KISQALI FEMARA CO-PACK- letrozole and ribociclib
Novartis Pharmaceuticals Corporation
The KISQALI® FEMARA® CO-PACK is indicated as initial endocrine-based therapy for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.
The KISQALI FEMARA CO-PACK is comprised of ribociclib tablets copackaged with letrozole tablets, to provide a 28-day treatment regimen.
The KISQALI FEMARA CO-PACK should be coadministered, with or without food, as follows:
- KISQALI: The recommended starting dose for KISQALI is 600 mg (three 200 mg tablets) taken orally, once daily for 21 consecutive days followed by 7 days off KISQALI treatment resulting in a complete cycle of 28 days.
- FEMARA: 2.5 mg (one tablet) taken once daily throughout the 28-day cycle.
Patients should take their doses of KISQALI FEMARA CO-PACK at approximately the same time each day, preferably in the morning.
Pre/perimenopausal women treated with KISQALI FEMARA CO-PACK should be treated with a luteinizing hormone-releasing hormone (LHRH) agonist according to current clinical practice standards.
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.
For additional information on KISQALI® and FEMARA® , refer to the Full Prescribing Information for each product.
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)].
|Dose||Number of Tablets||Dose||Number of Tablets|
|Starting dose||600 mg/day||three 200 mg tablets||2.5 mg/day||one 2.5 mg tablet|
|First dose reduction||400 mg/day||two 200 mg tablets||2.5 mg/day||one 2.5 mg tablet|
|Second dose reduction||200 mg/day*||one 200 mg tablet||2.5 mg/day||one 2.5 mg tablet|
|*If further dose reduction below 200 mg/day is required, discontinue KISQALI.|
Tables 2, 3, 4, 5, 6, and 7 summarize recommendations for dose interruption, reduction, or discontinuation of KISQALI in the management of specific adverse reactions. Dose modifications of KISQALI FEMARA CO-PACK are recommended based on individual safety and tolerability.
|Grade 1(asymptomatic)||Grade 2(symptomatic)||Grade 3 (severe symptomatic)or 4 (life-threatening)|
|ILD/Pneumonitis [see Warnings andPrecautions (5.1)]||No dose interruption or adjustment is required. Initiate appropriate medical therapy and monitor as clinically indicated.||Dose interruption until recoveryto Grade ≤ 1 then consider resuming KISQALI at the next lower dose level*.If Grade 2 recurs, discontinue KISQALI.||Discontinue KISQALI|
|Abbreviation: ILD, interstitial lung disease.Grading according to Common Terminology Criteria for Adverse Event (CTCAE) version 4.03.*An individualized benefit-risk assessment should be performed when considering resuming KISQALI.|
|Grade 1 (< 10% body surface area (BSA) with active skin toxicity, no signs of systemic involvement)||Grade 2 (10%-30% BSA with active skin toxicity, no signs of systemic involvement)||Grade 3 (severe rash not responsive to medical management; > 30% BSA with active skin toxicity, signs of systemic involvement present; SJS*)||Grade 4 (any % BSA associated with extensive superinfection, with IV antibiotics indicated; life threatening consequences; TEN**)|
|Cutaneous adverse reactions, including SCARs [see Warnings and Precautions (5.2)]||No dose adjustment is required. Initiate appropriate medical therapy and monitor as clinically indicated.||Interrupt KISQALI until the etiology of the reaction has been determined.If the etiology is a SCAR, permanently discontinue KISQALI.If the etiology is not a SCAR, interrupt dose until recovery to Grade ≤ 1, then resume KISQALI at same dose level.If the cutaneous adverse reaction still recurs at Grade 3, resume KISQALI at the next lower dose level.||Permanently discontinue KISQALI.|
|Abbreviations: BSA, body surface area; SCARs, severe cutaneous adverse reactions; SJS, stevens-johnson syndrome; TEN, toxic epidermal necrolysis.*SJS (Grade 3 and 4) is defined as skin sloughing covering < 10% BSA and 10%-30% BSA, respectively, with associated signs (e.g., erythema, purpura, epidermal detachment, and mucous membrane detachment).**TEN (Grade 4) is defined as skin sloughing covering ≥30% BSA with associated symptoms (e.g., erythema, purpura, epidermal detachment, and mucous membrane detachment).Grading according to Common Terminology Criteria for Adverse Event (CTCAE) version 4.03.|
|ECGs with QTcF* > 480 ms [see Warnings and Precautions (5.3)]|| |
|ECGs with QTcF > 500 ms [see Warnings and Precautions (5.3)]|| |
|Electrocardiograms (ECGs) should be assessed prior to initiation of treatment.Repeat ECGs at approximately Day 14 of the first cycle and at the beginning of the second cycle, and as clinically indicated.In case of (QTcF) prolongation at any given time during treatment, more frequent ECG monitoring is recommended.*QTcF = QT interval corrected by Fridericia’s formula.|
|Grade 1 (> ULN – 3 x ULN)||Grade 2 (> 3 to 5 x ULN)||Grade 3 (> 5 to 20 x ULN)||Grade 4 (> 20 x ULN)|
