Data from FDA - Curated by Marshall Pearce - Last updated 07 December 2017

Indication(s)

1 INDICATIONS AND USAGE YERVOY is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody indicated for: •Treatment of unresectable or metastatic melanoma in adults and pediatric patients (12 years and older). (1.1) •Adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy. (1.2) 1.1 Unresectable or Metastatic Melanoma YERVOY is indicated for the treatment of unresectable or metastatic melanoma in adults and pediatric patients (12 years and older) [see Clinical Studies (14.1)]. 1.2 Adjuvant Treatment of Melanoma YERVOY is indicated for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy [see Clinical Studies (14.2)].

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None. (4)
Adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. •Immune-mediated enterocolitis [see Warnings and Precautions (5.1)]. •Immune-mediated hepatitis [see Warnings and Precautions (5.2)]. •Immune-mediated dermatitis [see Warnings and Precautions (5.3)]. •Immune-mediated neuropathies [see Warnings and Precautions (5.4)]. •Immune-mediated endocrinopathies [see Warnings and Precautions (5.5)]. •Other immune-mediated adverse reactions, including ocular manifestations [see Warnings and Precautions (5.6)]. In patients receiving YERVOY 3 mg/kg for unresectable or metastatic melanoma in Trial 1, 15% of patients receiving monotherapy and 12% of patients treated in combination with gp100 peptide vaccine experienced Grade 3 to 5 immune-mediated reactions. In patients receiving YERVOY 10 mg/kg for adjuvant treatment of melanoma in Trial 2, 41% experienced Grade 3 to 5 immune-mediated reactions. Most common adverse reactions (≥5%) are fatigue, diarrhea, pruritus, rash, and colitis. Additional common adverse reactions at the 10 mg/kg dose (≥5%) include nausea, vomiting, headache, weight loss, pyrexia, decreased appetite, and insomnia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 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, the adverse reaction rates observed cannot be directly compared with rates in other clinical trials or experience with therapeutics in the same class and may not reflect the rates observed in clinical practice. The data described below reflect exposure to YERVOY 3 mg/kg in Trial 1, a randomized trial in patients with unresectable or metastatic melanoma and to YERVOY 10 mg/kg in Trial 2, a randomized trial in patients with resected Stage IIIA (>1 mm nodal involvement), IIIB, and IIIC (with no in-transit metastases) cutaneous melanoma. Clinically significant adverse reactions were evaluated in a total of 982 patients treated in Trials 1 and 2 and in 21 dose-ranging trials (n=2478) administering YERVOY at doses of 0.1 to 20 mg/kg [see Warnings and Precautions (5.6)]. Unresectable or Metastatic Melanoma The safety of YERVOY was evaluated in Trial 1, a randomized, double-blind clinical trial in which 643 previously treated patients with unresectable or metastatic melanoma received YERVOY 3 mg/kg for 4 doses given by intravenous infusion as a single agent (n=131), YERVOY with an investigational gp100 peptide vaccine (gp100) (n=380), or gp100 peptide vaccine as a single agent (n=132) [see Clinical Studies (14.1)]. Patients in the trial received a median of 4 doses (range: 1 to 4 doses). Trial 1 excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. The trial population characteristics were: median age 57 years (range: 19 to 90), 59% male, 94% white, and baseline ECOG performance status 0 (56%). YERVOY was discontinued for adverse reactions in 10% of patients. Table 2 presents selected adverse reactions from Trial 1, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3 to 5 events. Table 2: Selected Adverse Reactions in Trial 1 a Incidences presented in this table are based on reports of adverse events regardless of causality. Percentage (%) of Patientsa YERVOY 3 mg/kg n=131 YERVOY 3 mg/kg+gp100 n=380 gp100 n=132 System Organ Class/ Preferred Term Any Grade Grade 3 to 5 Any Grade Grade 3 to 5 Any Grade Grade 3 to 5 General Disorders and Administration-Site Conditions Fatigue 41 7 34 5 31 3 Gastrointestinal Disorders Diarrhea 32 5 37 4 20 1 Colitis 8 5 5 3 2 0 Skin and Subcutaneous Tissue Disorders Pruritus 31 0 21 <1 11 0 Rash 29 2 25 2 8 0 Table 3 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from Trial 1. Table 3: Severe to