Ibrance Drug Information

Recommended Dosage

The recommended dosage of IBRANCE is a 125 mg tablet taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days. IBRANCE tablet may be taken with or without food. 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 tablets should be swallowed whole (do not chew, crush, or split them prior to swallowing).

Tablets 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, IBRANCE plus inavolisib and fulvestrant therapy, or IBRANCE plus trastuzumab, with or without pertuzumab, plus endocrine 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, IBRANCE plus inavolisib and fulvestrant therapy, or IBRANCE plus trastuzumab, with or without pertuzumab, plus endocrine therapy, consider treatment with an LHRH agonist according to current clinical practice standards.

Refer to the Prescribing Information for recommended dosage for endocrine therapy, inavolisib, trastuzumab and pertuzumab administered in combination with IBRANCE.

Dose Modification

The recommended dose modifications for adverse reactions are listed in Tables 1, 2, and 3. Table 1. Recommended Modification and Management – Hematologic Toxicities Table applies to all hematologic adverse reactions except lymphopenia (unless associated with clinical events, e.g., opportunistic infections).

Modification and Management – Non-Hematologic Toxicities Permanently discontinue IBRANCE in patients with severe interstitial lung disease (ILD)/pneumonitis. Refer to the Full Prescribing Information for endocrine therapy, inavolisib, trastuzumab, and pertuzumab administered in combination with IBRANCE for dose adjustment guidelines in the event of toxicity and for other relevant safety information or contraindications. 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 IBRANCE dose to 75 mg once daily. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3 to 5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Dose Modifications for Hepatic Impairment 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.

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. PALOMA-2: IBRANCE plus Letrozole Patients with estrogen receptor (ER)-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine-based therapy The safety of IBRANCE plus letrozole was evaluated in a randomized, double-blind trial (PALOMA-2) in 666 patients with ER-positive, HER2-negative advanced breast cancer. The median duration of treatment for IBRANCE plus letrozole was 19.8 months while the median duration of treatment for placebo plus letrozole arm was 13.8 months.

Dose reductions due to an adverse reaction of any grade occurred in 36% of patients receiving IBRANCE plus letrozole. No dose reduction was allowed for letrozole in PALOMA-2. Adverse reactions leading to permanent discontinuation for patients receiving IBRANCE plus letrozole included neutropenia (1.1%) and alanine aminotransferase increase (0.7%).

The most common adverse reactions (≥10%) of any grade reported in patients in the IBRANCE plus letrozole arm by descending frequency were neutropenia, infections, leukopenia, fatigue, nausea, alopecia, stomatitis, diarrhea, anemia, rash, asthenia, thrombocytopenia, vomiting, decreased appetite, dry skin, pyrexia, and dysgeusia. The most frequently reported Grade ≥3 adverse reactions (≥5%) in patients receiving IBRANCE plus letrozole by descending frequency were neutropenia, leukopenia, infections, and anemia. Adverse reactions (≥10%) reported in patients who received IBRANCE plus letrozole or placebo plus letrozole in PALOMA-2 are listed in Table 4.

Table 5. Laboratory Abnormalities in PALOMA-2 PALOMA-3: IBRANCE plus Fulvestrant Patients with HR-positive, HER2-negative advanced or metastatic breast cancer who have had disease progression on or after prior adjuvant or metastatic endocrine therapy The safety of IBRANCE plus fulvestrant was evaluated in a randomized, double-blind trial (PALOMA-3) in 517 patients with HR-positive, HER2-negative advanced or metastatic breast cancer. The median duration of treatment for IBRANCE plus fulvestrant was 10.8 months while the median duration of treatment for placebo plus fulvestrant arm was 4.8 months.

No dose reduction was allowed for fulvestrant in PALOMA-3. Adverse reactions leading to discontinuation for those patients receiving IBRANCE plus fulvestrant included fatigue (0.6%), infections (0.6%), and thrombocytopenia (0.6%). Adverse reactions (≥10%) reported in patients who received IBRANCE plus fulvestrant or placebo plus fulvestrant in PALOMA-3 are listed in Table 6.

