Dose Modification The recommended dose modifications for adverse reactions are listed in Tables 1, 2, and 3. Table 1. Recommended Dose Modification for Adverse Reactions Dose Level Dose Recommended starting dose 125 mg/day First dose reduction 100 mg/day Second dose reduction 75 mg/day* *If further dose reduction below 75 mg/day is required, discontinue. Table 2. Dose Modification and Management – Hematologic Toxicitiesa Monitor complete blood counts prior to the start of Cykin (palbociclib) therapy and at the beginning of each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated. For patients who experience a maximum of Grade 1 or 2 neutropenia in the first 6 cycles, monitor complete blood counts for subsequent cycles every 3 months, prior to the beginning of a cycle and as clinically indicated. CTCAE Grade Dose Modifications Grade 1 or 2 No dose adjustment is required. Grade 3 Day 1 of cycle: Withhold Cykin (palbociclib), repeat complete blood count monitoring within 1 week. When recovered to Grade ≤2, start the next cycle at the same dose. Day 15 of first 2 cycles: If Grade 3 on Day 15, continue Cykin (palbociclib) at current dose to complete cycle and repeat complete blood count on Day 22. If Grade 4 on Day 22, see Grade 4 dose modification guidelines below. Consider dose reduction in cases of prolonged (>1 week) recovery from Grade 3 neutropenia or recurrent Grade 3 neutropenia on Day 1 of subsequent cycles Grade 3 neutropeniab with fever ≥38.5 ºC and/or infection At any time: Withhold Cykin (palbociclib) until recovery to Grade ≤2. Resume at the next lower dose. Grade 4 At any time: Withhold Cykin (palbociclib) until recovery to Grade ≤2. Resume at the next lower dose. Grading according to CTCAE 4.0. CTCAE=Common Terminology Criteria for Adverse Events; LLN=lower limit of normal. a Table applies to all hematologic adverse reactions except lymphopenia (unless associated with clinical events, e.g., opportunistic infections). b Absolute neutrophil count (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 3. Dose Modification and Management – Non-Hematologic Toxicities CTCAE Grade Dose Modifications Grade 1 or 2 No dose adjustment is required. Grade ≥3 non-hematologic toxicity (if persisting despite optimal medical treatment) Withhold until symptoms resolve to: • Grade ≤1; • Grade ≤2 (if not considered a safety risk for the patient) Resume at the next lower dose. Grading according to CTCAE 4.0. CTCAE=Common Terminology Criteria for Adverse Events. Dose Modifications for Use with Strong CYP3A Inhibitors Avoid concomitant use of strong CYP3A inhibitors and consider an alternative concomitant medication with no or minimal CYP3A inhibition. If patients must be coadministered a strong CYP3A inhibitor, reduce the Cykin (palbociclib) dose to 75 mg once daily. If the strong inhibitor is discontinued, increase the Cykin (palbociclib) dose (after 3 to 5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. DOSAGE AND ADMINISTRATION Recommended Dose and Schedule The recommended dose of Cykin (palbociclib) is a 125 mg capsule taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days. Cykin (palbociclib) should be taken with food. Administer the recommended dose of an aromatase inhibitor when given with Cykin (palbociclib). Please refer to the Full Prescribing Information for the aromatase inhibitor being used. When given with Cykin (palbociclib), the recommended dose of fulvestrant is 500 mg administered on Days 1, 15, 29, and once monthly thereafter. Please refer to the Full Prescribing Information of fulvestrant. Patients should be encouraged to take their dose of Cykin (palbociclib) at approximately the same time each day. If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time. Cykin (palbociclib) capsules should be swallowed whole (do not chew, crush, or open them prior to swallowing). Capsules should not be ingested if they are broken, cracked, or otherwise not intact. Pre/perimenopausal women treated with the combination Cykin (palbociclib) plus fulvestrant therapy should be treated with luteinizing hormone-releasing hormone (LHRH) agonists according to current clinical practice standards. Dose Modification The recommended dose modifications for adverse reactions are listed in Tables 1, 2, and 3. Table 1. Recommended Dose Modification for Adverse Reactions Dose Level Dose Recommended starting dose 125 mg/day First dose reduction 100 mg/day Second dose reduction 75 mg/day* *If further dose reduction below 75 mg/day is required, discontinue. Table 2. Dose Modification and Management – Hematologic Toxicitiesa Monitor complete blood counts prior to the start of Cykin (palbociclib) therapy and at the beginning of each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated. For patients who experience a maximum of Grade 1 or 2 neutropenia in the first 6 cycles, monitor complete blood counts for subsequent cycles every 3 months, prior to the beginning of a cycle and as clinically indicated. CTCAE Grade Dose Modifications Grade 1 or 2 No dose adjustment is required. Grade 3 Day 1 of cycle: Withhold Cykin (palbociclib), repeat complete blood count monitoring within 1 week. When recovered to Grade ≤2, start the next cycle at the same dose. Day 15 of first 2 cycles: If Grade 3 on Day 15, continue Cykin (palbociclib) at current dose to complete cycle and repeat complete blood count on Day 22. If Grade 4 on Day 22, see Grade 4 dose modification guidelines below. Consider dose reduction in cases of prolonged (>1 week) recovery from