DRUG INTERACTIONS-(summary)-

­ • CYP3A Inhibitors: Avoid concurrent use of IBRANCE with strong CYP3A inhibitors. If the strong inhibitor cannot be avoided, reduce the IBRANCE dose.

 • CYP3A Inducers: Avoid concurrent use of IBRANCE with strong and moderate CYP3A inducers.

• CYP3A Substrates: The dose of sensitive CYP3A4 substrates with narrow therapeutic indices may need to be reduced when given concurrently with IBRANCE. 

DRUG INTERACTIONS-(details)-

Palbociclib is primarily metabolized by CYP3A and sulfotransferase (SULT) enzyme SULT2A1. In vivo, palbociclib is a time-dependent inhibitor of CYP3A.

1. Agents That May Increase Palbociclib Plasma Concentrations-                                   Effect of CYP3A Inhibitors Coadministration of a strong CYP3A inhibitor (itraconazole) increased the plasma exposure of palbociclib in healthy subjects by 87%.

Avoid concomitant use of strong CYP3A inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, and voriconazole).

Avoid grapefruit or grapefruit juice during IBRANCE treatment. If coadministration of IBRANCE with a strong CYP3A inhibitor cannot be avoided, reduce the dose of IBRANCE

2. Agents That May Decrease Palbociclib Plasma Concentrations-                              Effect of CYP3A Inducers Coadministration of a strong CYP3A inducer (rifampin) decreased the plasma exposure of palbociclib in healthy subjects by 85%.

Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampin, carbamazepine and St John’s Wort) 

Coadministration of moderate CYP3A inducers may also decrease the plasma exposure of IBRANCE. Avoid concomitant use of moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) .

3. Drugs That May Have Their Plasma Concentrations Altered by Palbociclib- Coadministration of midazolam with multiple doses of IBRANCE increased the midazolam plasma exposure by 61%, in healthy subjects, compared with administration of midazolam alone

The dose of the sensitive CYP3A substrate with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus) may need to be reduced as IBRANCE may increase their exposure

BRIEF SUMMARY-

PALBOCICTIB- (Feb 2015)

Indn-  r indicated for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer..

Comp-   Capsules: 125 mg, 100 mg, and 75 mg     • Recommended starting dose: 125 mg once daily taken with food for 21 days followed by 7 days off treatment.

ADR-     ­ Most common adverse reactions (incidence =10%) were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and epistaxis.

CI-   None 

WARNINGS  -

­ • Hematologic: Neutropenia may occur. Monitor complete blood count prior to start of IBRANCE therapy and at the beginning of each cycle, as well as on Day 14 of the first two cycles, and as clinically indicated.

Pat Infrm-

 Advise patients to immediately report any signs or symptoms of myelosuppression or infection, such as fever, chills, dizziness, shortness of breath, weakness or any increased tendency to bleed and/or to bruise

 • Advise patients to immediately report any signs or symptoms of pulmonary embolism, such as shortness of breath, chest pain, tachypnea, and tachycardia

 • Advise patients to take IBRANCE with food and swallow IBRANCE capsules whole.

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Novel Drug Approvals for 2015

1.Name    IBRANE   

2. Active Ingredient-     Palbocictib

3. Indication-      is a kinase inhibitor indicated for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer..

Date of Approval  2/3/2015

HIGHLIGHTS OF PRESCRIBING INFORMATION-

 These highlights do not include all the information needed to use                              IBRANCE safely and effectively.

See full prescribing information for IBRANCE. IBRANCE® (palbociclib) capsules, for oral use

Initial U.S. Approval: 2015

INDICATIONS AND USAGE-

­ IBRANCE is a kinase inhibitor indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease.

This indication is approved under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

 ADVERSE REACTIONS-

­ Most common adverse reactions (incidence =10%) were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and epistaxis.

CONTRAINDICATIONS-

­ None 

WARNINGS AND PRECAUTIONS -

­ • Hematologic: Neutropenia may occur. Monitor complete blood count prior to start of IBRANCE therapy and at the beginning of each cycle, as well as on Day 14 of the first two cycles, and as clinically indicated.

 • Infections: Monitor for signs and symptoms and withhold dosing as appropriate.

 • Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception.

DOSAGE AND ADMINISTRATION-

­ IBRANCE capsules are taken orally with food in combination with letrozole.

