Ibrance 125mg

Ibrance 125mg capsules for oral administration contain 125 mg, 100 mg, or 75 mg of Ibrance 125mg, a kinase inhibitor. The molecular formula for Ibrance 125mg 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-2-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one.

Ibrance 125mg is a yellow to orange powder with pKa of 7.4 (the secondary piperazine nitrogen) and 3.9 (the pyridine nitrogen). At or below pH 4, Ibrance 125mg behaves as a high-solubility compound. Above pH 4, the solubility of the drug substance reduces significantly.

Excipients/Inactive Ingredients: Microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, and hard gelatin capsule shells. The light orange, light orange/caramel and caramel opaque capsule shells contain gelatin, red iron oxide, yellow iron oxide, and titanium dioxide; and the printing ink contains shellac, titanium dioxide, ammonium hydroxide, propylene glycol and simethicone.

Ibrance 125mg is indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. This indication is approved under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. (advanced Breast cancer; metastatic Breast cancer; refractory, advanced Breast cancer; refractory, metastatic Breast cancer;)

Ibrance 125mg (Ibrance 125mg) is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Ibrance 125mg is used together with letrozole (Femara) or fulvestrant (Faslodex) to treat certain types of advanced breast cancer in postmenopausal women. Ibrance 125mg is given in combination with another cancer medicine, either letrozole (Femara) or fulvestrant (Faslodex).

Ibrance 125mg was approved by the US Food and Drug Administration (FDA) on an "accelerated" basis. In clinical studies, Ibrance 125mg appeared to improve survival time. However, further studies are needed to determine if this medicine can lengthen survival time.

The recommended dose of Ibrance 125mg is a 125 mg capsule taken orally once daily for 21 consecutive days followed by 7 days off-treatment (Schedule 3/1) to comprise a complete cycle of 28 days in combination with letrozole 2.5 mg once daily given continuously throughout the 28-day cycle.

Ibrance 125mg should be taken with food. Patients should be encouraged to take their dose at approximately the same time each day. Continue the treatment as long as the patient is deriving clinical benefit from therapy.

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. Ibrance 125mg capsules should be swallowed whole (do not chew, crush or open them prior to swallowing). No capsule should be ingested if it is broken, cracked, or otherwise not intact.

Dose Modifications: Dose modification of Ibrance 125mg 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 2, 3 and 4.

No dose modifications are required on the basis of patient’s age, sex or body weight.

Elderly Population: No dose adjustment is necessary in patients ≥65 years of age.

Pediatric Population: The safety and efficacy of Ibrance 125mg in children and adolescents ≤18 years of age have not been established.

Hepatic Impairment: No dose adjustments 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 >1.0-1.5 × ULN and any AST]. Ibrance 125mg has not been studied in patients with moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and any AST).

Renal Impairment: No dose adjustments are required for patients with mild to moderate renal impairment [creatinine clearance (CrCl) ≥30 mL/min]. Ibrance 125mg has not been studied in patients with severe renal impairment (CrCl <30 mL/min) or requiring hemodialysis.

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What is the most important information I should know about Ibrance 125mg?

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to Ibrance 125mg or any component of the formulation

Use Ibrance 125mg as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Ibrance 125mg. Talk to your pharmacist if you have questions about this information.
• Follow how to take Ibrance 125mg as you have been told by your doctor. Do not use more than you were told to use.
• Take Ibrance 125mg by mouth with food.
• Swallow Ibrance 125mg whole. Do not chew, crush, or open before swallowing.
• Do not take capsules that are broken, cracked, or that look damaged.
• Do not eat grapefruit or drink grapefruit juice while you use Ibrance 125mg.
• Take Ibrance 125mg at the same time of day.
• To gain the most benefit, do not miss doses.
• Take as you have been told, even if you feel well.
• If you vomit after taking Ibrance 125mg, do not repeat the dose.
• If you miss a dose of Ibrance 125mg, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Ibrance 125mg.

