IBRANCE 75 mg hard capsules
IBRANCE 100 mg hard capsules
IBRANCE 125 mg hard capsules
IBRANCE 75 mg hard capsules
Each hard capsule contains 75 mg of palbociclib.
Excipients with known effect
Each hard capsule contains 56 mg of lactose (as monohydrate).
IBRANCE 100 mg hard capsules
Each hard capsule contains 100 mg of palbociclib.
Excipients with known effect
Each hard capsule contains 74 mg of lactose (as monohydrate).
IBRANCE 125 mg hard capsules
Each hard capsule contains 125 mg of palbociclib.
Excipients with known effect
Each hard capsule contains 93 mg of lactose (as monohydrate).
For the full list of excipients, see section 6.1.
Hard capsule.
IBRANCE 75 mg hard capsules
Opaque, hard capsule, with a light orange body (printed “PBC 75” in white) and a light orange cap (printed “Pfizer” in white). The capsule length is 18.0 ± 0.3 mm.
IBRANCE 100 mg hard capsules
Opaque, hard capsule, with a light orange body (printed “PBC 100” in white) and a caramel cap (printed “Pfizer” in white). The capsule length is 19.4 ± 0.3 mm.
IBRANCE 125 mg hard capsules
Opaque, hard capsule, with a caramel body (printed “PBC 125” in white) and a caramel cap (printed “Pfizer” in white). The capsule length is 21.7 ± 0.3 mm.
IBRANCE is indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer:
- in combination with an aromatase inhibitor;
- in combination with fulvestrant in women who have received prior endocrine therapy (see section 5.1).
In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinizing hormone-releasing hormone (LHRH) agonist.
Treatment with IBRANCE should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.
Posology
The recommended dose is 125 mg of palbociclib once daily for 21 consecutive days followed by 7 days off treatment (Schedule 3/1) to comprise a complete cycle of 28 days. The treatment with IBRANCE should be continued as long as the patient is deriving clinical benefit from therapy or until unacceptable toxicity occurs.
When coadministered with palbociclib, the recommended dose of letrozole is 2.5 mg taken orally once daily continuously throughout the 28-day cycle. Please refer to the Summary of Product Characteristics of letrozole. Treatment of pre/perimenopausal women with the combination of palbociclib plus letrozole should always be combined with an LHRH agonist (see section 4.4).
When coadministered with palbociclib, the recommended dose of fulvestrant is 500 mg administered intramuscularly on Days 1, 15, 29, and once monthly thereafter. Please refer to the Summary of Product Characteristics of fulvestrant. Prior to the start of treatment with the combination of palbociclib plus fulvestrant, and throughout its duration, pre/perimenopausal women should be treated with LHRH agonists according to local clinical practice.
Patients should be encouraged to take their dose at approximately the same time each day. If the patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time.
Dose adjustments
Dose modification of IBRANCE is recommended based on individual safety and tolerability.
Management of some adverse reactions may require temporary dose interruptions/delays, and/or dose reductions, or permanent discontinuation as per dose reduction schedules provided in Tables 1, 2, and 3 (see sections 4.4 and 4.8).
Table 1. IBRANCE recommended dose modifications for adverse reactions
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Dose level
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Dose
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Recommended dose
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125 mg/day
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First dose reduction
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100 mg/day
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Second dose reduction
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75 mg/day*
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*If further dose reduction below 75 mg/day is required, discontinue the treatment.
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Complete blood count should be monitored prior to the start of IBRANCE therapy and at the beginning of each cycle, as well as on Day 14 of the first 2 cycles, and as clinically indicated.
Absolute neutrophil counts (ANC) of ≥1000/mm3 and platelet counts of ≥50,000/mm3 are recommended to receive IBRANCE.
Table 2. IBRANCE dose modification and management – Haematological toxicities
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CTCAE Grade
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Dose modifications
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Grade 1 or 2
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No dose adjustment is required.
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Grade 3a
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Day 1 of cycle:
Withhold IBRANCE, repeat complete blood count monitoring within 1 week. When recovered to Grade ≤2, start the next cycle at the same dose.
Day 14 of first 2 cycles:
Continue IBRANCE at current dose to complete cycle. Repeat complete blood count on Day 21.
Consider dose reduction in cases of prolonged (>1 week) recovery from Grade 3 neutropenia or recurrent Grade 3 neutropenia in subsequent cycles.
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Grade 3 ANCb (<1000 to 500/mm3) + Fever ≥38.5 °C and/or infection
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Withhold IBRANCE until recovery to Grade ≤2
Resume at next lower dose.