Fatal Immune-Mediated Adverse Reactions in Trial 1 a Including fatal outcome. b Including intestinal perforation. c Underlying etiology not established. Percentage (%) of Patients YERVOY 3 mg/kg n=131 YERVOY 3 mg/kg+gp100 n=380 Any Immune-Mediated Adverse Reaction 15 12 Enterocolitisa,b 7 7 Hepatotoxicitya 1 2 Dermatitisa 2 3 Neuropathya 1 <1 Endocrinopathy 4 1 Hypopituitarism 4 1 Adrenal insufficiency 0 1 Other Pneumonitis 0 <1 Meningitis 0 <1 Nephritis 1 0 Eosinophiliac 1 0 Pericarditisa,c 0 <1 Adjuvant Treatment of Melanoma The safety of YERVOY was evaluated in Trial 2, a randomized (1:1), double-blind, placebo-controlled trial in which 945 patients with resected Stage IIIA (>1 mm nodal involvement), IIIB, and IIIC (with no in-transit metastases) cutaneous melanoma received YERVOY 10 mg/kg (n=471) or placebo (n=474) administered as an intravenous infusion for 4 doses every 3 weeks followed by 10 mg/kg every 12 weeks beginning at Week 24 up to a maximum of 3 years [see Clinical Studies (14.2)]. In this trial, 36% of patients received YERVOY for longer than 6 months and 26% of patients received YERVOY for longer than 1 year. YERVOY-treated patients in the trial received a median of 4 doses (range: 1 to 16). Trial 2 excluded patients with prior systemic therapy for melanoma, autoimmune disease, a condition requiring systemic immunosuppression, or a positive test for hepatitis B, hepatitis C, or HIV. The trial population characteristics were: median age 51 years (range: 18 to 84 years), 62% male, 99% white, and baseline ECOG performance status 0 (94%). YERVOY was discontinued for adverse reactions in 52% of patients. Table 4 presents selected adverse reactions from Trial 2 which occurred in at least 5% of YERVOY-treated patients and with at least 5% increased incidence over the placebo group for all-grade events. Table 4: Selected Adverse Reactions in Trial 2 Percentage (%) of Patientsa YERVOY 10 mg/kg n=471 Placebo n=474 a Incidences presented in this table are based on reports of adverse events regardless of causality. b Includes 1 death. System Organ Class/ Preferred Term Any Grade Grade 3 to 5 Any Grade Grade 3 to 5 Skin and Subcutaneous Tissue Disorders Rash 50 2.1 20 0 Pruritus 45 2.3 15 0 Gastrointestinal Disorders Diarrhea 49 10 30 2.1 Nausea 25 0.2 18 0 Colitisb 16 8 1.5 0.4 Vomiting 13 0.4 6 0.2 Investigations Weight Decreased 32 0.2 9 0.4 General Disorders and Administration-Site Conditions Fatigue 46 2.3 38 1.5 Pyrexia 18 1.1 4.9 0.2 Nervous System Disorders Headache 33 0.8 18 0.2 Metabolism and Nutrition Disorders Decreased Appetite 14 0.2 3.4 0.2 Psychiatric Disorders Insomnia 10 0 4.4 0 Table 5 presents selected laboratory abnormalities from Trial 2 which occurred in at least 10% of YERVOY-treated patients at a higher incidence compared to placebo. Table 5: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of YERVOY-Treated Patients (Trial 2)a a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available. Excluding lipase and amylase, YERVOY group (range: 466 to 470 patients) and placebo group (range: 472 to 474 patients). b For lipase and amylase, YERVOY group (range: 447 to 448 patients) and placebo group (range: 462 to 464 patients). Percentage of Patients with Worsening Laboratory Test from Baselinea Test YERVOY Placebo All Grades Grade 3 to 4 All Grades Grade 3 to 4 Chemistry Increased ALT 46 10 16 0 Increased AST 38 9 14 0.2 Increased lipaseb 26 9 17 4.5 Increased amylaseb 17 2.0 7 0.6 Increased alkaline phosphatase 17 0.6 6 0.2 Increased bilirubin 11 1.5 9 0 Increased creatinine 10 0.2 6 0 Hematology Decreased hemoglobin 25 0.2 14 0 Table 6 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from Trial 2. Table 6: Severe to Fatal Immune-Mediated Adverse Reactions in Trial 2 Percentage (%) of Patients YERVOY 10 mg/kg n=471 a Including fatal outcome. b Including intestinal perforation. c Underlying etiology not established. Any Immune-Mediated Adverse Reaction 41 Enterocolitisa,b 16 Hepatitis 11 Dermatitis 4.0 Neuropathya 1.7 Endocrinopathy 8 Hypopituitarism 7 Primary hypothyroidism 0.2 Hyperthyroidism 0.6 Other Myocarditisa 0.2 Meningitis 0.4 Pericarditisc 0.2 Pneumonitis 0.2 Uveitis 0.2 Other Clinical Experience Across clinical studies that utilized YERVOY doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence less than 1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of YERVOY. 