencing grade 3 events; no grade 4 events or fatalities were observed. Additionally, cases of ILD/pneumonitis, including fatal cases, have been reported in the post-marketing period (see section "Adverse reactions").

Patients should be monitored for early signs of pulmonary symptoms suggestive of ILD/pneumonitis (such as hypoxia, cough, dyspnea). If new or worsening respiratory symptoms occur and ILD/pneumonitis is suspected, palbociclib should be immediately discontinued and the patient should be referred for evaluation. Palbociclib should be permanently discontinued in patients with severe ILD or pneumonitis (see section "Dosage and administration").

Infections

Due to the myelosuppressive effect of palbociclib, patients may be more susceptible to infections.

Higher rates of infections have been reported in patients receiving palbociclib in randomized clinical trials compared to those in the control group. Grade 3 and 4 infections occurred in 5.6% and 0.9% of patients, respectively, who received palbociclib in any combination (see section "Adverse reactions").

Patients should be monitored for signs of infection and managed according to clinical guidelines (see section "Dosage and administration").

Physicians should inform patients about the necessity of immediately reporting any episodes of fever.

Venous thromboembolism

Venous thromboembolic events have been reported in patients receiving palbociclib (see section "Adverse reactions"). Patients should be monitored for signs and symptoms of deep vein thrombosis and pulmonary embolism and managed accordingly.

Hepatic impairment

Palbociclib should be used with caution in patients with moderate or severe hepatic impairment, with careful monitoring for signs of toxicity (see sections "Dosage and administration" and "Pharmacokinetics").

Renal impairment

Palbociclib should be administered with caution in patients with moderate or severe renal impairment, with careful monitoring for signs of toxicity (see sections "Dosage and administration" and "Pharmacokinetics").

Concomitant use with CYP3A4 inhibitors or inducers

Strong CYP3A4 inhibitors may increase the toxicity of the drug (see section "Interaction with other medicinal products and other forms of interaction"). Concomitant use of strong CYP3A4 inhibitors with palbociclib should be avoided. Concomitant use should be considered only after careful assessment of potential benefits and risks. If concomitant use of palbociclib with a strong CYP3A4 inhibitor cannot be avoided, the dose of palbociclib should be reduced to 75 mg once daily. After discontinuation of the strong CYP3A4 inhibitor, the palbociclib dose should be increased (after 3–5 half-lives of the inhibitor) to the dose used prior to initiation of the strong CYP3A4 inhibitor (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of CYP3A4 inducers may reduce the efficacy of palbociclib and lead to loss of therapeutic effect. Therefore, concomitant use of palbociclib with strong CYP3A4 inducers should be avoided. Dose adjustment is not required when palbociclib is used with moderate CYP3A4 inducers (see section "Interaction with other medicinal products and other forms of interaction").

Women of reproductive potential or their partners

Women of reproductive potential or their male partners should use highly effective contraception during treatment with palbociclib (see section "Pregnancy and breastfeeding").

Important information on excipients

Sodium

The medicinal product PALBOCICLIB-VISTA, 75 mg and 100 mg tablets, contains less than 1 mmol (23 mg) of sodium per tablet, i.e., essentially "sodium-free".

The medicinal product PALBOCICLIB-VISTA, 125 mg tablets, contains more than 1 mmol (26 mg) of sodium per tablet, which should be taken into account when treating patients on a controlled sodium diet.

Pregnancy and breastfeeding

Women of reproductive potential / contraception in women and men

Women of reproductive potential receiving this medicinal product, or their male partners, should use reliable methods of contraception (e.g., double barrier method of contraception) during therapy and for at least 3 weeks or 14 weeks after completion of therapy for women and men, respectively (see section "Interaction with other medicinal products and other forms of interaction").

Pregnancy

Data on the use of palbociclib in pregnant women are lacking or limited. Animal studies have demonstrated reproductive toxicity. Palbociclib is not recommended during pregnancy and in women of reproductive potential unless reliable contraception is used.

Breastfeeding

No studies have been conducted on the effect of palbociclib on breast milk production in humans or animals, its presence in breast milk, or its effect on breastfed infants. It is unknown whether palbociclib is excreted in human breast milk. Breastfeeding is contraindicated in patients receiving palbociclib.

Fertility

In preclinical fertility studies, no effects on the estrous cycle (in female rats) or mating and fertility in rats (males or females) were observed. However, there are no clinical data on the effect of palbociclib on human fertility. Based on data from preclinical safety studies showing effects on the male reproductive system (degeneration of seminiferous tubules, epididymal hypospermia, reduced sperm concentration and motility, reduced prostate secretion), male fertility may be impaired with palbociclib treatment. Therefore, men should consider sperm cryopreservation prior to starting palbociclib.

