CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`
`APPLICATION NUMBER:
`202788Orig1s000
`
`
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`

`

`
`
`
`
`NDA: 202788
`
`CLINICAL PHARMACOLOGY REVIEW
`
`Submission Date(s): March 4, 2011
`
`Proposed Brand Name
`
`SUBSYSTM
`
`Generic Name
`
`Fentanyl Sublingual Spray
`
`Reviewer
`
`Team Leader
`
`OCP Division
`
`OND division
`
`Sponsor
`
`Wei Qiu, Ph. D.
`
`Yun Xu, Ph.D.
`
`DCPII
`
`DAAAP
`
`Insys Therapeutics, Inc
`
`Relevant IND(s)
`
`72,411
`
`Submission Type
`
`505(b)(2), original
`
`Formulation; Strength(s) Sublingual Spray for transmucosal delivery; 100, 200, 400,
`600, and 800 mcg
`
`Dosing regimen
`
`Initial dose of 100 mcg; then titrate to a tolerable dose
`
`Management of breakthrough cancer pain in patients with
`malignancies who are already receiving and who are
`tolerant to opioid therapy for their underlying cancer
`
`Indication
`
`
`
`
`Table of Contents
`
` 1
`
` Executive Summary ................................................................................................................. 2
`1.1 Recommendation .............................................................................................................. 2
`1.2 Phase IV Commitments .................................................................................................... 2
`1.3 Summary of Clinical Pharmacology and Biopharmaceutics Findings .............................. 2
`2 Question Based Review........................................................................................................... 5
`2.1 General Attributes of the Drug .......................................................................................... 5
`2.2 General Clinical Pharmacology......................................................................................... 7
`2.3
`Intrinsic Factors................................................................................................................. 9
`2.4 Extrinsic Factors.............................................................................................................. 11
`
`
`
`Reference ID: 3051528
`
`1
`
`

`

`2.5 General Biopharmaceutics.............................................................................................. 14
`2.6 Analytical Section............................................................................................................ 16
`3 Detailed Labeling Recommendations .................................................................................... 16
`4 Appendix................................................................................................................................. 20
`4.1
`Filing memo..................................................................................................................... 20
`4.2
`Individual Study Synopsis ............................................................................................... 22
`
` Executive Summary
`
`1.1 Recommendation
`
`
`
` 1
`
`
`
`
`The Office of Clinical Pharmacology/Division of Clinical Pharmacology 2 (OCP/DCP-2)
`has reviewed the NDA 202788 submitted on March 4, 2011 and finds it acceptable from
`clinical pharmacology perspective.
`
`1.2 Phase IV Commitments
`
`
`None.
`
`
`1.3 Summary of Clinical Pharmacology and Biopharmaceutics Findings
`
`
`Insys submitted this 505(b)(2) NDA for Fentanyl Sublingual Spray, 100 mcg, 200 mcg,
`400 mcg, 600 mcg, and 800 mcg for the management of breakthrough cancer pain
`
` who are already receiving and who are tolerant
`to around-the-clock opioid therapy for their underlying persistent cancer pain. Sponsor
`proposed to rely on the Agency’s previous finding of the safety and efficacy of Actiq®
`fentanyl citrate oral transmucosal lozenge (NDA 020747).
`
`Fentanyl is an opioid agonist and available as injectable, transdermal, nasal spray, and
`transmucosal (oral transmucosal lozenge (Actiq® NDA 20747), buccal tablet (Fentora®
`NDA 21947), buccal film (Onsolis®, NDA 22266), and sublingual tablet (Abstral® NDA
`22510)) formulations. This current submission is for fentanyl sublingual spray.
`
`The clinical and clinical pharmacology database for this NDA consists of one
`efficacy/safety study (INS-05-001), one open-label safety study (INS-06-007), and four
`clinical pharmacology studies. These clinical pharmacology studies include (1) pilot
`ascending single dose PK study in healthy male subjects (FNY-P4-270), (2) single dose
`
`
`
`Reference ID: 3051528
`
`2
`
`(b)
`(4)
`
`

