Letrozole And Ribociclib

FDA Drug Information • Also known as: Kisqali Femara Co-Pack

Brand Names: Kisqali Femara Co-Pack
Dosage Form: KIT
Product Type: HUMAN PRESCRIPTION DRUG

Description

11 DESCRIPTION KISQALI FEMARA CO-PACK consists of ribociclib 200 mg film-coated tablets co-packaged with letrozole 2.5 mg tablets. Ribociclib KISQALI (ribociclib) is a kinase inhibitor. Ribociclib succinate is a light yellow to yellowish brown crystalline powder. The chemical name of ribociclib succinate is: Butanedioic acid—7-cyclopentyl- N , N -dimethyl-2-{[5-(piperazin-1-yl) pyridin-2-yl]amino}-7 H -pyrrolo[2,3- d ]pyrimidine-6-carboxamide (1/1). The molecular formula for ribociclib succinate is C 23 H 30 N 8 O.C 4 H 6 O 4 and the molecular weight is 552.64 g/mol [Free base: 434.55 g/mol] . The chemical structure of ribociclib is shown below: KISQALI film-coated tablets are supplied for oral use and contain 200 mg of ribociclib free base (equivalent to 254.40 mg ribociclib succinate). The tablets also contain colloidal silicon dioxide, crospovidone, hydroxypropylcellulose, magnesium stearate, and microcrystalline cellulose. The film-coating contains iron oxide black, iron oxide red, lecithin (soya), polyvinyl alcohol (partially hydrolyzed), talc, titanium dioxide, and xanthan gum as inactive ingredients. Letrozole FEMARA (letrozole) is a nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis). Letrozole is a white to yellowish crystalline powder, practically odorless, freely soluble in dichloromethane, slightly soluble in ethanol, and practically insoluble in water. It has a molecular weight of 285.31 g/mol, empirical formula C 17 H 11 N 5 , and a melting range of 184°C to 185°C. The chemical name of letrozole is 4,4'-(1H-1,2,4-Triazol-1ylmethylene) dibenzonitrile, and its structural formula is FEMARA is available as 2.5 mg tablets for oral administration. Inactive Ingredients: colloidal silicon dioxide, ferric oxide, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, maize starch, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, talc, and titanium dioxide. ribociclib structure letrozole structure

What Is Letrozole And Ribociclib Used For?

1 INDICATIONS AND USAGE KISQALI FEMARA CO-PACK, a co-packaged product containing ribociclib, a kinase inhibitor, and letrozole, an aromatase inhibitor, is indicated: for the adjuvant treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative stage II and III early breast cancer at high risk of recurrence. ( 1 ) as initial endocrine-based therapy for the treatment of adults with HR-positive, HER2-negative advanced or metastatic breast cancer therapy. ( 1 ) 1.1 Early Breast Cancer KISQALI ® FEMARA ® CO-PACK is indicated for the adjuvant treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative stage II and III early breast cancer at high risk of recurrence. 1.2 Advanced or Metastatic Breast Cancer KISQALI ® FEMARA ® CO-PACK indicated as initial endocrine-based therapy for the treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.