Table 7. Laboratory Abnormalities in PALOMA-3: IBRANCE plus Inavolisib and Fulvestrant Adults with PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer whose disease progressed during or within 12 months of completing adjuvant endocrine therapy and who have not received prior systemic therapy for locally advanced or metastatic disease The safety of the combination of IBRANCE plus inavolisib and fulvestrant was evaluated in a randomized, double-blind, placebo-controlled study (INAVO120) in 324 patients with PIK3CA -mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer. Patients received either IBRANCE 125 mg orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a cycle of 28 days plus fulvestrant in combination with inavolisib (n=162) or placebo (n=162).

The median duration of treatment for IBRANCE plus inavolisib and fulvestrant was 9 months (range: 0 to 39 months). Serious adverse reactions occurred in 24% of patients who received IBRANCE plus inavolisib and fulvestrant. Fatal adverse reactions occurred in 3.7% of patients who received IBRANCE plus inavolisib and fulvestrant, including (0.6% each) acute coronary syndrome, cerebral hemorrhage, cerebrovascular accident, COVID-19 infection, and gastrointestinal hemorrhage.

Adverse reactions leading to discontinuation of IBRANCE in patients receiving IBRANCE plus inavolisib and fulvestrant were neutropenia, infections, alanine aminotransferase increased, gastric ulcer, intestinal perforation, hyperglycemia, type 2 diabetes mellitus, bone pain, musculoskeletal pain, transitional cell carcinoma, and acute kidney injury (0.6% each). Dose reduction of IBRANCE due to an adverse reaction occurred in 38% of patients receiving IBRANCE plus inavolisib and fulvestrant and in 30% of patients receiving IBRANCE plus placebo and fulvestrant. Dose interruption of IBRANCE due to an adverse reaction occurred in 71% of patients receiving IBRANCE plus inavolisib and fulvestrant and in 61% of patients receiving IBRANCE plus placebo and fulvestrant.

Adverse reactions leading to dose interruption of IBRANCE in ≥2% patients receiving IBRANCE plus inavolisib and fulvestrant were neutropenia ( %) adverse reactions, including laboratory abnormalities, were decreased neutrophils, decreased hemoglobin, increased fasting glucose, decreased platelets, decreased lymphocytes, stomatitis, diarrhea, decreased calcium, fatigue, decreased potassium, increased creatinine, increased alanine aminotransferase (ALT), nausea, decreased sodium, decreased magnesium, rash, decreased appetite, COVID-19 infection, and headache. Adverse reactions and laboratory abnormalities in INAVO120 are summarized in Table 8 and Table 9, respectively. Table 8.

Adverse Reactions (≥10% with ≥5% or ≥2% Higher Incidence in the IBRANCE plus inavolisib and fulvestrant Arm) in I 0 Clinically relevant adverse reactions occurring in <10% of patients who received the triplet combination of IBRANCE plus inavolisib and fulvestrant included abdominal pain, dry eye, dysgeusia, and dyspepsia. Table 9. Select Laboratory Abnormalities (≥10% with a ≥2% Higher Incidence in the IBRANCE plus Inavolisib and Fulvestrant Arm) in I: IBRANCE in Combination with Trastuzumab, with or without Pertuzumab, and Endocrine Therapy Patients with HR-positive, HER2-positive locally advanced or metastatic breast cancer after induction therapy.

The safety of IBRANCE in combination with trastuzumab, with or without pertuzumab, and endocrine therapy was evaluated in a randomized, open-label trial (PATINA) in 509 patients with HR-positive, HER2-positive locally advanced or metastatic breast cancer. Patients received either IBRANCE 125 mg orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a cycle of 28 days in combination with trastuzumab, with or without pertuzumab, and endocrine therapy (n=260) or trastuzumab, with or without pertuzumab, and endocrine therapy (n=249). The median IBRANCE treatment duration was 28 months (range: 0.4 to 80 months).