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. Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) 6.3 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Eleven (1.1%) of 1024 evaluable patients with unresectable or metastatic melanoma tested positive for treatment-emergent binding antibodies against ipilimumab (TE-ADAs) in an electrochemiluminescent (ECL) based assay. This assay had substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Seven (4.9%) of 144 patients receiving ipilimumab and 7 (4.5%) of 156 patients receiving placebo for the adjuvant treatment of melanoma tested positive for TE-ADAs using an ECL assay with improved drug tolerance. No patients tested positive for neutralizing antibodies. No infusion-related reactions occurred in patients who tested positive for TE-ADAs. Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ipilimumab with the incidences of antibodies to other products may be misleading.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION •Unresectable or metastatic melanoma: ∘3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of 4 doses. (2.1) •Adjuvant melanoma: ∘10 mg/kg administered intravenously over 90 minutes every 3 weeks for 4 doses, followed by 10 mg/kg every 12 weeks for up to 3 years or until documented disease recurrence or unacceptable toxicity. (2.2) •Permanently discontinue for severe adverse reactions. (2.3) 2.1 Recommended Dosing for Unresectable or Metastatic Melanoma The recommended dose of YERVOY is 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a maximum of 4 doses. In the event of toxicity, doses may be delayed, but all treatment must be administered within 16 weeks of the first dose [see Clinical Studies (14.1)]. 2.2 Recommended Dosing for Adjuvant Treatment of Melanoma The recommended dose of YERVOY is 10 mg/kg administered intravenously over 90 minutes every 3 weeks for 4 doses followed by 10 mg/kg every 12 weeks for up to 3 years [see Clinical Studies (14.2)]. In the event of toxicity, doses are omitted, not delayed. 2.3 Recommended Dose Modifications Table 1: Recommended Treatment Modifications for Immune-Mediated Adverse Reactions of YERVOY Target/Organ System Adverse Reaction (CTCAE v3) Treatment Modification Endocrine Symptomatic endocrinopathy Withhold YERVOY Resume YERVOY in patients with complete or partial resolution of adverse reactions (Grade 0 to 1) and who are receiving less than 7.5 mg prednisone or equivalent per day. •Symptomatic reactions lasting 6 weeks or longer •Inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day Permanently discontinue YERVOY Ophthalmologic Grade 2 through 4 reactions •not improving to Grade 1 within 2 weeks while receiving topical therapy or •requiring systemic treatment Permanently discontinue YERVOY All Other Grade 2 Withhold YERVOY Resume YERVOY in patients with complete or partial resolution of adverse reactions (Grade 0 to 1) and who are receiving less than 7.5 mg prednisone or equivalent per day. •Grade 2 reactions lasting 6 weeks or longer •Inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day •Grade 3 or 4 Permanently discontinue YERVOY 2.4 Preparation and Administration •Do not shake product. •Inspect parenteral drug products visually for particulate matter and discoloration prior to administration. Discard vial if solution is cloudy, there is pronounced discoloration (solution may have pale-yellow color), or there is foreign particulate matter other than translucent-to-white, amorphous particles. Preparation of Solution •Allow the vials to stand at room temperature for approximately 5 minutes prior to preparation of infusion. •Withdraw the required volume of YERVOY and transfer into an intravenous bag. •Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare a diluted solution with a final concentration ranging from 1 mg/mL to 2 mg/mL. Mix diluted solution by gentle inversion. •Store the diluted solution for no more than 24 hours under refrigeration (2°C to 8°C, 36°F to 46°F) or at room temperature (20°C to 25°C, 68°F to 77°F). •Discard partially used vials or empty vials of YERVOY. Administration Instructions •Do not mix YERVOY with, or administer as an infusion with, other medicinal products. •Flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP after each dose. •Administer diluted solution over 90 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein-binding in-line filter.