Dosage and Administration

2 DOSAGE AND ADMINISTRATION KISQALI FEMARA CO-PACK tablets are taken in combination orally with or without food. ( 2 ) Early Breast Cancer KISQALI recommended starting dose: 400 mg orally (two 200 mg tablets) taken once daily for 21 consecutive days followed by 7 days off KISQALI treatment. ( 2.1 ) Advanced or Metastatic Breast Cancer KISQALI recommended starting dose: 600 mg orally (three 200 mg tablets) taken once daily for 21 consecutive days followed by 7 days off KISQALI treatment. ( 2.1 ) KISQALI dose interruption, reduction, and/or discontinuation may be required based on individual safety and tolerability. ( 2.2 ) FEMARA: 2.5 mg (one tablet) continuously for a 28-day cycle. ( 2.1 ) 2.1 Recommended Dosage Important Administration Instructions The KISQALI FEMARA CO-PACK is comprised of ribociclib tablets co-packaged with letrozole tablets, to provide a 28-day treatment regimen. KISQALI FEMARA CO-PACK can be taken with or without food [ see Clinical Pharmacology (12.3) ]. Pre/perimenopausal women, or men, treated with KISQALI FEMARA CO-PACK should be treated with a luteinizing hormone-releasing hormone (LHRH) agonist according to current clinical practice standards. Patients should take their doses of KISQALI FEMARA CO-PACK at approximately the same time each day, preferably in the morning. If the patient vomits after taking the dose or misses a dose, no additional dose should be taken that day. The next prescribed dose should be taken at the usual time. Tablets should be swallowed whole (tablets should not be chewed, crushed or split prior to swallowing). No tablet should be ingested if it is broken, cracked, or otherwise not intact. Early Breast Cancer KISQALI: The recommended dosage of KISQALI is 400 mg (two 200 mg film-coated tablets) taken orally, once daily for 21 consecutive days followed by 7 days off in 28-day treatment cycles. FEMARA: 2.5 mg (one tablet) taken once daily throughout the 28-day cycle. In patients with early breast cancer, treatment with KISQALI should continue for 3 years or until disease recurrence or unacceptable toxicity occurs. Advanced or Metastatic Breast Cancer KISQALI: The recommended dosage for KISQALI is 600 mg (three 200 mg film-coated tablets) taken orally, once daily for 21 consecutive days followed by 7 days off in 28-day treatment cycles. FEMARA: 2.5 mg (one tablet) taken once daily throughout the 28-day cycle. Refer to the Full Prescribing Information for the recommended dosage for each product. 2.2 Dose Modifications Dose Modifications for Adverse Reactions The recommended dose modifications of KISQALI for adverse reactions are listed in Table 1. Dose modifications are not recommended for FEMARA when administered with KISQALI for the adverse reactions of KISQALI, including neutropenia, hepatobiliary toxicity, or QT prolongation [see Dosage and Administration (2)] . Table 1: Recommended Dose Modification of KISQALI FEMARA CO-PACK for Adverse Reactions Level KISQALI FEMARA Dose Number of tablets Dose...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)] QT Interval Prolongation [see Warnings and Precautions (5.3)] Hepatobiliary Toxicity [see Warnings and Precautions (5.4)] Neutropenia [see Warnings and Precautions (5.5)] In patients with early breast cancer, the most common (incidence ≥ 20%) adverse reactions, including laboratory abnormalities, are lymphocytes decreased, leukocytes decreased, neutrophils decreased, hemoglobin decreased, alanine aminotransferase increased, aspartate aminotransferase increased, infections, creatinine increased, platelets decreased, headache, nausea, and fatigue. ( 6 ) In patients with advanced or metastatic breast cancer, the most common (incidence ≥ 20%) adverse reactions, including laboratory abnormalities, are leukocytes decreased, neutrophils decreased, hemoglobin decreased, lymphocytes decreased, alanine aminotransferase increased, aspartate aminotransferase increased, infections, nausea, fatigue, platelets decreased, diarrhea, headache, alopecia, vomiting, back pain, constipation, cough, rash, creatinine increased, and abdominal pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials 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. The data described in WARNINGS AND PRECAUTIONS reflect exposure to KISQALI plus non-steroidal aromatase inhibitor (NSAI) in 2526 patients with early breast cancer (NATALEE), of whom 51% completed 36 months of KISQALI treatment. The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were lymphocytes decreased (97%), leukocytes decreased (95%), neutrophils decreased (94%), hemoglobin decreased (47%), alanine aminotransferase increased (45%), aspartate aminotransferase increased (44%), infections (37%), creatinine increased (33%), platelets decreased (28%), headache (23%), nausea (23%), and fatigue (22%). In additions, the pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to KISQALI in 582 patients with advanced or metastatic breast cancer (MONALEESA-2 and MONALEESA-7), of whom 80% were exposed for 6 months or longer and 65% were exposed for greater than one year. The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were leukocytes decreased (94%), neutrophils decreased (94%), hemoglobin decreased (72%), lymphocytes decreased (59%), alanine aminotransferase increased (53%), aspartate aminotransferase increased (53%), infections (46%), nausea (46%), fatigue (36%), platelets decreased (34%), diarrhea (33%), headache (29%), alopecia (29%), vomiting (29%), back pain (25%), constipation (25%), cough (24%), rash (22%), creatinine increased (20%), and abdominal pain (20%). NATALEE: KISQALI in Combination with a Non-steroidal Aromatase Inhibitor as Adjuvant Treatment Adults with HR-positive, HER2-negative Stage II and III Early Breast Cancer at High Risk of Recurrence The safety of KISQALI was evaluated in NATALEE, a clinical trial of 5101 patients who received KISQALI plus NSAI or NSAI alone, with or without goserelin [see Clinical Studies (14)] . The median duration of exposure to KISQALI was 33 months. Serious adverse reactions occurred in 14% of patients who received KISQALI. Serious adverse reactions in > 0.5% of patients who received KISQALI included COVID-19 (1.1%), pneumonia (0.8%), and pulmonary embolism (0.6%). Fatal adverse reactions occurred in 0.6% of patients who received KISQALI. Fatal adverse reactions in ≥ 0.1%...

