Active IngredientRIBOCICLIB

NDA filling and Orange book information

Drug Name FDA Application No. Company Dosage Form;Route Strength RLD Strength Original Approval or
Tentative Approval Date
Exclusivity
Expiration
(NCE)
Exclusivity
Expiration
(ODE)
Chemical
Type
Review
Classification
Marketing
Status
TE Code
KISQALI NDA#209092 NOVARTIS PHARMS CORP TABLET;ORAL 200MG 200MG March 13, 2017 Mar 13, 2022 - 1 New molecular entity (NME) PRIORITY Prescription TBD

API Information

Parameters Details
Structural Formula structural formula
Chemical NameButanedioic acid—7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl) pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (1/1)
CAS No1211441-98-3
Molecular FormulaC23H30N8O·C4H6O4
Molecular Weight552.64 g/mol
Appearancea light yellow to yellowish brown crystalline powder
SolubilitySoluble in acidic aqueous media, becoming less soluble as pH increases
Water Solubility-
PolymorphismPolymorphism has been observed for ribociclib succinate. Production of the correct polymorphic form is ensured by an XRPD method in the active substance specification. As described under the stability section, ribociclib succinate form A has been demonstrated to be stable and not to convert into other polymorphic forms under long term and accelerated stability studies when stored in the proposed packaging.
pKa (Strongest Acidic)11.59 (Predicted)
pKa (Strongest Basic)8.87 (Predicted)
Log P2.38 (Predicted)
IdentificationIR, XRPD
DegradationStress tests were carried out in both solid and solution state. Samples were exposed to heat, heat and humidity, acid, base, humidity, and an oxidant. Impurities remained well within specification. No degradation was observed when solid ribociclib succinate was heated with oxygen
HygroscopicSlightly hygroscopic
Photostability studyPhotostable
Melting Point-
BCS ClassIV ( moderately permeable and low aqueous solubility)
Manufacture of API-

Label Information

Parameters Details
Indications and Usage KISQALI® is indicated in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.
Dosage and Administration The recommended dose of KISQALI is 600 mg (three 200 mg film-coated tablets) taken orally, once daily for 21 consecutive days followed by 7 days off treatment resulting in a complete cycle of 28 days. KISQALI can be taken with or without food.
Coadminister KISQALI with letrozole 2.5 mg taken once daily throughout the 28-day cycle. Refer to the full prescribing information of letrozole. For dosing and administration with other aromatase inhibitors refer to the applicable full prescribing information.
Patients should take their dose of KISQALI and letrozole 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. KISQALI 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.
Refer FDA Label for more information.
Mechanism of action KISQALI (ribociclib) is a kinase inhibitor.
Ribociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. These kinases are activated upon binding to Dcyclins and play a crucial role in signaling pathways which lead to cell cycle progression and cellular proliferation. The cyclin D-CDK4/6 complex regulates cell cycle progression through phosphorylation of the retinoblastoma protein (pRb).
In vitro, ribociclib decreased pRb phosphorylation leading to arrest in the G1 phase of the cell cycle and reduced cell proliferation in breast cancer cell lines. In vivo, treatment with single agent ribociclib in a rat xenograft model with human tumor cells led to decreased tumor volumes, which correlated with inhibition of pRb phosphorylation. In studies using patient-derived estrogen receptor positive breast cancer xenograft models, combination of ribociclib and antiestrogen (e.g. letrozole) resulted in increased tumor growth inhibition compared to each drug alone.
Absorption Ribociclib exhibited over-proportional increases in exposure (peak plasma concentrations (Cmax) and area under the time concentration curve (AUC)) across the dose range of 50 mg to 1200 mg following both single dose and repeated doses. Following repeated 600 mg once daily administration, steady-state was generally achieved after 8 days and ribociclib accumulated with a geometric mean accumulation ratio of 2.51 (range: 0.972 to 6.40).
The time to reach Cmax (Tmax) following ribociclib administration was between 1 and 4 hours.
Food Effect Compared to the fasted state, oral administration of a single 600 mg dose of KISQALI film-coated tablet with a high-fat, high-calorie meal (approximately 800 to 1000 calories with ~50% calories from fat, ~35% calories from carbohydrates, and ~15% calories from protein) had no effect on the rate and extent of absorption of ribociclib (Cmax GMR: 1.00; 90% CI: 0.898, 1.11; AUCinf GMR: 1.06; 90% CI: 1.01, 1.12).
Distribution Binding of ribociclib to human plasma proteins in vitro was approximately 70% and independent of concentration (10 to 10,000 ng/mL). Ribociclib was equally distributed between red blood cells and plasma with a mean in vivo blood-to plasma ratio of 1.04. The apparent volume of distribution at steady-state (Vss/F) was 1090 L based on population PK analysis.
Metabolism In vitro and in vivo studies indicated ribociclib undergoes extensive hepatic metabolism mainly via CYP3A4 in humans. Following oral administration of a single 600 mg dose of radio-labeled ribociclib to humans, the primary metabolic pathways for ribociclib involved oxidation (dealkylation, C and/or N-oxygenation, oxidation (-2H)) and combinations thereof. Phase II conjugates of ribociclib Phase I metabolites involved N-acetylation, sulfation, cysteine conjugation, glycosylation and glucuronidation. Ribociclib was the major circulating drug-derived entity in plasma (44%). The major circulating metabolites included metabolite M13 (CCI284, N-hydroxylation), M4 (LEQ803, N-demethylation), and M1 (secondary glucuronide), each representing an estimated 9%, 9%, and 8% of total radioactivity, and 22%, 20%, and 18% of ribociclib exposure. Clinical activity (pharmacological and safety) of ribociclib was due primarily to parent drug, with negligible contribution from circulating metabolites.
Ribociclib was extensively metabolized with unchanged drug accounting for 17% and 12% in feces and urine, respectively. Metabolite LEQ803 was a significant metabolite in excreta and represented approximately 14% and 4% of the administered dose in feces and urine, respectively. Numerous other metabolites were detected in both feces and urine in minor amounts (≤ 3% of the administered dose).
Elimination The geometric mean plasma effective half-life (based on accumulation ratio) was 32.0 hours (63% CV) and the geometric mean apparent oral clearance (CL/F) was 25.5 L/hr (66% CV) at steady-state at 600 mg in patients with advanced cancer. The geometric mean apparent plasma terminal half-life (T1/2) of ribociclib ranged from 29.7 to 54.7 hours and geometric mean CL/F of ribociclib ranged from 39.9 to 77.5 L/hr at 600 mg across studies in healthy subjects.
Ribociclib is eliminated mainly via feces, with a small contribution of the renal route. In 6 healthy male subjects, following a single oral dose of radio-labeled ribociclib, 92% of the total administered radioactive dose was recovered within 22 days; feces was the major route of excretion (69%), with 23% of the dose recovered in urine.
Peak plasma time (Tmax)1 and 4 hours
Half life32.0 hours
Bioavailability-
Age, gender Population PK analysis showed that there are no clinically relevant effects of age, body weight, gender, or race on the systemic exposure of ribociclib.

