Kisqali Femara Co-Pack

Ribociclib and letrozole combination is used in postmenopausal women with hormone receptor (HR)-positive, HER-2 negative advanced or metastatic breast cancer. It belongs to the group of medicines called antineoplastics.

Ribociclib interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal cells may also be affected by the medicine, other unwanted effects will also occur. Some of these may be serious and must be reported to your doctor.

Female hormones that occur naturally in the body can increase the growth of some breast cancers. Letrozole works by decreasing the amounts of these hormones in the body.

This medicine is available only with your doctor's prescription.

• It is used to treat breast cancer in women after change of life.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Kisqali Femara Co-Pack, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Kisqali Femara Co-Pack. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Kisqali Femara Co-Pack.

Review Date: October 4, 2017

Dosing and Administration

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. 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

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)].

Tables 2, 3, 4 and 5 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.

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) and 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)].

None.

QT Interval Prolongation

KISQALI has been shown to prolong the QT interval in a concentration-dependent manner, with estimated mean increase in QTc interval exceeding 20 ms (22.9 ms (90% CI: 21.6, 24.1)) at the mean steady-state Cmax following administration at 600 mg once daily dose [see Clinical Pharmacology (12.2)]. In Study 1 (MONALEESA-2), one patient (0.3%) had >500 msec post-baseline QTcF value (average of triplicate), and nine patients out of 329 patients (3%) had a >60 msec increase from baseline in QTcF intervals (average of triplicate). These ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption. There were no reported cases of Torsades de Pointes. Syncope occurred in 9 patients (2.7%) in the KISQALI plus letrozole arm versus 3 (0.9%) in placebo plus letrozole arm. On the KISQALI plus letrozole treatment arm, there was one (0.3%) sudden death in a patient with Grade 3 hypokalemia and Grade 2 QT prolongation [see Adverse Reactions (6)].

Assess ECG prior to initiation of treatment. Initiate treatment with Kisqali Femara Co-Pack only in patients with QTcF values less than 450 msec. Repeat ECG at approximately Day 14 of the first cycle and the beginning of the second cycle, and as clinically indicated.

Monitor serum electrolytes (including potassium, calcium, phosphorous and magnesium) prior to the initiation of treatment, at the beginning of the first 6 cycles, and as clinically indicated. Correct any abnormality before starting Kisqali Femara Co-Pack therapy [see Dosage and Administration (2.2)].

Avoid the use of Kisqali Femara Co-Pack in patients who already have or who are at significant risk of developing QTc prolongation, including patients with:

• long QT syndrome
  
  
• uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina and bradyarrhythmias
  
  
• electrolyte abnormalities

Avoid using Kisqali Femara Co-Pack with drugs known to prolong QTc interval and/or strong CYP3A inhibitors as this may lead to prolongation of the QTcF interval [see Drug Interactions (7.4), Clinical Pharmacology (12.3)].

Based on the observed QT prolongation during treatment, KISQALI may require dose interruption, reduction or discontinuation as described in Table 4 [see Dosage and Administration (2.2) and Drug Interactions (7.4)].

Hepatobiliary Toxicity

In Study 1, increases in transaminases were observed. Grade 3 or 4 increases in ALT (10% versus 1%) and AST (7% versus 2%) were reported in the Kisqali Femara Co-Pack and placebo arms respectively.

Among the patients who had Grade ≥ 3 ALT/AST elevation, the median time-to-onset was 57 days for the Kisqali Femara Co-Pack treatment group. The median time to resolution to Grade ≤ 2 was 24 days in the KISQALI plus letrozole treatment group.

Concurrent elevations in ALT or AST greater than three times the ULN and total bilirubin greater than two times the ULN, with normal alkaline phosphatase, in the absence of cholestasis occurred in 4 (1%) patients in Study 1 and all patients recovered after discontinuation of KISQALI.

Perform LFTs before initiating therapy with Kisqali Femara Co-Pack. Monitor LFTs every 2 weeks for first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated [see Dosage and Administration (2.2)].

Based on the severity of the transaminase elevations, KISQALI may require dose interruption, reduction, or discontinuation as described in Table 3 (Dose Modification and Management for Hepatobiliary toxicity) [see Dosage and Administration (2.2)]. Recommendations for patients who have elevated AST/ALT Grade ≥ 3 at baseline have not been established.

Neutropenia

In Study 1, neutropenia was the most frequently reported adverse reaction (75%) and a Grade 3/4 decrease in neutrophil count (based on laboratory findings) was reported in 60% of patients receiving Kisqali Femara Co-Pack. Among the patients who had Grade 2, 3, or 4 neutropenia, the median time to Grade > 2 neutropenia was 16 days. The median time to resolution of Grade ≥3 (to normalization or Grade < 3) was 15 days in the Kisqali Femara Co-Pack treatment group.  Febrile neutropenia was reported in 1.5% of patients receiving Kisqali Femara Co-Pack. Treatment discontinuation due to neutropenia was 0.9%.

Perform CBC before initiating therapy with Kisqali Femara Co-Pack. Monitor CBC every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated.