Serious adverse reactions occurred in 25% of patients who received IBRANCE in combination with trastuzumab, with or without pertuzumab, and endocrine therapy. Permanent discontinuation of IBRANCE associated with an adverse reaction occurred in 46 (18%) patients receiving IBRANCE in combination with trastuzumab, with or without pertuzumab, and endocrine therapy. Adverse reactions leading to discontinuation of IBRANCE in ≥1% of patients receiving IBRANCE in combination with trastuzumab, with or without pertuzumab, and endocrine therapy included neutropenia (3.8%), infections and stomatitis (1.5% each), and fatigue (1.2%).

Dose reduction of IBRANCE due to an adverse reaction occurred in 137 (53%) patients receiving IBRANCE in combination with trastuzumab, with or without pertuzumab, and endocrine therapy. Dose interruption of IBRANCE due to an adverse reaction occurred in 181 (70%) patients receiving IBRANCE in combination with trastuzumab, with or without pertuzumab, and endocrine therapy. The most common (≥20%) adverse reactions, including laboratory abnormalities, were white blood cell decreased, neutrophil count decreased, creatinine increased, hemoglobin decreased, diarrhea, infections, platelet count decreased, stomatitis, aspartate aminotransferase increased, decreased calcium, alanine aminotransferase increased, decreased potassium, fatigue, alkaline phosphatase increased, nausea, asthenia, headache, rash, pruritus, and muscle spasms.

Adverse reactions and laboratory abnormalities in PATI Clinically relevant adverse reactions in <10% of patients who received IBRANCE with trastuzumab, with or without pertuzumab, and endocrine therapy included alopecia, lacrimation increased, dry eye, dysgeusia, vision blurred, palmar-plantar erythrodysesthesia syndrome, interstitial lung disease/pneumonitis, and febrile neutropenia. Table 11. Select Laboratory Abnormalities (≥10% with a ≥2% Higher Incidence in the IBRANCE with anti-HER2 and Endocrine Therapies Arm) in PATI 0 0 Other Clinical Trials Experience The following adverse reaction has been reported following administration of IBRANCE: venous thromboembolism.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of IBRANCE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Respiratory Disorders: Interstitial lung disease (ILD)/non-infectious pneumonitis Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome (PPES) Male Patients with HR-Positive, HER2-Negative Advanced or Metastatic Breast Cancer Based on limited data from postmarketing reports and electronic health records, the safety profile for men treated with IBRANCE is consistent with the safety profile in women treated with IBRANCE.

Agents That May Increase Palbociclib Plasma Concentrations Effect of CYP3A Inhibitors Coadministration of a strong CYP3A inhibitor (itraconazole) increased the plasma exposure of 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 IBRANCE treatment.

If coadministration of IBRANCE with a strong CYP3A inhibitor cannot be avoided, reduce the dose of IBRANCE.

Agents That May Decrease Palbociclib Plasma Concentrations Effect of CYP3A Inducers Coadministration of a strong CYP3A inducer (rifampin) decreased the plasma exposure of 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 IBRANCE 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 IBRANCE may increase its exposure.

Pregnancy Risk Summary 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 (see Data ).

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.

Data Animal Data In a fertility and early embryonic development study in female rats, palbociclib was administered orally for 15 days before mating through to Day 7 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. 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.

Pediatric Use The safety and effectiveness of IBRANCE in pediatric patients have not been established. The safety and effectiveness of IBRANCE were assessed but not established in three trials: one open-label trial that included 98 pediatric patients 2 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 4 to <17 years of age who received IBRANCE as a single agent for recurrent or refractory solid tumors or primary central nervous system (CNS) tumors. 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 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 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.