IBRANCE

Palbociclib is a piperazine pyridopyrimidine 3 that acts in the cell cycle machinery.

It is a second generation cyclin-dependent kinase inhibitor 4 selected from a group of pyridopyrimidine compounds due to its favorable physical and pharmaceutical properties.

Palbociclib was developed by Pfizer

Inc after the discovery that identified the cyclin-dependent kinases as key regulators of cell growth.

It was originally FDA approved on March for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer and its indications were updated in April to include male patients based on findings from postmarketing reports and electronic health records demonstrating safety and clinical efficacy.

Palbociclib is indicated in combination with letrozole as initial endocrine-based therapy for the treatment of human epidermal growth factor receptor type 2 (HER2)-negative and hormone receptor(HR)-positive tumors in adult patients with advanced/metastatic breast cancer.

It is as well approved in combination with fulvestrant in patients with disease progression with prior endocrine therapy.

In the official labeling, the use of palbociclib should be accompanied with either an aromatase inhibition, no restricted to letrozole, as initial endocrine-based therapy in postmenopausal women or in man.

The breast cancer starts as a group of cancer cells that grow into and destroy the nearby breast tissue.

This growth can spread into other parts of the body which is called metastasis.

According to the location of the cancer cells, it can be categorized in ductal carcinoma and lobular carcinoma.

However, other types of breast cancer include inflammatory breast cancer, Paget disease of the breast, triple negative breast cancer non-Hodgkin lymphoma and soft tissue sarcoma.

In males, breast cancer is usually treated as the cases of postmenopausal women and almost all the cases are ductal carcinoma.

Due to its mechanism of action, palbociclib inhibits cell growth and suppresses DNA replication in retinoblastoma tumor suppressor gene (RB) proficient cancer cells.

As expected, these RB cells present a significant increase in the proportion of cells in G1 state and the presence of palbociclib produces effective dephosphorylation of RB, reduce proliferation and induce senescence causing cell-cycle arrest.

In vitro studies showed the potential for palbociclib to reduce cellular proliferation of estrogen receptor-positive breast cancer cell lines through the inhibition of the cell-cycle progression from G1 to S phase.

In this study, it was demonstrated that the sensitivity of the cells significantly increased with the expression of RB1 and CCND1 and low expression of CDKN2A.

As well, palbociclib, combined with antiestrogens, enhanced in vivo antitumor activity in estrogen receptor-positive breast cancer mouse models.

In clinical trials, palbociclib, in combination with letrozole, was shown to significantly increase the progression-free survival (PFS) in patients with metastatic breast cancer without prior endocrine treatment.

In the results, the PFS increased from 4.5-9.5 months with an overall response rate (ORR) of 24.6%.

Palbociclib presents a linear pharmacokinetic profile and its peak plasma concentration was observed 6-12 hours after oral administration.

The oral bioavailability is reported to be of 46% with a steady-state reached after 8 days and a median accumulation ratio of 2.4.

The absorption of palbociclib is significantly reduced under fasting conditions and hence, food intake is recommended when this drug is administered.

The mean apparent distribution of palbociclib is 2583 L which suggests that palbociclib penetrates extensively into peripheral tissues.

Palbociclib is mainly hepatically transformed. 3 the metabolism is mainly performed by the activities of the cytochrome P450 isoenzyme 3A and the sulfotransferase 2A1.

The metabolism of palbociclib is represented mainly by reactions of oxidation and sulfonation followed by acylation and glucuronidation as minor reactions.

After its metabolism, palbociclib forms mainly inactive glucuronide and sulfamic acid conjugates.

The major circulating metabolite, accounting for 1.5% of the dose in excreta is is the glucuronide conjugate.

Hover over products below to view reaction partners Palbociclib Palbociclib M1 + Palbociclib M11 + Palbociclib M2 + Palbociclib M3 Palbociclib M14 + Palbociclib M4 Palbociclib M5 Palbociclib M6 Palbociclib M7 Palbociclib M8 Palbociclib M9 Palbociclib M10 Palbociclib M12 Palbociclib M13.

The main route of elimination of palbociclib is through feces after hepatic metabolism while renal clearance seems to play a minor role accounting only for 17.5% of the eliminated dose.

The mean plasma elimination half-life of palbociclib is 29 hours.

