FDA label 41a8662a-8aa7-4c63-8fc6-b29286e08ac8

5 WARNINGS AND PRECAUTIONS • Anaphylaxis, Anaphylactic Shock and Other Serious Hypersensitivity Reactions : May occur during or soon after infusion. Most occur immediately following initiation of infusion. If symptoms occur, stop VARUBI injectable emulsion, initiate appropriate medical management including epinephrine and/or an antihistamine. Permanently discontinue VARUBI injectable emulsion. ( 5.1 ) • CYP2D6 Substrates : Rolapitant is a moderate inhibitor of CYP2D6 and significantly increases the plasma concentrations of CYP2D6 substrates for at least 28 days following single dose administration of VARUBI. Before starting VARUBI, consider if patients require: • thioridazine or pimozide; if so, use an alternative antiemetic to VARUBI or an alternative to thioridazine or pimozide that is not metabolized by CYP2D6. • other CYP2D6 substrates; if so, consult the prescribing information for the CYP2D6 substrate for additional information about interactions with CYP2D6 inhibitors. ( 4 , 5.2 , 7.1 ) 5.1 Anaphylaxis, Anaphylactic Shock and Other Serious Hypersensitivity Reactions Anaphylaxis, anaphylactic shock and other serious hypersensitivity reactions have been reported in the postmarketing setting, some requiring hospitalization [see Adverse Reactions (6.2) ]. These reactions have occurred during or soon after the infusion of VARUBI injectable emulsion. Most reactions have occurred within the first few minutes of administration. Symptoms of anaphylaxis can include wheezing or difficulty breathing; swelling of the face or throat; hives or flushing; itching; abdominal cramping, abdominal pain or vomiting; back pain or chest pain; hypotension or shock. Consult with patients to determine if the patient is hypersensitive to any component of the product (including soybean oil). Furthermore, as cross reactions to other allergens is possible, patients with known allergies to legumes or other related allergens should be monitored closely. Patients with a potential hypersensitivity should not be administered VARUBI injectable emulsion [see Contraindications (4) ]. Appropriate treatment should be available for immediate use in the event of an anaphylactic reaction during treatment with VARUBI injectable emulsion . If anaphylaxis or any other serious hypersensitivity/infusion reaction occurs: • administration of VARUBI injectable emulsion should be stopped immediately. • appropriate medical management (including epinephrine and or antihistamines) should be initiated, and • VARUBI injectable emulsion should be permanently discontinued. 5.2 Interaction with CYP2D6 Substrates Rolapitant is a moderate inhibitor of CYP2D6. Exposure to dextromethorphan, a CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan concentrations, the last time point measured. The inhibitory effect of rolapitant on CYP2D6 is expected to persist beyond 28 days for an unknown duration following administration of VARUBI [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ] . Narrow Therapeutic Index Drugs (Thioridazine and Pimozide) VARUBI is contraindicated in patients taking CYP2D6 substrates with a narrow therapeutic index such as thioridazine and pimozide. Increased plasma concentrations of thioridazine and pimozide are associated with serious and/or life-threatening events of QT prolongation and Torsades de Pointes [see Contraindications (4) ]. Before starting treatment with VARUBI, consider whether patients require treatment with thioridazine or pimozide. If patients require these drugs, use an alternative antiemetic to VARUBI or an alternative to thioridazine or pimozide that is not metabolized by CYP2D6. Other Drugs VARUBI can also increase plasma concentrations of other CYP2D6 substrates for at least 28 days following administration of VARUBI and may result in adverse reactions. Before starting treatment with VARUBI, consult the prescribing information for CYP2D6 substrates to obtain additional information about interactions with CYP2D6 inhibitors.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Anaphylaxis, Anaphylactic Shock and Other Serious Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] • Interaction with CYP2D6 Substrates [see Contraindications (4) and Warnings and Precautions (5.2) ] 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. 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. VARUBI Tablets In 4 controlled clinical trials in patients receiving emetogenic cancer chemotherapy, VARUBI tablets were given in combination with a 5-HT 3 receptor antagonist and dexamethasone. On Day 1 of Cycle 1 of chemotherapy, 1567 patients were treated with VARUBI tablets 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 tablets was four. VARUBI tablets 180 mg were administered to 1294 patients. In Cycle 1 adverse reactions were reported in approximately 7% of patients treated with VARUBI tablets 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 tablets, Dexamethasone, and 5-HT 3 Receptor Antagonist) N = 624 Control (Placebo, Dexamethasone, and 5-HT 3 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 tablets, Dexamethasone, and 5-HT 3 Receptor Antagonist) N = 670 Control (Placebo, Dexamethasone, and 5-HT 3 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. VARUBI Injectable Emulsion In healthy subjects receiving the recommended therapeutic dose of VARUBI injectable emulsion, infusion-related adverse reactions were reported in 2.6% (2/78) of subjects during the infusion and included sensation of warmth, abdominal pain, dizziness and paresthesia. Since VARUBI injectable emulsion is the same active substance (rolapitant) as VARUBI tablets, adverse reactions associated with VARUBI tablets might also be expected to occur with VARUBI injectable emulsion. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of VARUBI injectable emulsion. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In postmarketing experience, severe systemic reactions have occurred within minutes of the start of infusion with VARUBI injectable emulsion. Immune system disorders : hypersensitivity reactions including anaphylaxis, anaphylactoid reactions and anaphylactic shock, including back pain and chest pain Gastrointestinal disorders: abdominal pain Skin and subcutaneous disorders: erythema General disorders and administration site conditions: feeling hot Vascular disorders: generalized flushing, dizziness

<table ID="_RefID0EJPAE" width="75%"><caption>Table 2:Most Common Adverse Reactions in Patients Receiving Cisplatin-Based Highly Emetogenic Chemotherapy (Cycle 1)<footnote ID="_RefID0ENPAE">all reactions occurring at &#x2265;3% in the VARUBI group and for which the rate for VARUBI exceeds the rate for control</footnote></caption><col width="18%"/><col width="34%"/><col width="34%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">VARUBI Regimen</content> <content styleCode="bold">(VARUBI tablets, Dexamethasone, and 5-HT₃ Receptor Antagonist)</content> <content styleCode="bold">N = 624</content></th><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Control</content> <content styleCode="bold">(Placebo, Dexamethasone, and 5-HT₃ Receptor Antagonist)</content> <content styleCode="bold">N = 627</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Neutropenia</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>9%</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>8%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hiccups</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>5%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Abdominal Pain</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>3%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr></tbody></table>

<table ID="_RefID0EIRAE" width="75%"><caption>Table 3: Most Common Adverse Reactions in Patients Receiving Moderately Emetogenic Chemotherapy and Combinations of Anthracycline and Cyclophosphamide (Cycle 1)<footnote ID="_RefID0EMRAE">all reactions occurring at &#x2265;3% in the VARUBI group and for which the rate for VARUBI exceeds the rate for control.</footnote></caption><col width="18%"/><col width="34%"/><col width="34%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">VARUBI Regimen</content> <content styleCode="bold">(VARUBI tablets, Dexamethasone, and 5-HT₃ Receptor Antagonist)</content> <content styleCode="bold">N = 670</content></th><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Control</content> <content styleCode="bold">(Placebo, Dexamethasone, and 5-HT₃ Receptor Antagonist)</content> <content styleCode="bold">N = 674</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Decreased appetite</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>9%</paragraph></td><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>7%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Neutropenia</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>7%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dizziness</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>6%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dyspepsia</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>4%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Urinary tract infection</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>4%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Stomatitis</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>4%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Anemia</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>3%</paragraph></td><td styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr></tbody></table>