Ibrance 125mg is used to treat a certain type of breast cancer in women. It is a chemotherapy drug that works by slowing or stopping the growth of cancer cells.

How to use Ibrance 125mg

Read the Patient Information Leaflet if available from your pharmacist before you start taking Ibrance 125mg and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

Take this medication by mouth with food as directed by your doctor, usually once daily for 21 days, then stopping the medication for 7 days. This is one cycle of treatment. Continue taking the medication this way as directed by your doctor. Swallow the capsules whole. Do not crush, chew, or open the capsules. Do not take capsules that are broken or look damaged. If you vomit after taking the medication, do not take another dose of the medication that day. Take the next dose at the usual time the next day.

The dosage is based on your medical condition, laboratory tests, response to treatment, and other medications you may be taking. Be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products). Your doctor may stop your medication for a while or reduce your dose if you get any side effects. Talk to your doctor for more details.

Avoid eating grapefruit or drinking grapefruit juice while using this medication unless your doctor or pharmacist says you may do so safely. Grapefruit can increase the chance of side effects with this medicine. Ask your doctor or pharmacist for more details.

Use this medication regularly to get the most benefit from it. To help you remember, take it at the same time on the days you are scheduled to take the medication.

Do not increase your dose or use this drug more often or for longer than prescribed. Your condition will not improve any faster, and your risk of serious side effects will increase.

Since this drug can be absorbed through the skin and lungs and may harm an unborn baby, women who are pregnant or who may become pregnant should not handle this medication or breathe the dust from the capsules.

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What other drugs will affect Ibrance 125mg?

Ibrance 125mg is primarily metabolized by CYP3A and sulfotransferase (SULT) enzyme SULT2A1. In vivo, Ibrance 125mg is a time-dependent inhibitor of CYP3A.

Agents that may Increase Ibrance 125mg Plasma Concentrations: Effect of CYP3A Inhibitors: Data from a drug-drug interaction (DDI) study in healthy subjects indicate that co-administration of multiple 200 mg doses of itraconazole with a single 125 mg Ibrance 125mg dose increased Ibrance 125mg total exposure (area under the curve, AUC_inf) and the peak exposure (C_max) by approximately 87% and 34%, respectively, relative to a single 125 mg Ibrance 125mg dose given alone. The concomitant use of strong CYP3A inhibitors including, but not limited to: Amprenavir, atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, voriconazole, and grapefruit or grapefruit juice, should be avoided.

Agents that may Decrease Ibrance 125mg Plasma Concentrations: Effect of CYP3A inducers: Data from a DDI study in healthy subjects indicate that co-administration of multiple 600-mg doses of rifampin with a single 125-mg Ibrance 125mg dose decreased Ibrance 125mg AUC_inf and C_max by 85% and 70%, respectively, relative to a single 125-mg Ibrance 125mg dose given alone.

The concomitant use of strong CYP3A inducers including, but not limited to: Carbamazepine, felbamate, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin, and St. John's wort, should be avoided.

Effect of Acid Reducing Agents: Data from a DDI study in healthy subjects indicated that co-administration of a single dose of Ibrance 125mg with multiple doses of the PPI rabeprazole under fed conditions decreased 125 mg Ibrance 125mg C_max by 41%, but had limited impact on AUC_inf (13% decrease) compared with a single dose of Ibrance 125mg administered alone.

Given the reduced effect on gastric pH of H₂-receptor antagonists and local antacids compared to PPIs, under fed conditions there is no clinically relevant effect of PPIs, H2-receptor antagonists, or local antacids on Ibrance 125mg exposure.

Data from another DDI study in healthy subjects indicated that co-administration of a single dose of Ibrance 125mg with multiple doses of the PPI rabeprazole under fasted conditions decreased 125 mg Ibrance 125mg AUC_inf and C_max by 62% and 80%, respectively, when compared with a single dose of Ibrance 125mg administered alone.

