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VARUBI™ (rolapitant) tablets

2015-11-02 08:37:12 来源: 作者: 【大中小】浏览:378次评论:0条

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use VARUBI safely and effectively. See full prescribing information for VARUBI.

VARUBI™ (rolapitant) tablets, for oral use
Initial U.S. Approval: 2015

INDICATIONS AND USAGE

VARUBI is a substance P/neurokinin 1 (NK1) receptor antagonist indicated in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. (1)
DOSAGE AND ADMINISTRATION

The recommended dosage is 180 mg rolapitant administered approximately 1 to 2 hours prior to the start of chemotherapy (2)
Administer in combination with dexamethasone and a 5-HT3 receptor antagonist, see full prescribing information for dosing information (2)
No dosage adjustment for dexamethasone is required. (2)

DOSAGE FORMS AND STRENGTHS

Tablets: 90 mg of rolapitant (3)
CONTRAINDICATIONS

Concurrent use with thioridazine, a CYP2D6 substrate (4)
WARNINGS AND PRECAUTIONS

Interaction with CYP2D6 Substrates with a Narrow Therapeutic Index: The inhibitory effect of a single dose of VARUBI on CYP2D6 lasts at least 7 days and may last longer. Avoid use of pimozide; monitor for adverse reactions if concomitant use with other CYP2D6 substrates with a narrow therapeutic index cannot be avoided (4, 5.1, 7.1)

ADVERSE REACTIONS

Most common adverse reactions (≥ 5%) are:

Cisplatin Based Highly Emetogenic Chemotherapy: neutropenia and hiccups (6.1)
Moderately Emetogenic Chemotherapy and Combinations of Anthracycline and Cyclophosphamide: decreased appetite, neutropenia and dizziness (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Tesaro at 1-844-4-TESARO or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

BCRP and P-gp Substrates with a Narrow Therapeutic Index: inhibition of BCRP and P-gp by VARUBI can increase plasma concentrations of the concomitant drug and potential for adverse reactions. See full prescribing information for specific examples. (7.1)
Strong CYP3A4 Inducers (e.g., rifampin): significantly reduced plasma concentrations of rolapitant can decrease the efficacy of VARUBI; avoid use of VARUBI in patients who require chronic administration of such drugs. (7.2)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 9/2015

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Interaction with CYP2D6 Substrates with a Narrow Therapeutic Index

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

7 DRUG INTERACTIONS

7.1 Effect of VARUBI on Other Drugs

7.2 Effect of Other Drugs on VARUBI

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*: Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS AND USAGE

VARUBI™ is indicated in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy.

2 DOSAGE AND ADMINISTRATION

Prevention of Nausea and Vomiting Associated with Emetogenic Cancer Chemotherapy

The recommended dosage of VARUBI in adults in combination with a 5-HT3 receptor antagonist and dexamethasone is shown in Table 1. There is no drug interaction between rolapitant and dexamethasone, so no dosage adjustment for dexamethasone is required. Administer a dexamethasone dose of 20 mg on Day 1 [see Clinical Pharmacology (12.3)].

Administer VARUBI prior to the initiation of each chemotherapy cycle, but at no less than 2 week intervals.

Administer VARUBI without regards to meals.

Table 1: Recommended Dosing Regimen
	Day 1	Day 2	Day 3	Day 4
Prevention of Nausea and Vomiting Associated with Cisplatin-Based Highly Emetogenic Cancer Chemotherapy
VARUBI	180 mg; Approximately 1 to 2 hours prior to chemotherapy	None
Dexamethasone	20 mg; 30 min prior to chemotherapy	8 mg twice daily	8 mg twice daily	8 mg twice daily
5-HT3 receptor antagonist	See the prescribing information for the co- administered 5-HT3 receptor antagonist for appropriate dosing information.	None
Prevention of Nausea and Vomiting Associated with Moderately Emetogenic Cancer Chemotherapy and Combinations of Anthracycline and Cyclophosphamide
VARUBI	180 mg; Approximately 1 to 2 hours prior to chemotherapy	None
Dexamethasone	20 mg; 30 min prior to chemotherapy	None
5-HT3 receptor antagonist	See the prescribing information for the co- administered 5-HT3 receptor antagonist for appropriate dosing information.	See the prescribing information for the co- administered 5-HT3 receptor antagonist for appropriate dosing information.

3 DOSAGE FORMS AND STRENGTHS

Tablets: 90 mg rolapitant; film-coated capsule shaped, blue tablets, debossed with T0101 on one side and 100 on the other side.

4 CONTRAINDICATIONS

VARUBI is contraindicated in patients receiving thioridazine, a CYP2D6 substrate. A significant increase in plasma concentrations of thioridazine may result in QT prolongation and Torsades de Pointes.

