Palbociclib

Coadministration of multiple 400 mg daily doses of modafinil, a moderate CYP3A inducer, with a single 125 mg palbociclib dose decreased palbociclib AUC_inf and C_max by 32% and 11%, respectively, relative to a single 125 mg palbociclib dose given alone. No dose adjustments are required for moderate CYP3A inducers.

Based on in vitro data, palbociclib may inhibit the uptake transporter organic cationic transporter OCT1 and then may increase the exposure of medical product substrates of this transporter (e.g., metformin).

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 AUC_inf and C_max 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 palbociclib as palbociclib may increase their exposure.

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

Palbociclib is primarily metabolised by CYP3A and sulphotransferase (SULT) enzyme SULT2A1. In vivo, palbociclib is a weak, time-dependent inhibitor of CYP3A.

Coadministration of multiple 200 mg doses of itraconazole with a single 125 mg palbociclib dose increased palbociclib total exposure (AUC_inf) and the peak concentration (C_max) 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.

No dose adjustments are needed for mild and moderate CYP3A inhibitors.

Coadministration of multiple 600 mg doses of rifampin with a single 125 mg palbociclib dose decreased palbociclib AUC_inf and C_max 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.

For patients with severe hepatic impairment (Child-Pugh class C), the recommended dose of palbociclib is 75 mg once daily on Schedule 3/1.

There were no effects on oestrous cycle (female rats) or mating and fertility in rats (male or female) in non-clinical reproductive studies. However, no clinical data have been obtained on fertility in humans. Based on male reproductive organ findings (seminiferous tubule degeneration in testis, epididymal hypospermia, lower sperm motility and density, and decreased prostate secretion) in nonclinical safety studies, male fertility may be compromised by treatment with palbociclib. Thus, men may consider sperm preservation prior to beginning therapy with palbociclib.

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 palbociclib decreased palbociclib C_max by 41%, but had limited impact on AUC_inf (13% decrease) compared with a single dose of 125 mg palbociclib administered alone.

Under fasting conditions, the coadministration of multiple doses of the proton pump inhibitor (PPI) rabeprazole with a single dose of 125 mg palbociclib decreased palbociclib AUC_inf and C_max by 62% and 80%, respectively. Therefore, palbociclib should be taken with food, preferably a meal.

Severe, life-threatening, or fatal ILD and/or pneumonitis can occur in patients treated with palbociclib when taken in combination with endocrine therapy.

Across clinical trials (PALOMA-1, PALOMA-2, PALOMA-3), 1.4% of palbociclib-treated patients had ILD/pneumonitis of any grade, 0.1% had Grade 3, and no Grade 4 or fatal cases were reported. Additional cases of ILD/pneumonitis have been observed in the post-marketing setting, with fatalities reported.

Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis (e.g. hypoxia, cough, dyspnoea). In patients who have new or worsening respiratory symptoms and are suspected to have developed ILD/pneumonitis, interrupt palbociclib immediately and evaluate the patient. Permanently discontinue palbociclib in patients with severe ILD or pneumonitis.

Since palbociclib has myelosuppressive properties, it may predispose patients to infections.

Infections have been reported at a higher rate in patients treated with palbociclib 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 palbociclib in any combination.

Patients should be monitored for signs and symptoms of infection and treated as medically appropriate.

Physicians should inform patients to promptly report any episodes of fever.

For patients who experience a maximum of Grade 1 or 2 neutropenia in the first 6 cycles, complete blood counts for subsequent cycles should be monitored every 3 months, prior to the beginning of a cycle and as clinically indicated.

Absolute neutrophil counts (ANC) of ≥1,000/mm³ and platelet counts of ≥50,000/mm³ are recommended to receive palbociclib.

Palbociclib dose modification and management – Haematological toxicities:

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 – 1,500/mm³; Grade 2: ANC 1,000 - <1,500/mm³; Grade 3: ANC 500 - <1,000/mm³; Grade 4: ANC <500/mm³.

There are no or limited amount of data from the use of palbociclib in pregnant women. Studies in animals have shown reproductive toxicity. Palbociclib is not recommended during pregnancy and in women of childbearing potential not using contraception.