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Grade 4a
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Withhold IBRANCE until recovery to Grade ≤2.
Resume at next lower dose.
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Grading according to CTCAE 4.0.
ANC=absolute neutrophil counts; CTCAE=Common Terminology Criteria for Adverse Events; LLN=lower limit of normal.
a Table applies to all haematological adverse reactions except lymphopenia (unless associated with clinical events, 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.
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Table 3. IBRANCE dose modification and management – Non-haematological toxicities
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CTCAE Grade
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Dose modifications
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Grade 1 or 2
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No dose adjustment is required.
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Grade ≥3 non-haematological toxicity (if persisting despite medical treatment)
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Withhold until symptoms resolve to:
• Grade ≤1;
• Grade ≤2 (if not considered a safety risk for the patient)
Resume at the next lower dose.
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Grading according to CTCAE 4.0.
CTCAE=Common Terminology Criteria for Adverse Events.
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Special populations
Elderly
No dose adjustment of IBRANCE is necessary in patients ≥65 years of age (see section 5.2).
Hepatic impairment
No dose adjustments of IBRANCE are required for patients with mild hepatic impairment (total bilirubin ≤1 × upper limit of normal [ULN] and aspartate aminotransferase [AST] >1 × ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST). Insufficient data are available in patients with moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and any AST) to provide any dose adjustment recommendation. Administer IBRANCE to patients with moderate and severe hepatic impairment only after careful consideration of the potential benefits and risks and with close monitoring of signs of toxicity (see section 5.2).
Renal impairment
No dose adjustments of IBRANCE are required for patients with mild to moderate renal impairment (creatinine clearance [CrCl] ≥30 mL/min). Insufficient data are available in patients with severe renal impairment (CrCl <30 mL/min) or requiring haemodialysis to provide any dose adjustment recommendation. Administer IBRANCE to patients with severe renal impairment only after careful consideration of the potential benefits and risks and with close monitoring of signs of toxicity (see section 5.2).
Paediatric population
The safety and efficacy of IBRANCE in children and adolescents ≤18 years of age have not been established. No data are available.
Method of administration
IBRANCE is for oral use. It should be taken with food, preferably a meal to ensure consistent palbociclib exposure (see section 5.2). Palbociclib should not be taken with grapefruit or grapefruit juice (see section 4.5).
IBRANCE capsules should be swallowed whole (should not be chewed, crushed, or opened prior to swallowing). No capsule should be ingested if it is broken, cracked, or otherwise not intact.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Use of preparations containing St. John's Wort (see section 4.5).
Pre/perimenopausal women
Ovarian ablation or suppression with an LHRH agonist is mandatory when pre/perimenopausal women are administered IBRANCE in combination with an aromatase inhibitor, due to the mechanism of action of aromatase inhibitors. Palbociclib in combination with fulvestrant in pre/perimenopausal women has only been studied in combination with an LHRH agonist.
Critical visceral disease
The efficacy and safety of palbociclib have not been studied in patients with critical visceral disease (see section 5.1).
Haematological disorders
Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia. Appropriate monitoring should be performed (see sections 4.2 and 4.8).
Infections
Since IBRANCE has myelosuppressive properties, it may predispose patients to infections.
Infections have been reported at a higher rate in patients treated with IBRANCE in randomised clinical studies compared to patients treated in the respective comparator arm. Grade 3 and Grade 4 infections occurred respectively in 4.5% and 0.7% of patients treated with IBRANCE in any combination (see section 4.8).
Patients should be monitored for signs and symptoms of infection and treated as medically appropriate (see section 4.2).
Physicians should inform patients to promptly report any episodes of fever.
Hepatic impairment
In the absence of data, IBRANCE should be administered with caution in patients with moderate and severe hepatic impairment (see sections 4.2 and 5.2).
Renal impairment
In the absence of data, IBRANCE should be administered with caution in patients with severe renal impairment (see sections 4.2 and 5.2).
Concomitant treatment with inhibitors or inducers of CYP3A4
Strong inhibitors of CYP3A4 may lead to increased toxicity (see section 4.5). Concomitant use of strong CYP3A inhibitors during treatment with palbociclib should be avoided. Coadministration should only be considered after careful eva luation of the potential benefits and risks. If coadministration with a strong CYP3A inhibitor is unavoidable, reduce the IBRANCE dose to 75 mg once daily. When the strong inhibitor is discontinued, increase the IBRANCE dose (after 3–5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor (see section 4.5).