API Drug Master File

DMF Status Type Submit Date Holder
Not Available

Innovator Formulation Information

Parameters Details
Strength 200 mg ribociclib (equivalent to 254.40 mg ribociclib succinate)
Excipients used colloidal silicon dioxide, crospovidone, hydroxypropylcellulose, magnesium stearate and microcrystalline cellulose
Composition of coating material iron oxide black, iron oxide red, lecithin (soya) (0.344 mg), polyvinyl alcohol (partially hydrolysed), talc, titanium dioxide, and xanthan gum
Composition of caspule shell -
Pharmaceutical Development The active substance is a BCS class 4 molecule with moderate permeability. It is soluble in acidic media below pH 5.5 but solubility decreases at neutral and basic pH and stable in the solid form. A dry granulation process was developed in order to prevent changes in polymorphic form which could impact bioavailability. Suitable controls are in place to prevent detrimental solid form changes and ensure manufacturability. Excipients were chosen to enable manufacture of a robust film-coated tablet which performs adequately in vivo. Compatibility of the active substance with the chosen excipients was demonstrated through stability studies.
Manufacture of the product Blending of intra-granular components; roller
compaction; milling and blending with extra-granular excipients; compression; film-coating
Tablet / Capsule Image
Appearance Film coated, light greyish violet, round, curved with beveled edges, debossed with “RIC” on one side and “NVR” on the other side.
Imprint code / Engraving / Debossment Debossed with “RIC” on one side and “NVR” on the other side
Score no score
Color Light greyish violet
Shape Round, curved with beveled edges
Dimension 11 mm
Mfg by Novartis Pharma GmbH (EU)
Mfg for -
Marketed by -
Distributed by Novartis Pharmaceuticals Corporation

Orange Book Listed Patent

Application No. Prod No Patent No Patent Expiration Drug Substance Claim Drug Product Claim Patent Use Code Delist Requested Link
N209092 1 8324225 June 17, 2028 DS DP - - Download
N209092 1 8415355 February 19, 2031 DS DP - - Download
N209092 1 8685980 May 25, 2030 DS DP - - Download
N209092 1 8962630 December 9, 2029 - - U-1981 - Download
N209092 1 9193732 November 9, 2031 DS DP - - Download
N209092 1 9416136 August 20, 2029 - - U-1981 - Download

Office of Generic Drug Media

USP Apparatus Speed (RPMs) Medium Volume (mL) Recommended Sampling Times (minutes) Date Updated
II (Paddle) 50 0.01N HCl (Degassed) 900 10, 15, 20, 30, 45 and 60 November 2, 2017

Packaging System

Market EU US
Strength Packaging System
200 MG PVC/PCTFE (polyvinylchloride/polychlorotrifluoroethylene) or PA/alu/PVC
(polyamide/aluminium/polyvinylchloride) blisters containing 14 or 21 film-coated tablets.
Unit packs containing 21, 42 or 63 film-coated tablets and multipacks containing 63 (3 packs of 21),
126 (3 packs of 42) or 189 (3 packs of 63) film-coated tablets.
Blister pack (21 tablets) – each blister pack contains 21 tablets (200 mg per tablet) (600 mg daily dose)
Outer container - 3 Blister packs per outer container NDC 0078-0874-63
Blister pack (14 tablets) – each blister pack contains 14 tablets (200 mg per tablet) (400 mg daily dose)
Outer container - 3 Blisters packs per outer container NDC 0078-0867-42
Blister pack (21 tablets) – each blister pack contains 21 tablets (200 mg per tablet) (200 mg daily dose)
Outer container – 1 Blister pack per outer container NDC 0078-0860-01
Storage Does not require any special storage conditions Store at 20°C to 25°C (68°F to 77°F). Store in the original package.

Innovator Product Information

Label Link
FDA label Download
FDA chemistry review Download
FDA Pharmacology Review(s)
FDA Clinical Pharmacology Biopharmaceutics Review(s) Download
FDA BE Recommendation
European Public Assessment Report Download

Product Available

Territory Brand name / Generic company name Link
EU KISQALI Download
UK KISQALI Download
US KISQALI Download

Remarks

Date of first authorisation/renewal of the authorisation in EU: 22 August 2017

References

www.accessdata.fda.gov, www.drugbank.ca, www.ema.europa.eu, www.medicines.org.uk, dailymed.nlm.nih.gov

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