5 WARNINGS AND PRECAUTIONS

5.1 Interaction with CYP2D6 Substrates with a Narrow Therapeutic Index

The inhibitory effect of VARUBI on CYP2D6 lasts at least 7 days and may last longer after a single dose administration of VARUBI [see Contraindications (4), Drug Interactions (7), Clinical Pharmacology (12.3)]. Avoid use of VARUBI in patients who are receiving pimozide, a CYP2D6 substrate. An increase in plasma concentrations of pimozide may result in QT prolongation. Monitor for adverse reactions if concomitant use of VARUBI and other CYP2D6 substrates with a narrow therapeutic index cannot be avoided.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of VARUBI was eva luated in approximately 2800 patients in 4 controlled clinical trials in patients receiving emetogenic cancer chemotherapy. VARUBI was given in combination with a 5-HT3 receptor antagonist and dexamethasone. On Day 1 of Cycle 1 of chemotherapy, 1567 patients were treated with VARUBI and 1198 of these patients continued into the optional multiple cycle extension for up to 6 cycles of chemotherapy. The median number of cycles administered 180 mg of VARUBI was four. VARUBI 180 mg was administered to 1294 patients.

In Cycle 1 adverse reactions were reported in approximately 7% of patients treated with VARUBI compared with approximately 6% of patients treated with control therapy. The most common adverse reactions reported with an incidence of ≥3% and greater than control are listed in Table 2 and Table 3.

Table 2: Most Common Adverse Reactions in Patients Receiving Cisplatin-Based Highly Emetogenic Chemotherapy (Cycle 1)*
*all reactions occurring at ≥ 3% in the VARUBI group and for which the rate for VARUBI exceeds the rate for control
	VARUBI Regimen (VARUBI, Dexamethasone, and 5-HT3 Receptor Antagonist) N = 624	Control (Placebo, Dexamethasone, and 5-HT3 Receptor Antagonist) N = 627
Neutropenia	9%	8%
Hiccups	5%	4%
Abdominal Pain	3%	2%

Table 3: Most Common Adverse Reactions in Patients Receiving Moderately Emetogenic Chemotherapy and Combinations of Anthracycline and Cyclophosphamide (Cycle 1)*
*all reactions occurring at ≥ 3% in the VARUBI group and for which the rate for VARUBI exceeds the rate for control.
	VARUBI Regimen (VARUBI, Dexamethasone, and 5-HT3 Receptor Antagonist) N = 670	Control (Placebo, Dexamethasone, and 5-HT3 Receptor Antagonist) N = 674
Decreased appetite	9%	7%
Neutropenia	7%	6%
Dizziness	6%	4%
Dyspepsia	4%	2%
Urinary tract infection	4%	3%
Stomatitis	4%	2%
Anemia	3%	2%

Adverse reactions in the multiple-cycle extensions of highly and moderately emetogenic chemotherapy studies for up to 6 cycles of chemotherapy were generally similar to that observed in Cycle 1.

7 DRUG INTERACTIONS

7.1 Effect of VARUBI on Other Drugs

Rolapitant is not an inhibitor or inducer of CYP3A4. Therefore, no dosage adjustment for dexamethasone (CYP3A4 substrate) is needed when co-administered with VARUBI [see Dosage and Administration (2)].

Rolapitant is a moderate CYP2D6 inhibitor, an inhibitor of Breast-Cancer-Resistance Protein (BCRP) and an inhibitor of P-glycoprotein (P-gp) [see Clinical Pharmacology (12.3)].

CYP2D6 Substrates with a Narrow Therapeutic Index: Increased plasma concentration of CYP2D6 substrates may result in potential adverse reactions. A 3-fold increase in the exposure of dextromethorphan, a CYP2D6 substrate, was observed 7 days after a single dose of VARUBI. The duration of CYP2D6 inhibition was not studied beyond 7 days and may last longer [see Clinical Pharmacology (12.3)]. Concomitant use with Thioridazine is contraindicated [see Contraindications (4)]. Avoid use of VARUBI with pimozide [see Warnings and Precautions (5.1)]. Monitor for QT prolongation if concomitant use with pimozide cannot be avoided. Monitor for adverse reactions if concomitant use with CYP2D6 substrates with a narrow therapeutic index cannot be avoided.

BCRP Substrates with a Narrow Therapeutic Index (e.g., Methotrexate, topotecan, or irinotecan): Increased plasma concentrations of BCRP substrates may result in potential adverse reactions. Monitor for adverse reactions related to the concomitant drug if use of VARUBI cannot be avoided. Use the lowest effective dose of rosuvastatin (see prescribing information for additional information on recommended dosing).

P-gp Substrates with a Narrow Therapeutic Index: Increased plasma concentrations of digoxin, or other P-gp substrates, may result in potential adverse reactions [see Clinical Pharmacology (12.3)]. Monitor for increased digoxin concentrations. Monitor for adverse reactions if concomitan