Coadministration of CYP3A inducers may lead to decreased palbociclib exposure and consequently a risk for lack of efficacy. Therefore, concomitant use of palbociclib with strong CYP3A4 inducers should be avoided. No dose adjustments are required for coadministration of palbociclib with moderate CYP3A inducers (see section 4.5).
Women of childbearing potential or their partners
Women of childbearing potential or their male partners must use a highly effective method of contraception while taking IBRANCE (see section 4.6).
Lactose
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
Palbociclib is primarily metabolised by CYP3A and sulphotransferase (SULT) enzyme SULT2A1. In vivo, palbociclib is a weak, time-dependent inhibitor of CYP3A.
Effects of other medicinal products on the pharmacokinetics of palbociclib
Effect of CYP3A inhibitors
Coadministration of multiple 200 mg doses of itraconazole with a single 125 mg palbociclib dose increased palbociclib total exposure (AUCinf) and the peak concentration (Cmax) by approximately 87% and 34%, respectively, relative to a single 125 mg palbociclib dose given alone.
The concomitant use of strong CYP3A inhibitors including, but not limited to: clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole, and grapefruit or grapefruit juice, should be avoided (see sections 4.2 and 4.4).
No dose adjustments are needed for mild and moderate CYP3A inhibitors.
Effect of CYP3A inducers
Coadministration of multiple 600 mg doses of rifampin with a single 125 mg palbociclib dose decreased palbociclib AUCinf and Cmax by 85% and 70%, respectively, relative to a single 125 mg palbociclib dose given alone.
The concomitant use of strong CYP3A inducers including, but not limited to: carbamazepine, enzalutamide, phenytoin, rifampin, and St. John's Wort should be avoided (see sections 4.3 and 4.4).
Coadministration of multiple 400 mg daily doses of modafinil, a moderate CYP3A inducer, with a single 125 mg IBRANCE dose decreased palbociclib AUCinf and Cmax by 32% and 11%, respectively, relative to a single 125 mg IBRANCE dose given alone. No dose adjustments are required for moderate CYP3A inducers (see section 4.4).
Effect of acid reducing agents
Under fed conditions (intake of a moderate-fat meal), coadministration of multiple doses of the proton pump inhibitor (PPI) rabeprazole with a single dose of 125 mg IBRANCE decreased palbociclib Cmax by 41%, but had limited impact on AUCinf (13% decrease) compared with a single dose of 125 mg IBRANCE administered alone.
Under fasting conditions, the coadministration of multiple doses of the proton pump inhibitor (PPI) rabeprazole with a single dose of 125 mg IBRANCE decreased palbociclib AUCinf and Cmax by 62% and 80%, respectively. Therefore, IBRANCE should be taken with food, preferably a meal (see sections 4.2 and 5.2).
Given the reduced effect on gastric pH of H2-receptor antagonists and local antacids compared to PPIs, no clinically relevant effect of H2-receptor antagonists or local antacids on palbociclib exposure is expected when palbociclib is taken with food.
Effects of palbociclib on the pharmacokinetics of other medicinal products
Palbociclib is a weak, time-dependent inhibitor of CYP3A following daily 125 mg dosing at steady state. Coadministration of multiple doses of palbociclib with midazolam increased the midazolam AUCinf and Cmax values by 61% and 37%, respectively, as compared with administration of midazolam alone.
The dose of sensitive CYP3A substrates with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus) may need to be reduced when coadministered with IBRANCE as IBRANCE may increase their exposure.
Drug-drug interaction between palbociclib and letrozole
Data from the drug-drug interaction (DDI) eva luation portion of a clinical study in patients with breast cancer showed that there was no drug interaction between palbociclib and letrozole when the 2 medicinal products were coadministered.
Effect of tamoxifen on palbociclib exposure
Data from a DDI study in healthy male subjects indicated that palbociclib exposures were comparable when a single dose of palbociclib was coadministered with multiple doses of tamoxifen and when palbociclib was given alone.
Drug-drug interaction between palbociclib and fulvestrant
Data from a clinical study in patients with breast cancer showed that there was no clinically relevant drug interaction between palbociclib and fulvestrant when the two medicinal products were coadministered.
Drug-drug interaction between palbociclib and oral contraceptives
DDI studies of palbociclib with oral contraceptives have not been conducted (see section 4.6).
In vitro studies with transporters
Based on in vitro data, palbociclib is predicted to inhibit intestina