 • Recommended starting dose: 125 mg once daily taken with food for 21 days followed by 7 days off treatment.

 • Dosing interruption and/or dose reductions are recommended based on individual safety and tolerability.

DOSAGE FORMS AND STRENGTHS-

­ Capsules: 125 mg, 100 mg, and 75 mg

PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient Information).

• Advise patients to immediately report any signs or symptoms of myelosuppression or infection, such as fever, chills, dizziness, shortness of breath, weakness or any increased tendency to bleed and/or to bruise

 • Advise patients to immediately report any signs or symptoms of pulmonary embolism, such as shortness of breath, chest pain, tachypnea, and tachycardia

 • Advise patients to take IBRANCE with food and swallow IBRANCE capsules whole.

• IBRANCE may interact with grapefruit. Patients should not consume grapefruit products while on treatment with IBRANCE.

• Inform patients to avoid strong CYP3A inhibitors and strong CYP3A inducers.

• Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products

 • If the patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time. IBRANCE capsules should be swallowed whole (do not chew, crush or open them prior to swallowing).

No capsule should be ingested if it is broken, cracked, or otherwise not intact.

• Advise females of reproductive potential to use effective contraception during IBRANCE therapy and for at least two weeks after the last dose.

Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with IBRANCE..

CLINICAL PHARMACOLOGY

1. Mechanism of Action-

Palbociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. Cyclin D1 and CDK4/6 are downstream of signaling pathways which lead to cellular proliferation. In vitro, palbociclib reduced cellular proliferation of estrogen receptor (ER)-positive breast cancer cell lines by blocking progression of the cell from G1 into S phase of the cell cycle.

2. Pharmacodynamics-                                                                                               Cardiac Electrophysiolo-                                                                                              The effect of palbociclib on the QTc interval was evaluated in 184 patients with advanced cancer.

No large change (i.e., >20 ms) in the QTc interval was detected at the mean observed maximal steady-state palbociclib concentration following a therapeutic schedule (e.g., 125 mg daily for 21 consecutive days followed by 7 days off to comprise a complete cycle of 28 days).

3. Pharmacokinetics-                                                                                                            The pharmacokinetics of palbociclib were characterized in patients with solid tumors including advanced breast cancer and in healthy subjects.

Absorption-                                                                                                                      The mean Cmax of palbociclib is generally observed between 6 to 12 hours (time to reach maximum concentration, Tmax) following oral administration.

The mean absolute bioavailability of IBRANCE after an oral 125 mg dose is 46%. In the dosing range of 25 mg to 225 mg, the AUC and Cmax increased proportionally with dose in general.

Steady state was achieved within 8 days following repeated once daily dosing. With repeated once daily administration, palbociclib accumulated with a median accumulation ratio of 2.4 (range 1.5-4.2)

 Food effect:                                                                                                                        Food intake increased the palbociclib exposure in this small subset of the population, but did not alter palbociclib exposure in the rest of the population to a clinically relevant extent.

Therefore, food intake reduced the intersubject  Compared to IBRANCE given under overnight fasted conditions, the population average AUCinf and Cmax of palbociclib increased by 21% and 38%, respectively, when given with high-fat, high-calorie food (approximately 800 to 1000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate and fat, respectively), by 12% and 27%, respectively, when given with low-fat, low-calorie food (approximately 400 to 500 calories with 120, 250, and 28 to 35 calories from protein, carbohydrate and fat, respectively), and by 13% and 24%, respectively, when moderate-fat, standard calorie food (approximately 500 to 700 calories with 75 to 105, 250 to 350 and 175 to 245 calories from protein, carbohydrate and fat, respectively) was given one hour before and two hours after IBRANCE dosing.

Distribution-                                                                                                                Binding of palbociclib to human plasma proteins in vitro was approximately 85%, with no concentration dependence over the concentration range of 500 ng/mL to 5000 ng/mL.

The geometric mean apparent volume of distribution (Vz/F) was 2583 L (26% CV).

Metabolism-                                                                                                                       In vitro and in vivo studies indicated that palbociclib undergoes hepatic metabolism in humans.

Following oral administration of a single 125 mg dose of [14C]palbociclib to humans, the primary metabolic pathways for palbociclib involved oxidation and sulfonation, with acylation and glucuronidation contributing as minor pathways. Palbociclib was the major circulating drug-derived entity in plasma (23%).