Drug Interactions

7 DRUG INTERACTIONS Ribociclib CYP3A4 Inhibitors: Avoid concomitant use of KISQALI FEMARA CO-PACK with strong CYP3A inhibitors. If strong inhibitors cannot be avoided, reduce KISQALI dose. ( 2.2, 7.1 ) CYP3A4 Inducers: Avoid concomitant use of KISQALI FEMARA CO-PACK with strong CYP3A inducers. ( 7.2 ) CYP3A Substrates: The dose of CYP3A substrates with narrow therapeutic indices may need to be reduced when given concurrently with KISQALI FEMARA CO-PACK. ( 7.3 ) Drugs Known to Prolong QT Interval: Avoid concomitant use of drugs known to prolong QT interval, such as anti-arrhythmic medicines. ( 7.4 ) 7.1 Drugs That May Increase Ribociclib Plasma Concentrations CYP3A4 Inhibitors Coadministration of a strong CYP3A4 inhibitors increases ribociclib exposure [see Clinical Pharmacology (12.3)] . Increased ribociclib concentrations may increase the incidence and severity of adverse reactions, including QTcF prolongation [see Warnings and Precautions (5.3)] . Avoid concomitant use of strong CYP3A inhibitors with KISQALI and consider alternative concomitant medications with less potential for CYP3A inhibition. In patients with early breast cancer, if coadministration of KISQALI with a strong CYP3A inhibitor cannot be avoided, reduce the dose of KISQALI to 200 mg once daily. In patients with advanced or metastatic breast cancer, if coadministration of KISQALI with a strong CYP3A inhibitor cannot be avoided, reduce the dose of KISQALI to 400 mg once daily [see Dosage and Administration (2.2)] . 7.2 Drugs That May Decrease Ribociclib Plasma Concentrations CYP3A4 Inducers Coadministration of a strong CYP3A4 inducers decreases the plasma exposure of ribociclib [see Clinical Pharmacology (12.3)] . Avoid concomitant use of strong CYP3A inducers and consider an alternate concomitant medication with no or minimal potential to induce CYP3A. 7.3 Effect of KISQALI on Other Drugs CYP3A Substrates Coadministration of sensitive CYP3A4 substrates with multiple doses of KISQALI increases the substrate exposure [see Clinical Pharmacology (12.3)] . For CYP3A substrates where minimal increases in the concentration may increase CYP3A substrate adverse reactions, monitor for increased adverse reactions of the CYP3A substrate during treatment with KISQALI. The dose of a sensitive CYP3A substrate may need to be reduced as KISQALI can increase its exposure. 7.4 Drugs That Prolong the QT Interval Avoid coadministration of KISQALI with products with a known potential to prolong QT interval, such as antiarrhythmic drugs that are known to prolong the QT interval. If concomitant use cannot be avoided, monitor ECG when initiating, during concomitant use, and as clinically indicated [see Warnings and Precautions (5.3), Clinical Pharmacology (12.2)] .

Contraindications

4 CONTRAINDICATIONS Known hypersensitivity to the active substance (letrozole), or to any of the excipients of FEMARA. Refer to FEMARA Prescribing Information. Known hypersensitivity to letrozole, or to any excipients of FEMARA. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary Based on findings from animal studies and the mechanisms of action, KISQALI FEMARA CO-PACK can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)] . There are no available human data informing the drug-associated risk. In animal reproduction studies, administration of ribociclib to pregnant animals during organogenesis resulted in increased incidences of post implantation loss and reduced fetal weights in rats and increased incidences of fetal abnormalities in rabbits at exposures 0.6 or 1.5 times the exposure in humans, respectively, at the highest recommended dose of 600 mg/day based on AUC (see Data) . Advise pregnant women of the potential risk to a fetus. In animal reproduction studies, administration of letrozole to pregnant animals during organogenesis resulted in increased post-implantation pregnancy loss and resorptions, fewer live fetuses, and fetal malformations affecting the renal and skeletal systems in rats and rabbits at doses approximately 0.1 times the daily MRHD on a mg/m 2 basis (see Data) . The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk of major birth defects is 2% - 4% and of miscarriage is 15% - 20% of clinically recognized pregnancies in the U.S. general population. Data Animal Data - Ribociclib In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of ribociclib up to 1000 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis. In rats, 300 mg/kg/day resulted in reduced maternal body weight gain and reduced fetal weights accompanied by skeletal changes related to the lower fetal weights. There were no significant effects on embryo-fetal viability or fetal morphology at 50 or 300 mg/kg/day. In rabbits at doses ≥ 30 mg/kg/day, there were adverse effects on embryo-fetal development, including increased incidences of fetal abnormalities...

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING KISQALI FEMARA CO-PACK is dispensed in a carton for a total of 28 days of therapy. Each carton contains individual ribociclib and letrozole drug products as follows: KISQALI (ribociclib) Tablets: 200 mg tablets. Light greyish violet, round, curved with beveled edge, debossed with “RIC” on one side and “NVR” on the other side. FEMARA (letrozole) Tablets: 2.5 mg tablets. Dark yellow, round, slightly biconvex, with beveled edges, imprinted with the letters “FV” on one side and “CG” on the other side. KISQALI FEMARA CO-PACK Cartons: NDC 0078-0923-61 – Carton of 3 blister packs (63 tablets total) – each blister pack contains a 7-day supply of 21 tablets (200 mg per tablet) (600 mg daily dose) of KISQALI plus one 28-tablet count bottle of FEMARA NDC 0078-0916-61 – Carton of 3 blister packs (42 tablets total) – each blister pack contains a 7-day supply of 14 tablets (200 mg per tablet) (400 mg daily dose) of KISQALI plus one 28-tablet count bottle of FEMARA NDC 0078-0909-61 – Carton of 1 blister pack (21 tablets total) – each blister pack contains a 21-day supply of 21 tablets (200 mg per tablet) (200 mg daily dose) of KISQALI plus one 28-tablet count bottle of FEMARA Store at room temperature at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F). Store in the original blister package in order to protect from moisture.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.