Kisqali Femara Co-Pack Dosage

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.

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.

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.

Table 1: Recommended Dose Modification of KISQALI FEMARA CO-PACK for Adverse Reactions

Level	KISQALI		FEMARA
	Dose	Number of tablets	Dose	Number of tablets
Early breast cancer
Starting dose	400 mg/day	two 200 mg tablets	2.5 mg/day	one 2.5 mg tablet
Dose reduction	200 mg/day*	one 200 mg tablet	2.5 mg/day	one 2.5 mg tablet
Advanced or metastatic breast cancer
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 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 modification of KISQALI FEMARA CO-PACK is recommended based on individual patient safety and tolerability.

Table 2: Dose Modification and Management for Interstitial Lung Disease/Pneumonitis

	Grade 1 (asymptomatic)	Grade 2 (symptomatic)	Grade 3 (severe symptomatic) or 4 (life-threatening)
ILD/Pneumonitis	No dose interruption or adjustment is required. Initiate appropriate medical therapy and monitor as clinically indicated.	Dose interruption until recovery to 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 Events (CTCAE) version 4.03. *An individualized benefit-risk assessment should be performed when considering resuming KISQALI.

Table 3: Dose Modification and Management for Cutaneous Adverse Reactions, Including SCARs

	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	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 Events (CTCAE) version 4.03.

Table 4: Dose Modification and Management of KISQALI for QT Prolongation

QTcF* prolongation	Early breast cancer	Advanced or metastatic breast cancer
> 480 ms and ≤ 500 ms	Interrupt KISQALI treatment and wait until QTcF resolves to ≤ 480 ms
	Resume at the same dose	Reduce to the next lower dose level
	If QTcF > 480 ms recurs, interrupt KISQALI treatment and wait until QTcF resolves to ≤ 480 ms, then resume at next lower dose level.
> 500 ms	Interrupt KISQALI treatment and wait until QTcF resolves to ≤ 480 ms, then resume at next lower dose level. If QTcF > 500 ms recurs, discontinue KISQALI.
Permanently discontinue KISQALI if QTcF interval prolongation is either > 500 ms or > 60 ms change from baseline AND associated with any of the following: Torsades de Pointes, polymorphic ventricular tachycardia, syncope, or signs/symptoms of serious arrhythmia.
Note: If dose reduction below 200 mg/day is required, discontinue KISQALI. Electrocardiograms (ECGs) should be assessed prior to initiation of treatment in all patients. Repeat ECGs at approximately Day 14 of the first cycle, and as clinically indicated. In case of QTcF prolongation at any given time during treatment, monitor ECG more frequently, and as clinically indicated. *QTcF = QT interval corrected by Fridericia’s formula.

Table 5: Dose Modification and Management of KISQALI for Hepatobiliary Toxicity

	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	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	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, monitor more frequently, and as clinically indicated.
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 Events (CTCAE) version 4.03.

Table 6: Dose Modification and Management of KISQALI for Neutropenia

	Grade 1 or 2 (ANC 1000/mm3 – < LLN)	Grade 3 (ANC 500 - < 1000/mm3)	Grade 3 Febrile* Neutropenia	Grade 4 (ANC < 500/mm3)
Neutropenia	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) 38°C or above for more than one hour and/or concurrent infection. Grading according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Table 7: Dose Modification and Management of KISQALI for Other Toxicities*

	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 Events (CTCAE) version 4.03.

​Refer to the Full Prescribing Information for the coadministered aromatase inhibitor for dose modification guidelines in the event of toxicity and other relevant safety information.

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.

​If a strong CYP3A inhibitor must be coadministered, reduce the KISQALI dose as shown in Table 8

Table 8: Dose Modification for Use with Strong CYP3A Inhibitors

Indication	Co-administration with Strong CYP3A Inhibitors
Early breast cancer	Reduce the KISQALI dose to 200 mg once daily.
Advanced or metastatic breast cancer	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.

Dose Modification for Hepatic Impairment

​The recommended dose modifications for patients with hepatic impairment are shown in Table 9.

Table 9: Dose Modification for Hepatic Impairment

Indication	Mild hepatic impairment (Child-Pugh class A)	Moderate and severe hepatic impairment (Child-Pugh class B or C)
Early breast cancer	No dose adjustment is necessary	No dose adjustment is necessary
Advanced or metastatic breast cancer	No dose adjustment is necessary	KISQALI 400 mg once daily

​The dose of FEMARA in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50%. 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. Review the Full Prescribing Information for the coadministered aromatase inhibitor or fulvestrant for dose modifications related to hepatic impairment.

Dose Modification for Renal Impairment

The recommended starting dose is 200 mg KISQALI once daily for patients with severe renal impairment.

No dosage adjustment of FEMARA is required for patients with renal impairment if creatinine clearance is greater than or equal to 10 mL/min.