Grade 3 neutropenia or recurrent Grade 3 neutropenia on Day 1 of subsequent cycles Grade 3 neutropeniab with fever ≥38.5 ºC and/or infection At any time: Withhold Cykin (palbociclib) until recovery to Grade ≤2. Resume at the next lower dose. Grade 4 At any time: Withhold Cykin (palbociclib) until recovery to Grade ≤2. Resume at the next lower dose. Grading according to CTCAE 4.0. CTCAE=Common Terminology Criteria for Adverse Events; LLN=lower limit of normal. a Table applies to all hematologic adverse reactions except lymphopenia (unless associated with clinical events, e.g., opportunistic infections). b Absolute neutrophil count (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 3. Dose Modification and Management – Non-Hematologic Toxicities CTCAE Grade Dose Modifications Grade 1 or 2 No dose adjustment is required. Grade ≥3 non-hematologic toxicity (if persisting despite optimal medical treatment) Withhold until symptoms resolve to: • Grade ≤1; • Grade ≤2 (if not considered a safety risk for the patient) Resume at the next lower dose. Grading according to CTCAE 4.0. CTCAE=Common Terminology Criteria for Adverse Events. Dose Modifications for Use with Strong CYP3A Inhibitors Avoid concomitant use of strong CYP3A inhibitors and consider an alternative concomitant medication with no or minimal CYP3A inhibition. If patients must be coadministered a strong CYP3A inhibitor, reduce the Cykin (palbociclib) dose to 75 mg once daily. If the strong inhibitor is discontinued, increase the Cykin (palbociclib) dose (after 3 to 5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. CLINICAL PHARMACOLOGY Mechanism of Action Palbociclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin D1 and CDK4/6 are downstream of signaling pathways which lead to cellular proliferation. In vitro, palbociclib reduced cellular proliferation of estrogen receptor (ER)-positive breast cancer cell lines by blocking progression of the cell from G1 into S phase of the cell cycle. Treatment of breast cancer cell lines with the combination of palbociclib and antiestrogens leads to decreased retinoblastoma (Rb) protein phosphorylation resulting in reduced E2F expression and signaling, and increased growth arrest compared to treatment with each drug alone. In vitro treatment of ER-positive breast cancer cell lines with the combination of palbociclib and antiestrogens led to increased cell senescence compared to each drug alone, which was sustained for up to 6 days following palbociclib removal and was greater if antiestrogen treatment was continued. In vivo studies using a patient-derived ER-positive breast cancer xenograft model demonstrated that the combination of palbociclib and letrozole increased the inhibition of Rb phosphorylation, downstream signaling, and tumor growth compared to each drug alone. Human bone marrow mononuclear cells treated with palbociclib in the presence or absence of an anti- estrogen in vitro did not become senescent and resumed proliferation following palbociclib withdrawal. Pharmacodynamics Cardiac Electrophysiology The effect of palbociclib on the QT interval corrected for heart rate (QTc) was evaluated using time- matched electrocardiograms (ECGs) evaluating the change from baseline and corresponding pharmacokinetic data in 77 patients with breast cancer. Palbociclib had no large effect on QTc (i.e. > 20 ms) at 125 mg once daily (Schedule 3/1). Pharmacokinetics The pharmacokinetics (PK) of palbociclib were characterized in patients with solid tumors including advanced breast cancer and in healthy subjects. Absorption The mean maximum observed concentration (Cmax) of palbociclib is generally observed between 6 to 12 hours (time to reach maximum concentration, Tmax) following oral administration. The mean absolute bioavailability of palbociclib after an oral 125 mg dose is 46%. In the dosing range of 25 mg to 225 mg, the AUC and Cmax increased proportionally with dose in general. Steady state was achieved within 8 days following repeated once daily dosing. With repeated once daily administration, palbociclib accumulated with a median accumulation ratio of 2.4 (range 1.5 to 4.2). Food effect: Palbociclib absorption and exposure were very low in approximately 13% of the population under the fasted condition. Food intake increased the palbociclib exposure in this small subset of the population, but did not alter palbociclib exposure in the rest of the population to a clinically relevant extent. Therefore, food intake reduced the intersubject variability of palbociclib exposure, which supports administration of palbociclib with food. Compared to palbociclib given under overnight fasted conditions, the population average area under the concentration-time curve from zero to infinity (AUCINF) and Cmax of palbociclib increased by 21% and 38%, respectively, when given with high-fat, high-calorie food (approximately 800 to 1000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively), by 12% and 27%, respectively, when given with low-fat, low-calorie food (approximately 400 to 500 calories with 120, 250, and 28 to 35 calories from protein, carbohydrate, and fat, respectively), and by 13% and 24%, respectively, when moderate-fat, standard calorie food (approximately 500 to 700 calories with 75 to 105, 250 to 350 and 175 to 245 calories from protein, carbohydrate, and fat, respectively) was given 1 hour before and 2 hours after palbociclib dosing. Distribution Binding of palbociclib to human plasma proteins in vitro was approximately 