|AST and/or ALT elevations from baseline*, WITHOUT increase in total bilirubin above 2 x ULN [see Warnings and Precautions (5.4)]||No dose adjustment is required.||Baseline* at < Grade 2:Dose interruption until recovery to ≤ baseline grade, and then resume KISQALI at same dose level. If Grade 2 recurs, resume KISQALI at next lower dose level. —————————–Baseline* at Grade 2:No dose interruption.||Dose interruption until recovery to ≤ baseline* grade, and then resume at next lower dose level.If Grade 3 recurs, discontinue KISQALI.||Discontinue KISQALI.|
|Combined elevations in AST and/or ALT WITH total bilirubin increase, in the absence of cholestasis [see Warnings and Precautions (5.4)]||If patients develop ALT and/or AST > 3 x ULN along with total bilirubin > 2 x ULN irrespective of baseline grade, discontinue KISQALI.|
|Perform Liver Function Tests (LFTs) before initiating treatment with KISQALI.Monitor LFTs every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated. If Grade ≥ 2 abnormalities are noted, more frequent monitoring is recommended.|
|Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; ULN, upper limit of normal.*Baseline = prior to treatment initiation.Grading according to Common Terminology Criteria for Adverse Event (CTCAE) version 4.03.|
|Grade 1 or 2 (ANC 1000/mm3 – < LLN)||Grade 3 (ANC 500 — < 1000/mm3)||Grade 3 Febrile* Neutropenia||Grade 4 (ANC < 500/mm3)|
|Neutropenia [see Warnings and Precautions (5.5)]||No dose adjustment is required.||Dose interruption until recovery to Grade ≤ 2.Resume KISQALI at the same dose level.If toxicity recurs at Grade 3, dose interruption until recovery, then resume KISQALI at the next lower dose level.||Dose interruption until recovery of neutropenia to Grade ≤ 2. Resume KISQALI at the next lower dose level.||Dose interruption until recovery to Grade ≤ 2.Resume KISQALI at the next lower dose level.|
|Perform complete blood counts (CBCs) before initiating treatment with KISQALI.Monitor CBC every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated.|
|Abbreviations: ANC, absolute neutrophil count; LLN, lower limit of normal.*Grade 3 neutropenia with single episode of fever > 38.3°C (or) above 38°C for more than one hour and/or concurrent infection.Grading according to Common Terminology Criteria for Adverse Event (CTCAE) version 4.03.|
|Grade 1 or 2||Grade 3||Grade 4|
|Other Toxicities||No dose adjustment is required. Initiate appropriate medical therapy and monitor as clinically indicated.||Dose interruption until recovery to Grade ≤ 1 then resume KISQALI at same dose level.If Grade 3 recurs, resume KISQALI at the next lower dose level.||Discontinue KISQALI.|
|*Excluding interstitial lung disease (ILD)/pneumonitis, cutaneous adverse reactions, including severe cutaneous adverse reactions (SCARs), QT interval prolongation, hepatobiliary toxicity, and neutropenia.Grading according to Common Terminology Criteria for Adverse Event (CTCAE) version 4.03.|
Dose Modification for Use with Strong CYP3A Inhibitors
Avoid concomitant use of KISQALI FEMARA CO-PACK with strong CYP3A inhibitors and consider an alternative concomitant medication with less potential for CYP3A inhibition [see Drug Interactions (7.1)]. If a strong CYP3A inhibitor must be coadministered, reduce the KISQALI dose to 400 mg once daily. If the strong inhibitor is discontinued, change the KISQALI dose (after at least 5 half-lives of the strong CYP3A inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].
Dose Modification for Hepatic Impairment
No dose adjustment of KISQALI is necessary in patients with mild hepatic impairment (Child-Pugh class A). The recommended starting dose is 400 mg KISQALI once daily for patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C) [see Clinical Pharmacology (12.3)].
No dose adjustment of FEMARA is necessary in patients with mild (Child-Pugh class A) to moderate (Child-Pugh class B) hepatic impairment. The dose of FEMARA in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50% [see Clinical Pharmacology (12.3)]. The recommended dose of FEMARA for such patients is 2.5 mg administered every other day. The effect of hepatic impairment on FEMARA exposure in noncirrhotic cancer patients with elevated bilirubin levels has not been determined [see Clinical Pharmacology (12.3)].
Dose Modification for Renal Impairment
No dose adjustment is necessary in patients with mild or moderate renal impairment. The recommended starting dose is 200 mg KISQALI once daily for patients with severe renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].
No dosage adjustment of FEMARA is required for patients with renal impairment if creatinine clearance is greater than or equal to 10 mL/min [see Clinical Pharmacology (12.3)].
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