Therefore, Ibrance 125mg should be taken with food.

Effects of Ibrance 125mg on Other Drugs: Ibrance 125mg is a weak time-dependent inhibitor of CYP3A following daily 125 mg dosing at steady-state in humans. In a drug-drug interaction study in healthy subjects, co-administration of midazolam with multiple doses of Ibrance 125mg increased the midazolam AUC_inf and C_max values by 61% and 37%, respectively, as compared with administration of midazolam alone.

In vitro, Ibrance 125mg is not an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, and 2D6, and is not an inducer of CYP1A2, 2B6, 2C8, and 3A4 at clinically relevant concentrations.

Drug-Drug Interaction Between Ibrance 125mg and Letrozole: Data from the drug-drug interaction evaluation portion of a clinical study in patients with breast cancer showed that there was no drug interaction between Ibrance 125mg and letrozole when the two drugs were co-administered.

Effect of Tamoxifen on Ibrance 125mg Exposure: Data from a drug-drug interaction study in healthy male subjects indicated that Ibrance 125mg exposures were comparable when a single dose of Ibrance 125mg was co-administered with multiple doses of tamoxifen and when Ibrance 125mg was given alone.

In Vitro Studies with Transporters: In vitro evaluations indicate that Ibrance 125mg has low potential to inhibit the activities of drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2, organic anion transporting polypeptide (OATP)1B1, OATP1B3, and bile salt export pump (BSEP) at clinically relevant concentrations. Based on in vitro data, P-gp and BCRP mediated transport are unlikely to affect the extent of oral absorption of Ibrance 125mg at therapeutic doses.

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What are the possible side effects of Ibrance 125mg?

The safety of Ibrance 125mg was evaluated in Study 1. A total of 165 patients with ER-positive, HER2-negative advanced breast cancer were randomized 1:1 to receive the combination Ibrance 125mg plus letrozole or letrozole alone. The data described below reflect the exposure of the 83 patients who received at least 1 dose of the combination, and of the 77 patients who received at least 1 dose of letrozole alone in the Phase 2 portion of Study 1.

The median duration of treatment for Ibrance 125mg was 13.8 months while the median duration of treatment for letrozole on the letrozole-alone arm was 7.6 months.

Dose reductions due to an adverse reaction (as listed in Table 5) of any grade occurred in 36% of patients receiving Ibrance 125mg plus letrozole. No dose reduction was allowed for letrozole in Study 1.

Permanent discontinuation due to an adverse reaction occurred in 7 of 83 (8%) patients receiving Ibrance 125mg plus letrozole, and in 2 of 77 (2.6%) patients receiving letrozole alone. Adverse reactions leading to discontinuation for those patients receiving Ibrance 125mg plus letrozole included neutropenia (6%), asthenia (1%) and fatigue (1%).

The most common adverse drug reactions of any grade reported in patients in the Ibrance 125mg plus letrozole arm were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, neuropathy peripheral and epistaxis.

The most frequently reported serious adverse reaction in patients receiving Ibrance 125mg plus letrozole were pulmonary embolism (3 of 83; 4%) and diarrhea (2 of 83; 2%).

An increase incidence of infections events was observed in Ibrance 125mg plus letrozole arm (55%) compared to the letrozole alone arm (34%). Febrile neutropenia events have been reported in the Ibrance 125mg clinical program, although no cases were observed in Study 1. Grade ≥3 neutropenia was managed by dose reductions and/or dose delay or temporary discontinuation consistent with a permanent discontinuation rate of 6% due to neutropenia.

Overall, neutropenia of any grade was reported in 62 (74.7%) patients in the combination arm, with Grade 3 neutropenia being reported in 40 (48.2%) patients, and Grade 4 neutropenia being reported in 5 (6.0%) patients.

Adverse drug reactions (≥10%) reported in patients who received Ibrance 125mg plus letrozole or letrozole alone in Study 1 are listed in Table 5.