The major circulating metabolite was a glucuronide conjugate of palbociclib, although it only represented 1.5% of the administered dose in the excreta.

Palbociclib was extensively metabolized with unchanged drug accounting for 2.3% and 6.9% of radioactivity in feces and urine, respectively. In feces, the sulfamic acid conjugate of palbociclib was the major drug-related component, accounting for 26% of the administered dose. In vitro studies with human hepatocytes, liver cytosolic and S9 fractions, and recombinant SULT enzymes indicated that CYP3A and SULT2A1 are mainly involved in the metabolism of palbociclib.

Elimination-                                                                                                                    The geometric mean apparent oral clearance (CL/F) of palbociclib was 63.1 L/hr (29% CV), and the mean (± standard deviation) plasma elimination half-life was 29 (±5) hours in patients with advanced breast cancer. In 6 healthy male subjects given a single oral dose of [14C]palbociclib, a median of 91.6% of the total administered radioactive dose was recovered in 15 days; feces (74.1% of dose) was the major route of excretion, with 17.5% of the dose recovered in urine.

The majority of the material was excreted as metabolites.

Age, Gender, and Body Weight Based on a population pharmacokinetic analysis in 183 patients with cancer (50 male and 133 female patients, age range from 22 to 89 years, and body weight range from 37.9 to 123 kg), gender had no effect on the exposure of palbociclib, and age and body weight had no clinically important effect on the exposure of palbociclib.

Pediatric Population-                                                                                            Pharmacokinetics of IBRANCE have not been evaluated in patients <18 years of age.

 Drug Interactions-                                                                                                            In vitro data indicate that CYP3A and SULT enzyme SULT2A1 are mainly involved in the metabolism of palbociclib.

Palbociclib is a weak time-dependent inhibitor of CYP3A following daily 125 mg dosing to steady state in humans. In vitro, palbociclib is not an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, and 2D6, and is not an inducer of CYP1A2, 2B6, 2C8, and 3A4 at clinically relevant concentrations.

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                                            Based on findings in animals and mechanism of action, IBRANCE can cause fetal harm when administered to a pregnant woman

 In animal studies, palbociclib was teratogenic and fetotoxic at maternal exposures that were =4 times the human clinical exposure based on AUC at the recommended human dose. There are no available human data informing the drug-associated risk

 Advise pregnant women of the potential risk to a fetus

The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies

.2. Lactation Risk Summary-                                                                                               There are no data on the presence of palbociclib in human milk, the effects of IBRANCE on the breastfed child, or the effects of IBRANCE on milk production.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IBRANCE, advise a nursing woman to discontinue breastfeeding during treatment with IBRANCE.

3. Females and Males of Reproductive Potential-

Contraception Females-                                                                                             Advise females of reproductive potential to use effective contraception during treatment with IBRANCE and for at least two weeks after the last dose.

Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with IBRANCE

Infertility- Males-                                                                                                                Based on findings in animals, male fertility may be compromised by treatment with IBRANCE [see Carcinogenesis, Mutagenesis,

4. Pediatric Us-                                                                                                              The safety and efficacy of IBRANCE in pediatric patients have not been studied.

5. Geriatric Use-                                                                                                                  Of 84 patients who received IBRANCE in Study 1, 37 patients (44%) were =65 years of age and 8 patients (10%) were =75 years of age.

No overall differences in safety or effectiveness of IBRANCE were observed between these patients and younger patients but greater sensitivity of some older individuals cannot be ruled out.

6. Hepatic Impairment-                                                                                                    Based on a population pharmacokinetic analysis that included 183 patients, where 40 patients had mild hepatic impairment (total bilirubin = ULN and AST > ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST), mild hepatic impairment had no effect on the exposure of palbociclib.

The pharmacokinetics of palbociclib have not been studied in patients with moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and any AST)

7. Renal Impairment-                                                                                                         Based on a population pharmacokinetic analysis that included 183 patients, where 73 patients had mild renal impairment (60 mL/min = CrCl <90 mL/min) and 29 patients had moderate renal impairment (30 mL/min = CrCl <60 mL/min), mild and moderate renal impairment had no effect on the exposure of palbociclib.

The pharmacokinetics of palbociclib have not been studied in patients with severe renal impairment

OVERDOSAGE-

There is no known antidote for IBRANCE. The treatment of overdose of IBRANCE should consist of general supportive measures.