Use in special populations
8 USE IN SPECIFIC POPULATIONS •Lactation: Discontinue nursing during treatment with YERVOY. (8.2) 8.1 Pregnancy Risk Summary Based on data from animal studies and its mechanism of action, YERVOY can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. In animal reproduction studies, administration of ipilimumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in higher incidences of abortion, stillbirth, premature delivery (with corresponding lower birth weight), and higher incidences of infant mortality in a dose-related manner (see Data). The effects of ipilimumab are likely to be greater during the second and third trimesters of pregnancy. Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus. There is insufficient human data for YERVOY exposure in pregnant women. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. A Pregnancy Safety Surveillance Study has been established to collect information about pregnancies in women who have received YERVOY. Healthcare providers are encouraged to enroll patients or have their patients enroll directly by calling 1-844-593-7869. Data Animal Data In a combined study of embryo-fetal and peri-postnatal development, pregnant cynomolgus monkeys received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through parturition. No treatment-related adverse effects on reproduction were detected during the first two trimesters of pregnancy. Beginning in the third trimester, administration of ipilimumab at doses resulting in exposures approximately 2.6 to 7.2 times the human exposure at a dose of 3 mg/kg resulted in dose-related increases in abortion, stillbirth, premature delivery (with corresponding lower birth weight), and an increased incidence of infant mortality. In addition, developmental abnormalities were identified in the urogenital system of 2 infant monkeys exposed in utero to 30 mg/kg of ipilimumab (7.2 times the AUC in humans at the 3 mg/kg dose). One female infant monkey had unilateral renal agenesis of the left kidney and ureter, and 1 male infant monkey had an imperforate urethra with associated urinary obstruction and subcutaneous scrotal edema. Genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/−), the target for ipilimumab, appeared healthy and gave birth to healthy CTLA-4+/− heterozygous offspring. Mated CTLA-4+/− heterozygous mice also produced offspring deficient in CTLA-4 (homozygous negative, CTLA-4−/−). The CTLA-4−/− homozygous negative offspring appeared healthy at birth, exhibited signs of multiorgan lymphoproliferative disease by 2 weeks of age, and all died by 3 to 4 weeks of age with massive lymphoproliferation and multiorgan tissue destruction. 8.2 Lactation Risk Summary It is not known whether YERVOY is present in human milk. In monkeys, ipilimumab was present in milk (see Data). There are no data to assess the effects of YERVOY on milk production. Advise women to discontinue nursing during treatment with YERVOY and for 3 months following the final dose. Data In monkeys treated at dose levels resulting in exposures 2.6 and 7.2 times higher than those in humans at a 3 mg/kg dose, ipilimumab was present in milk at concentrations of 0.1 mcg/mL and 0.4 mcg/mL, representing a ratio of up to 0.3% of the steady-state serum concentration of the drug. 8.3 Females and Males of Reproductive Potential Contraception Based on its mechanism of action, YERVOY can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with YERVOY and for 3 months following the last dose of YERVOY. 