Based on the severity of the neutropenia, KISQALI may require dose interruption, reduction or discontinuation as described in Table 2 [see Dosage and Administration (2.2)].

Embryo-Fetal Toxicity

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.

In animal reproduction studies, administration of ribociclib to pregnant rats and rabbits during organogenesis caused embryo-fetal toxicities at maternal exposures that were 0.6 and 1.5 times the human clinical exposure, respectively, based on area under the curve (AUC).

Letrozole caused embryo-fetal toxicities in rats and rabbits at maternal exposures that were below the maximum recommended human dose (MHRD) on a mg/m2 basis.

Advise pregnant women of the potential risk to a fetus. Advise women of reproductive potential to use effective contraception during therapy with Kisqali Femara Co-Pack and for at least 3 weeks after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

Kisqali Femara Co-Pack consists of ribociclib 200 mg film coated tablets copackaged 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 acid7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl) pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (1/1).

The molecular formula for ribociclib succinate is C23H30N8O.C4H6O4 and the molecular weight is 552.64 g/mole [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, empirical formula C17H11N5, 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Ribociclib

Carcinogenesis studies have not been conducted with ribociclib.

Ribociclib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro human lymphocyte chromosomal aberration assay or an in vivo rat bone marrow micronucleus assay.

Fertility studies in animals have not been performed with ribociclib. In repeat-dose toxicity studies with oral administration of ribociclib daily for 3 weeks on /1 week off in rats up to 26 weeks duration and dogs up to 39 weeks duration, atrophic changes in testes were reported. Findings included degeneration of seminiferous tubular epithelia in the testes and hypospermia and luminal cellular debris in the epididymides of rats and dogs and vacuolation of epithelia in the epididymides of rats. These findings were observed at doses ≥75 mg/kg in rats and ≥1 mg/kg in dogs which resulted in systemic exposures that were 1.4 and 0.03 times the human exposure at the highest recommended daily dose of 600 mg/day based on AUC, respectively. These effects can be linked to a direct anti-proliferative effect on the testicular germ cells resulting in atrophy of the seminiferous tubules and showed a trend towards reversibility in rats and dogs after a four-week non-dosing period.

Letrozole

A conventional carcinogenesis study in mice at doses of 0.6 to 60 mg/kg/day (about 1 to 100 times the daily maximum recommended human dose on a mg/m2 basis) administered by oral gavage for up to 2 years revealed a dose-related increase in the incidence of benign ovarian stromal tumors. The incidence of combined hepatocellular adenoma and carcinoma showed a significant trend in females when the high dose group was excluded due to low survival. In a separate study, plasma AUC0-12hr levels in mice at 60 mg/kg/day were 55 times higher than the AUC0-24hr level in breast cancer patients at the recommended dose. The carcinogenicity study in rats at oral doses of 0.1 to 10 mg/kg/day (about 0.4 to 40 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years also produced an increase in the incidence of benign ovarian stromal tumors at 10 mg/kg/day. Ovarian hyperplasia was observed in females at doses equal to or greater than 0.1 mg/kg/day. At 10 mg/kg/day, plasma AUC0-24hr levels in rats were 80 times higher than the level in breast cancer patients at the recommended dose. The benign ovarian stromal tumors observed in mice and rats were considered to be related to the pharmacological inhibition of estrogen synthesis and may be due to increased luteinizing hormone resulting from the decrease in circulating estrogen.

Letrozole was not mutagenic in in vitro tests (Ames and E.coli bacterial tests) but was observed to be a potential clastogen in in vitro assays (CHO K1 and CCL 61 Chinese hamster ovary cells). Letrozole was not clastogenic in vivo (micronucleus test in rats).

In a fertility and early embryonic developmental toxicity study in female rats, oral administration of letrozole starting 2 weeks before mating until pregnancy day 6 resulted in decreases in the incidence of successful mating and pregnancy at doses ≥ 0.03 mg/kg/day (approximately 0.1 times the recommended human dose on a mg/m2 basis). In repeat-dose toxicity studies, administration of letrozole caused sexual inactivity in females and atrophy of the reproductive tract in males and females at doses of 0.6, 0.1 and 0.03 mg/kg in mice, rats and dogs, respectively (approximately 1, 0.4 and 0.4 times the daily maximum recommended human dose on a mg/m2 basis, respectively).

Animal Toxicology and/or Pharmacology

Ribociclib

In vivo cardiac safety studies in dogs demonstrated dose and concentration related QTc interval prolongation at an exposure similar to patients receiving the recommended dose of 600 mg. There is a potential to induce incidences of premature ventricular contractions (PVCs) at elevated exposures (approximately 5-fold the anticipated clinical Cmax).

Applies to letrozole / ribociclib: oral tablet therapy pack

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Feeling tired or weak.
• Headache.
• Upset stomach or throwing up.
• Back pain.
• Hard stools (constipation).
• Loose stools (diarrhea).
• Not hungry.
• Not able to sleep.
• Mouth irritation or mouth sores.
• Belly pain.
• Hair loss.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.