No studies have been conducted in humans or animals to assess the effect of palbociclib on milk production, its presence in breast milk, or its effects on the breast-fed child. It is unknown whether palbociclib is excreted in human milk. Patients receiving palbociclib should not breast feed.

Women of childbearing potential / Contraception

Females of childbearing potential who are receiving this medicinal product, or their male partners should use adequate contraceptive methods (e.g., double-barrier contraception) during therapy and for at least 3 weeks or 14 weeks after completing therapy for females and males, respectively.

Fertility

There were no effects on oestrous cycle (female rats) or mating and fertility in rats (male or female) in non-clinical reproductive studies. However, no clinical data have been obtained on fertility in humans. Based on male reproductive organ findings (seminiferous tubule degeneration in testis, epididymal hypospermia, lower sperm motility and density, and decreased prostate secretion) in nonclinical safety studies, male fertility may be compromised by treatment with palbociclib. Thus, men may consider sperm preservation prior to beginning therapy with palbociclib.

Palbociclib has minor influence on the ability to drive and use machines. However, palbociclib may cause fatigue and patients should exercise caution when driving or using machines.

Summary of the 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 randomised clinical studies in HR-positive, HER2-negative advanced or metastatic breast cancer.

The most common (≥20%) adverse reactions of any grade reported in patients receiving palbociclib in randomised clinical studies were neutropenia, infections, leukopenia, fatigue, nausea, stomatitis, anaemia, diarrhoea, alopecia and thrombocytopenia. The most common (≥2%) Grade ≥3 adverse reactions of palbociclib were neutropenia, leukopenia, infections, anaemia, aspartate aminotransferase (AST) increased, fatigue, and alanine aminotransferase (ALT) increased.

Dose reductions or dose modifications due to any adverse reaction occurred in 38.4% of patients receiving palbociclib in randomised clinical studies regardless of the combination.

Permanent discontinuation due to an adverse reaction occurred in 5.2% of patients receiving palbociclib in randomised clinical studies regardless of the combination.

Tabulated list of adverse reactions

Table 4 reports the adverse reactions from the pooled dataset of 3 randomised studies. The median duration of palbociclib treatment across the pooled dataset at the time of the final overall survival (OS) analysis was 14.8 months.

Table 5 reports the laboratory abnormalities observed in pooled datasets from 3 randomised studies.

The adverse reactions are listed by system organ class and frequency category. Frequency categories are defined as: very common (≥1/10), common (≥1/100 to <1/10), and uncommon (≥1/1,000 to <1/100). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 4. Adverse reactions based on pooled dataset from 3 randomised studies (N=872):

ALT=alanine aminotransferase; AST=aspartate aminotransferase; ILD=interstitial lung disease; N/n=number of patients; N/A=not applicable.
* Adverse Drug Reaction (ADR) identified post-marketing.
^a Preferred Terms (PTs) are listed according to MedDRA 17.1.
^b Infections includes all PTs that are part of the System Organ Class Infections and infestations.
^c Neutropenia includes the following PTs: Neutropenia, Neutrophil count decreased.
^d Leukopenia includes the following PTs: Leukopenia, White blood cell count decreased.
^e Anaemia includes the following PTs: Anaemia, Haemoglobin decreased, Haematocrit decreased.
^f Thrombocytopenia includes the following PTs: Thrombocytopenia, Platelet count decreased.
^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, Rash maculo-papular, Rash pruritic, Rash erythematous, Rash papular, Dermatitis, Dermatitis acneiform, Toxic skin eruption.
ⁱ ILD/pneumonitis includes any reported PTs that are part of the Standardised MedDRA Query Interstitial Lung Disease (narrow).

Table 5. Laboratory abnormalities observed in pooled dataset from 3 randomised studies (N=872):

WBC-white blood cells; AST-aspartate aminotransferase; ALT-alanine aminotransferase; N-number of patients; N/A-not applicable.
Note: Laboratory results are graded according to the NCI CTCAE version 4.0 severity grade.
* letrozole or fulvestrant

Description of selected adverse reactions

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

The median time to first episode of any grade neutropenia was 15 days (12-700 days) and the median duration of Grade ≥3 neutropenia was 7 days across 3 randomised clinical studies.

Febrile neutropenia has been 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 has been reported in about 2% of patients exposed to palbociclib across the overall clinical programme.