8.4 Pediatric Use The safety and effectiveness of YERVOY have been established in pediatric patients 12 years and older. Use of YERVOY in this age group is supported by evidence from adequate and well-controlled studies of YERVOY in adults and population pharmacokinetic data demonstrating that the exposure at a dose of 3 mg/kg in the pediatric and adult populations is comparable. In addition, the tumor biology and course of advanced melanoma is sufficiently similar in adults and pediatric patients 12 years and older to allow extrapolation of data from adults to pediatric patients. The safety and effectiveness for pediatric patients less than 12 years of age has not been established [see Dosage and Administration (2.1), Clinical Pharmacology (12.3), and Clinical Studies (14)]. YERVOY was evaluated in a total of 45 pediatric patients across two clinical trials. In a dose-finding trial, 33 pediatric patients with relapsed or refractory solid tumors were evaluated. The median age was 13 years (range 2 to 21 years), and 20 patients were >12 years old. YERVOY was administered at doses of 1, 3, 5, and 10 mg/kg intravenously over 90 minutes every 3 weeks for 4 doses and then every 12 weeks thereafter until progression or treatment discontinuation. YERVOY was also evaluated in an open-label, single-arm, trial in 12 pediatric patients >12 years old (range 12 to 16 years) with previously treated or untreated, unresectable Stage 3 or 4 malignant melanoma. Patients received YERVOY 3 mg/kg (4 patients) or 10 mg/kg (8 patients) intravenously over 90 minutes every 3 weeks for 4 doses. Of the 17 patients >12 years of age with melanoma treated with YERVOY across both studies, two patients experienced objective responses including one partial response that was sustained for 16 months. There were no responses in patients with non-melanoma solid tumors. The overall safety profile of YERVOY in children and adolescents was consistent with the safety profile in adults. Pediatric Pharmacokinetics (PK) Based on a population PK analysis using available pooled data from 565 patients from 4 phase 2 adult studies (N=521) and 2 pediatric studies (N=44), body weight normalized clearance of ipilimumab is comparable between adult and pediatric patients. In pediatric patients with a dosing regimen of 3 mg/kg every 3 weeks, the model simulated geometric mean (CV%) steady-state serum peak and trough concentrations of ipilimumab were 65.8 (17.6%) and 20.7 (33.1%) mcg/mL (for 2 to 6 years old), 70.1 (19.6%) and 19.6 (42.9%) mcg/mL (for 6 to <12 years old), and 73.3 (20.6%) and 17.8 (50.8%) mcg/mL (for 12 years and older), which are comparable to those in adult patients. 8.5 Geriatric Use Of the 511 patients treated with YERVOY in Trial 1, 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years). Trial 2 did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. 8.6 Renal Impairment No dose adjustment is needed for patients with renal impairment [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dose adjustment is needed for patients with mild hepatic impairment (total bilirubin [TB] >1.0 to 1.5 times the upper limit of normal [ULN] or AST >ULN). YERVOY has not been studied in patients with moderate (TB >1.5 to 3.0 times ULN and any AST) or severe (TB >3 times ULN and any AST) hepatic impairment [see Clinical Pharmacology (12.3)].

Interactions

7 DRUG INTERACTIONS No formal pharmacokinetic drug interaction studies have been conducted with YERVOY.

More information

Category Value
Authorisation number BLA125377
Agency product number 6T8C155666
Orphan designation No
Product NDC 0003-2328,0003-2327
Date Last Revised 20-10-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1657005
Marketing authorisation holder E.R. Squibb & Sons, L.L.C.
Warnings WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions [see Dosage and Administration (2.3) ]. Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy, and evaluate clinical chemistries including liver function tests, adrenocorticotropic hormone (ACTH) level, and thyroid function tests, at baseline and before each dose [see Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5)]. WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS See full prescribing information for complete boxed warning. YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. (2.3) Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests, adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline and before each dose. (5.1, 5.2, 5.3, 5.4, 5.5)