Ability to affect the speed of reactions when driving or operating machinery

Palbociclib has a minor influence on the ability to drive or operate machinery. However, due to the risk of fatigue during palbociclib treatment, patients should be advised to exercise caution when driving or operating machinery.

Administration and Dosage

Treatment with the medicinal product PALBOCICLIB-VISTA should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

Dosage

The recommended dose is 125 mg of palbociclib taken orally once daily for 21 consecutive days followed by a 7-day break (3-weeks-on, 1-week-off schedule), forming a complete 28-day cycle. Treatment with palbociclib should continue as long as clinical benefit is maintained or until unacceptable toxicity occurs.

When used in combination with palbociclib, an aromatase inhibitor should be administered according to the dosing regimen specified in the product information for that medicinal product. In premenopausal or perimenopausal women, combination therapy with palbociclib and an aromatase inhibitor should always be combined with a GnRH agonist (see section "Special precautions").

When used in combination with palbociclib, the recommended dose of fulvestrant is 500 mg administered intramuscularly on day 1, day 15, and day 29 of treatment, and once monthly thereafter. For more detailed information, refer to the fulvestrant product information. Premenopausal or perimenopausal women should receive GnRH agonists in accordance with local clinical practice guidelines before and during combination treatment with palbociclib and fulvestrant.

Patients should be advised to take palbociclib at approximately the same time each day. If a patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time.

Dose Modifications

Dose adjustments of palbociclib are recommended based on individual safety and tolerability.

Management of certain adverse reactions may require temporary interruption of therapy/delaying the next dose and/or dose reduction, or permanent discontinuation of the medicinal product, according to the dose modification schemes outlined in Tables 6, 7, and 8 (see sections "Special precautions" and "Adverse reactions").

Table 6

Recommended dose modification of PALBOCICLIB-VISTA in the event of adverse reactions

*If further dose reduction (below 75 mg/day) is required, treatment should be discontinued.

Prior to initiating palbociclib treatment and at the beginning of each cycle, as well as on day 15 of the first 2 cycles and whenever clinically indicated, a complete blood count should be performed.

For patients who experience neutropenia of no more than grade 1 or 2 during the first 6 cycles, complete blood counts should be performed every 3 months for subsequent cycles, prior to the start of each cycle or whenever clinically indicated.

It is recommended to administer the medicinal product PALBOCICLIB-VISTA if the absolute neutrophil count (ANC) is ≥1000/mm³ and platelet count is ≥50,000/mm³.

Table 7

Dose modification of the medicinal product PALBOCICLIB-VISTA and management –
Hematological toxicity

Determination of severity according to CTCAE 4.0.

ANC – absolute neutrophil count; CTCAE – Common Terminology Criteria for Adverse Events; LLN – lower limit of normal.

a Applies to all hematological adverse reactions except lymphopenia (unless associated with clinical manifestations, e.g., opportunistic infections).

b ANC: Grade 1: ANC < LLN – 1500/mm³; Grade 2: ANC 1000 – <1500/mm³; Grade 3: ANC 500 – <1000/mm³; Grade 4: ANC <500/mm³.

Table 8

Dose modification of PALBOCICLIB-VISTA drug and management – Non-hematological toxicity

Determination of severity according to CTCAE 4.0.

CTCAE — Common Terminology Criteria for Adverse Events.

Treatment with PALBOCICLIB-VISTA should be permanently discontinued in patients with severe forms of interstitial lung disease (ILD)/pneumonitis (see section "Special Instructions").

Special patient groups

Elderly patients

Dose adjustment of PALBOCICLIB-VISTA is not required for elderly patients (aged 65 years and older) (see section "Pharmacokinetics").

Hepatic impairment

Dose adjustment of PALBOCICLIB-VISTA is not required in patients with mild or moderate hepatic impairment (Child-Pugh classes A and B).

For patients with severe hepatic impairment (Child-Pugh class C), a recommended dose is 75 mg once daily on a 3/1 schedule (see sections "Special Instructions" and "Pharmacokinetics").

Renal impairment

Dose adjustment of PALBOCICLIB-VISTA is not required in patients with mild, moderate, or severe renal impairment (creatinine clearance [CrCl] ≥15 mL/min). There are insufficient data to provide dosing recommendations for patients requiring hemodialysis (see sections "Special Instructions" and "Pharmacokinetics").

Method of administration

PALBOCICLIB-VISTA is intended for oral use. Palbociclib should be taken with food, preferably during a meal, to ensure consistent exposure of palbociclib (see section "Pharmacokinetics"). Grapefruit or grapefruit juice should be avoided during treatment with palbociclib (see section "Interaction with other medicinal products and other forms of interaction").