85%, with no concentration dependence over the concentration range of 500 ng/mL to 5000 ng/mL. The geometric mean apparent volume of distribution (Vz/F) was 2583 L with a coefficient of variation (CV) of 26%. Metabolism In vitro and in vivo studies indicated that palbociclib undergoes hepatic metabolism in humans. Following oral administration of a single 125 mg dose of palbociclib to humans, the primary metabolic pathways for palbociclib involved oxidation and sulfonation, with acylation and glucuronidation contributing as minor pathways. Palbociclib was the major circulating drug-derived entity in plasma (23%). The major circulating metabolite was a glucuronide conjugate of palbociclib, although it only represented 1.5% of the administered dose in the excreta. Palbociclib was extensively metabolized with unchanged drug accounting for 2.3% and 6.9% of radioactivity in feces and urine, respectively. In feces, the sulfamic acid conjugate of palbociclib was the major drug-related component, accounting for 26% of the administered dose. In vitro studies with human hepatocytes, liver cytosolic and S9 fractions, and recombinant SULT enzymes indicated that CYP3A and SULT2A1 are mainly involved in the metabolism of palbociclib. Elimination The geometric mean apparent oral clearance (CL/F) of palbociclib was 63.1 L/hr (29% CV), and the mean (± standard deviation) plasma elimination half-life was 29 (±5) hours in patients with advanced breast cancer. In 6 healthy male subjects given a single oral dose of palbociclib, a median of 91.6% of the total administered radioactive dose was recovered in 15 days; feces (74.1% of dose) was the major route of excretion, with 17.5% of the dose recovered in urine. The majority of the material was excreted as metabolites. Age, Gender, and Body Weight Based on a population pharmacokinetic analysis in 183 patients with cancer (50 male and 133 female patients, age range from 22 to 89 years, and body weight range from 37.9 to 123 kg), gender had no effect on the exposure of palbociclib, and age and body weight had no clinically important effect on the exposure of palbociclib. Pediatric Population Pharmacokinetics of palbociclib have not been evaluated in patients <18 years of age. WARNINGS AND PRECAUTIONS Neutropenia Neutropenia was the most frequently reported adverse reaction in Study 1 (PALOMA-2) with an incidence of 80% and Study 2 (PALOMA-3) with an incidence of 83%. A Grade ≥3 decrease in neutrophil counts was reported in 66% of patients receiving palbociclib plus letrozole in Study 1 and 66% of patients receiving palbociclib plus fulvestrant in Study 2. In Study 1 and 2, the median time to first episode of any grade neutropenia was 15 days and the median duration of Grade ≥3 neutropenia was 7 days. Monitor complete blood counts prior to starting palbociclib therapy and at the beginning of each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia. Febrile neutropenia has been reported in 1.8% of patients exposed to palbociclib across Studies 1 and 2. One death due to neutropenic sepsis was observed in Study 2. Physicians should inform patients to promptly report any episodes of fever. Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, palbociclib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of palbociclib to pregnant rats and rabbits during organogenesis resulted in embryo-fetal toxicity at maternal exposures that were ≥4 times the human clinical exposure based on area under the curve (AUC). Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with palbociclib and for at least 3 weeks after the last dose. ADVERSE REACTIONS • Neutropenia DRUG INTERACTIONS Cykin (palbociclib) is primarily metabolized by CYP3A and sulfotransferase (SULT) enzyme SULT2A1. In vivo, Cykin (palbociclib) is a time-dependent inhibitor of CYP3A. Agents That May Increase Palbociclib Plasma Concentrations Effect of CYP3A Inhibitors Coadministration of a strong CYP3A inhibitor (itraconazole) increased the plasma exposure of Cykin (palbociclib) in healthy subjects by 87%. Avoid concomitant use of strong CYP3A inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole). Avoid grapefruit or grapefruit juice during Palbociclib treatment. If coadministration of Palbociclib with a strong CYP3A inhibitor cannot be avoided, reduce the dose of Cykin (palbociclib). Agents That May Decrease Palbociclib Plasma Concentrations Effect of CYP3A Inducers Coadministration of a strong CYP3A inducer (rifampin) decreased the plasma exposure of Cykin (palbociclib) in healthy subjects by 85%. Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampin, carbamazepine, enzalutamide, and St John’s Wort). Drugs That May Have Their Plasma Concentrations Altered by Palbociclib Coadministration of midazolam with multiple doses of Cykin (palbociclib) increased the midazolam plasma exposure by 61%, in healthy subjects, compared to administration of midazolam alone. The dose of the sensitive CYP3A substrate with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus) may need to be reduced, as Cykin (palbociclib) may increase its exposure. OVERDOSAGE There is no known antidote for Cykin (palbociclib). The treatment of overdose of Cykin (palbociclib) should consist of general supportive measures. PHARMACEUTICAL INFORMATIONS Storage condition Store below 30°C. store in a cool & dry place. Keep away from light. Keep out of the reach of children. HOW SUPPLIED Cykin (palbociclib INN 125 mg capsule): Each commercial box contains 7×4’s capsules in alu-alu blister.