The mean apparent oral clearance of palbociclib is of 63.1 L/h.

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The reported oral

Ld50 is of 100 mg/kg.

Palbociclib was showed to present clastogenic activities in in vitro and in vivo assays.

As well, it has been reported to produce fetal harm due to its mechanism of action.

Lastly, it was shown to increase the incidence of microglial cell tumors in the central nervous system at high doses.

capsules are taken orally with food in combination with an aromatase inhibitor, fulvestrant, or inavolisib and fulvestrant.

• Recommended starting dose: 125 mg once daily taken with food for 21 days followed by 7 days off treatment.

• Dosing interruption and/or dose reductions are recommended based on individual safety and tolerability. 2.1 Recommended Dose and Schedule The recommended dose of IBRANCE 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.

IBRANCE capsule should be taken with food.

Administer the recommended dose of an aromatase inhibitor when given with IBRANCE.

Please refer to the Full Prescribing

Information for the aromatase inhibitor being used.

When given with

IBRANCE, the recommended dose of fulvestrant is 500 mg administered on Days 1, 15, 29, and once monthly thereafter.

Information of fulvestrant.

Information for inavolisib and fulvestrant for dosing information.

Advise patients to take their dose of IBRANCE 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.

IBRANCE 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 IBRANCE plus an aromatase inhibitor or fulvestrant or IBRANCE plus inavolisib and fulvestrant therapy should also be treated with luteinizing hormone-releasing hormone (LHRH) agonists according to current clinical practice standards.

For men treated with combination IBRANCE plus aromatase inhibitor or IBRANCE plus inavolisib and fulvestrant therapy, consider treatment with an LHRH agonist according to current clinical practice standards. 2.2 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 Toxicities Table applies to all hematologic adverse reactions except lymphopenia (unless associated with clinical events, e.g., opportunistic infections).

Grading according to

CTCAE 4.0.

CTCAE=Common Terminology Criteria for Adverse Events; LLN=lower limit of normal.

Monitor complete blood counts prior to the start of IBRANCE therapy and at the beginning of each cycle, as well as on Day 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.

Grade 1 or 2 No dose adjustment is required.

Grade 3 Day 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 of first 2 cycles: If Grade on Day 15, continue IBRANCE at current dose to complete cycle and repeat complete blood count on Day 22.

If Grade 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 of subsequent cycles.

Grade 3 neutropenia Absolute neutrophil count (ANC): Grade 1: ANC < LLN.

• 1500/mm 3; Grade 2: ANC 1000.

• <1500/mm 3; Grade 3: ANC 500.

• <1000/mm 3; Grade 4: ANC <500/mm 3. with fever ≥38.5 ºC and/or infection At any time: Withhold IBRANCE until recovery to Grade ≤2.

Resume at the next lower dose.

Grade At any time

Withhold IBRANCE until recovery to Grade ≤2.

Table 3.

Management – Non-Hematologic Toxicities CTCAE Grade Dose Modifications Grading according to CTCAE 4.0.

CTCAE=Common Terminology Criteria for Adverse Events.

• Grade ≤1;

• Grade ≤2 (if not considered a safety risk for the patient) Resume at the next lower dose.

Permanently discontinue

IBRANCE in patients with severe interstitial lung disease (ILD)/pneumonitis.

Information for coadministered endocrine therapy and/or inavolisib dose adjustment guidelines in the event of toxicity and other relevant safety information or contraindications.

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 IBRANCE dose to 75 mg once daily.

If the strong inhibitor is discontinued, increase the IBRANCE dose (after to 5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor.

No dose adjustment is required for patients with mild or moderate hepatic impairment (Child-Pugh classes A and B).

For patients with severe hepatic impairment (Child-Pugh class C), the recommended dose of IBRANCE is 75 mg once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days.

is supplied in the following strengths and package configurations: IBRANCE Capsules Package Configuration Capsule Strength (mg) NDC Capsule Description Bottles of 21 capsules 125 NDC 0069-0189-21 opaque, hard gelatin capsules, size 0, with caramel cap and body, printed with white ink "Pfizer" on the cap, "PBC 125" on the body Bottles of 21 capsules 100 NDC 0069-0188-21 opaque, hard gelatin capsules, size 1, with caramel cap and light orange body, printed with white ink "Pfizer" on the cap, "PBC 100" on the body Bottles of 21 capsules 75 NDC 0069-0187-21 opaque, hard gelatin capsules, size 2, with light orange cap and body, printed with white ink "Pfizer" on the cap, "PBC 75" on the body Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 °F to 86 °F) .

Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 °F to 86 °F) .

Based on findings from animal studies and its mechanism of action, IBRANCE can cause fetal harm when administered to a pregnant woman.

There are no available data in pregnant women to inform the drug-associated risk.

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 AUC.

Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.

In a fertility and early embryonic development study in female rats, palbociclib was administered orally for 15 days before mating through to Day of pregnancy, which did not cause embryo toxicity at doses up to 300 mg/kg/day with maternal systemic exposures approximately 4 times the human exposure (AUC) at the recommended dose.

In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of palbociclib up to 300 mg/kg/day and 20 mg/kg/day, respectively, during the period of organogenesis.

The maternally toxic dose of 300 mg/kg/day was fetotoxic in rats, resulting in reduced fetal body weights.

At doses ≥100 mg/kg/day in rats, there was an increased incidence of a skeletal variation (increased incidence of a rib present at the seventh cervical vertebra).

At the maternally toxic dose of 20 mg/kg/day in rabbits, there was an increased incidence of skeletal variations, including small phalanges in the forelimb.

At 300 mg/kg/day in rats and 20 mg/kg/day in rabbits, the maternal systemic exposures were approximately and 9 times the human exposure (AUC) at the recommended dose, respectively.

CDK4/6 double knockout mice have been reported to die in late stages of fetal development (gestation Day 14.5 until birth) due to severe anemia.

However, knockout mouse data may not be predictive of effects in humans due to differences in degree of target inhibition.

The safety and effectiveness of

IBRANCE in pediatric patients have not been established.

IBRANCE were assessed but not established in three trials: one open-label trial [A5481092, (NCT03709680)] that included 98 pediatric patients to <17 years of age who received IBRANCE in combination with chemotherapy for recurrent or refractory solid tumors and two open-label trials that included 42 pediatric patients to <17 years of age who received IBRANCE as a single agent for recurrent or refractory solid tumors [APEC1621I, (NCT03526250)] or primary central nervous system (CNS) tumors [PBTC-042, (NCT02255461). No new safety signals were observed in these trials. Palbociclib exposures in pediatric patients who received IBRANCE as a single agent or in combination were within range of those observed in adults given a similar dose based on body surface area. Juvenile Animal Toxicity Data Altered glucose metabolism (glycosuria, hyperglycemia, decreased insulin) associated with changes in the pancreas (islet cell vacuolation), eye (cataracts, lens degeneration), kidney (tubule vacuolation, chronic progressive nephropathy) and adipose tissue (atrophy) were identified in a 27 week repeat-dose toxicology study in rats that were immature at the beginning of the studies and were most prevalent in males at oral palbociclib doses ≥30 mg/kg/day (approximately 11 times the adult human exposure [AUC] at the recommended dose).

Some of these findings (glycosuria/hyperglycemia, pancreatic islet cell vacuolation, and kidney tubule vacuolation) were present with lower incidence and severity in a 15 week repeat-dose toxicology study in immature rats.

Altered glucose metabolism or associated changes in the pancreas, eye, kidney and adipose tissue were not identified in a 27-week repeat-dose toxicology study in rats that were mature at the beginning of the study and in dogs in repeat-dose toxicology studies up to 39 weeks duration.

Toxicities in teeth independent of altered glucose metabolism were observed in rats.

Administration of 100 mg/kg palbociclib for 27 weeks (approximately 15 times the adult human exposure [AUC] at the recommended dose) resulted in abnormalities in growing incisor teeth (discolored, ameloblast degeneration/necrosis, mononuclear cell infiltrate).

Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals.

Of 444 patients who received IBRANCE in PALOMA-2, 181 patients (41%) were ≥65 years of age and 48 patients (11%) were ≥75 years of age.

Of 347 patients who received IBRANCE in PALOMA-3, 86 patients (25%) were ≥65 years of age and 27 patients (8%) were ≥75 years of age.

No overall differences in safety or effectiveness of IBRANCE were observed between these patients and younger patients.