PALBOCICLIB-VISTA tablets should be swallowed whole (must not be chewed). Do not take tablets if they are broken, cracked, or otherwise damaged.

Children

Safety and efficacy of PALBOCICLIB-VISTA in children and adolescents (under 18 years of age) have not been established. No data are available.

Overdose

In case of palbociclib overdose, gastrointestinal (e.g., nausea, vomiting) and hematological toxicities (e.g., neutropenia) may occur. General supportive treatment should be administered.

Adverse Reactions

Summary of safety profile

The overall safety profile of palbociclib is based on pooled data from 872 patients who received palbociclib in combination with endocrine therapy (N = 527 in combination with letrozole and N = 345 in combination with fulvestrant) in randomized clinical trials for HR-positive, HER2-negative advanced or metastatic breast cancer.

The most commonly reported adverse reactions (≥ 20%) of any grade in patients receiving palbociclib in randomized clinical trials included neutropenia, infections, leukopenia, fatigue, nausea, stomatitis, anemia, diarrhea, alopecia, and thrombocytopenia. The most common adverse reactions (≥ 2%) of Grade 3 or higher with palbociclib were neutropenia, leukopenia, infections, anemia, increased aspartate aminotransferase (AST) levels, fatigue, and increased alanine aminotransferase (ALT) levels.

Dose reductions or modifications due to any adverse reaction were reported in 38.4% of patients receiving palbociclib in randomized clinical trials, regardless of combination.

Treatment was permanently discontinued due to adverse reactions in 5.2% of patients receiving palbociclib in randomized clinical trials, regardless of combination.

Tabulated summary of adverse reactions

Table 9 lists adverse reactions reported during three randomized trials. The median duration of treatment with palbociclib at the time of final overall survival (OS) analysis in the pooled dataset was 14.8 months.

Table 10 presents laboratory abnormalities observed during three randomized trials.

Adverse reactions are listed by system organ class and frequency. Frequencies are defined as: very common (≥1/10); common (≥1/100, <1/10); and uncommon (>1/1000, <1/100).

Table 9

Adverse reactions based on pooled data from three randomized trials (N=872) and from post-marketing experience

ALT - alanine aminotransferase; AST - aspartate aminotransferase; ILD - interstitial lung disease; N(n) - number of patients; N/A - not applicable.

a Preferred terms (PT) are listed according to MedDRA 17.1.

b All PTs belonging to the System Organ Class: infections and infestations.

c Neutropenia includes the following PTs: neutropenia, decreased neutrophil count.

d Leukopenia includes the following PTs: leukopenia, decreased white blood cell count.

e Anemia includes the following PTs: anemia, decreased hemoglobin, decreased hematocrit.

f Thrombocytopenia includes the following PTs: thrombocytopenia, decreased platelet count.

g Stomatitis includes the following PTs: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, stomatitis.

h Rash includes the following PTs: rash, maculopapular rash, rash with itching, erythematous rash, papular dermatitis, dermatitis, acneiform dermatitis, toxic skin eruption.

i Cases of ILD/pneumonitis include any reported events identified by preferred terms from the MedDRA dictionary using the standardized query "lung disease" (narrow search).

j Venous thromboembolism includes the following PTs: pulmonary embolism, embolism, deep vein thrombosis, peripheral embolism, thrombosis. Table 10

Laboratory abnormalities observed in 3 randomized studies (N=872)

AST – aspartate aminotransferase; ALT – alanine aminotransferase; N – number of patients; n/a – not applicable.

Note: The severity grade of abnormalities was determined according to the National Cancer Institute (NCI) CTCAE 4.0 scale.

* Letrozole or fulvestrant.

Description of individual adverse reactions

Overall, neutropenia of any grade was reported in 716 (82.1%) patients receiving palbociclib regardless of combination, grade 3 neutropenia was reported in 500 (57.3%) patients, and grade 4 neutropenía was reported in 97 (11.1%) patients (see Table 9).

In three randomized clinical trials, the median time to first episode of neutropenia of any grade was 15 days (range: 13–317), and the median duration of grade 3 or higher neutropenia was 7 days.

Febrile neutropenia was reported in 0.9% of patients receiving palbociclib in combination with fulvestrant and in 1.7% of patients receiving palbociclib in combination with letrozole.

Febrile neutropenia was reported in 2% of patients receiving palbociclib across the entire clinical development program.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. No special storage conditions required. Keep out of reach and sight of children.

Packaging. 7 tablets per blister, 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Sandoz España, S.L.

Manufacturer's address and place of business

C/Castello, n°1, Sant Boi de Llobregat, Barcelona, 08830, Spain.