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COMPOSITION

Each hard gelatin capsule contains Palbociclib INN 125 mg.

DESCRIPTION

Cykin (palbociclib) capsules for oral administration contain 125 mg, 100 mg, or 75 mg of palbociclib, a kinase inhibitor. The molecular formula for palbociclib is C24H29N7O2. The molecular weight is 447.54 daltons. The chemical name is 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2­yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one.

PHARMACEUTICAL DOSAGE FORM AND STRENGTHS

Cykin (palbociclib) is presented as 125 mg hard gelatin capsule for oral administration.

THERAPEUTIC INDICATIONS

Palbociclib is indicated for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer in combination with:

  • an aromatase inhibitor as initial endocrine based therapy in postmenopausal women; or
  • fulvestrant in women with disease progression following endocrine therapy.

Recommended Dose and Schedule

The recommended dose of Cykin (palbociclib) is a 125 mg capsule taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days. Cykin (palbociclib) should be taken with food.

Administer the recommended dose of an aromatase inhibitor when given with Cykin (palbociclib). Please refer to the Full Prescribing Information for the aromatase inhibitor being used.

When given with Cykin (palbociclib), the recommended dose of fulvestrant is 500 mg administered on Days 1, 15, 29, and once monthly thereafter. Please refer to the Full Prescribing Information of fulvestrant. Patients should be encouraged to take their dose of Cykin (palbociclib) at approximately the same time each day. If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time. Cykin (palbociclib) capsules should be swallowed whole (do not chew, crush, or open them prior to swallowing). Capsules should not be ingested if they are broken, cracked, or otherwise not intact.

Pre/perimenopausal women treated with the combination Cykin (palbociclib) plus fulvestrant therapy should be treated with luteinizing hormone-releasing hormone (LHRH) agonists according to current clinical practice standards.