`

`relative bioavailability study in comparison to Actiq® transmucosal lozenge and Fentanyl
`Citrate Injection in healthy subjects (INS-06-003), (3) a single dose crossover study to
`evaluate Fentanyl Sublingual Spray dose proportionality and to evaluate the potential
`effects of temperature and pH on relative bioavailability in healthy subjects (INS-06-004),
`and (4) a single dose PK study in opioid tolerant cancer patients with and without
`mucositis (Study INS-09-011). This review focused on Studies INS-06-003, INS-06-004,
`and INS-09-011. The pilot study FNY-P4-270 was not thoroughly reviewed
`
`and the dose levels were further studied
`
`in a more comprehensive Study INS-06-004.
`
`Absolute Bioavailability:
`The mean absolute bioavailability of Fentanyl Sublingual Spray 400 mcg in comparison
`to fentanyl citrate intravenous injection 100 mcg was 72.1% and 75.6% based dose
`normalized AUClast and AUCinf values, respectively.
`
`Relative Bioavailability as Compared to Actiq®:
`Single dose of the 1 x 400 mcg fentanyl sublingual spray exhibits 34% and 36% greater
`Cmax and AUCinf values as compared to Actiq® 1 x 400 mcg under fasting condition.
`The point estimates of the geometric mean ratio (Fentanyl Sublingual Spray 400
`mcg/Actiq® 400 mcg) for Cmax, AUClast, and AUCinf are 133.67%, 133.44% and
`136.27%, respectively. The corresponding 90% confidence intervals are 119.67% –
`149.31%, 121.47% – 146.58%, and 121.21% – 153.20%, respectively.
`
`Dose Proportionality:
`The systemic exposure of fentanyl increased in an approximate dose proportional
`manner over the 100 mcg – 800 mcg range under fasting condition based on the
`ANOVA and linear regression of the dose-normalized Cmax, AUClast, and AUCinf
`values. When each lower strength (100 mcg, 200 mcg, 400 mcg, and 600 mcg) was
`compared to the highest strength 800 mcg, ANOVA analysis showed that for
`Cmax/Dose, all the 90% confidence interval fell within the 80-125% range except for the
`600 mcg strength (lower bound of the 90% confidence interval was 79.47%). For
`AUCinf/Dose, all 90% confidence interval fell within the 80-125% limit except for the 100
`mcg strength (lower bound of the 90% confidence interval was 77.44%). For
`AUClast/Dose, the 90% confidence interval for the 400 mcg and 600 mcg fell within the
`
`
`
`Reference ID: 3051528
`
`3
`
`(b) (4)
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`

`

`80-125% while the lower bounds for the 100 mcg and 200 mcg were 67.95% and
`76.95%, respectively.
`
`Linear regression results showed that the slopes for Cmax/Dose and AUCinf/Dose were
`not significant different from 0. The value of the slope for AUClast/Dose (2.89 E-04) was
`2.89 E-04 significant different from zero, however, the value is very close to zero.
`
`
`Effect of pretreatment of oral cavity with beverages which have different
`temperatures and pH levels:
`The pretreatment of oral cavity with hot water did not affect the PK of fentanyl sublingual
`spray. The Cmax, AUClast, AUCinf values after pretreatment with hot water were
`bioequivalent to the reference (no pretreatment) based on the 90% confidence interval
`(81.70% – 114.76% for Cmax; 83.71% – 113.03% for AUClast; 85.87% – 119.38% for
`AUCinf) falling within the 80-125% limits. The cold water decreased the AUC values of
`fentanyl by 5 to 8% and had no effect on fentanyl Cmax values. The point estimate of
`the geometric mean ratio (cold water/no pretreatment) for Cmax, AUClast and AUCinf
`are 100.08%, 94.78%, and 92.23%, respectively. The corresponding 90% confidence
`interval is 83.07% – 120.58%, 75.95% – 118.29%, and 73.38% – 115.93%, respectively.
`
`The pretreatment of oral cavity with low pH beverage decreased fentanyl Cmax by 17%
`but had no effect on the AUC values. The point estimate of the geometric mean ratio
`(low pH/no pretreatment) for Cmax, AUClast, and AUCinf are 83.26%, 91.93%, and
`95.68%, respectively. The corresponding 90% confidence intervals are 70.81% -
`97.90%, 81.70% - 103.44%, and 84.39% - 108.49%, respectively. The pretreatment of
`oral cavity with high pH beverage increased fentanyl Cmax, AUClast, and AUCinf by
`23%, 19%, and 18%, respectively.
`
`Effect of Mucositis:
`In opioid tolerant cancer patients with Grade 1 mucositis, mean fentanyl Cmax and
`AUClast values were 73% and 52% greater than the patients without mucositis following
`the administration of 100 mcg fentanyl sublingual spray. In the two patients with Grade 2
`mucositis (subject 804 and 910), fentanyl Cmax values were 7-fold and 4-fold greater
`than the mean Cmax values obtained in patients without mucositis for subject 804 and
`subject 910, respectively. The corresponding fentanyl AUClast values were 17-fold and
`
`
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`Reference ID: 3051528
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`4
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`

`

`3-fold higher than the values in patients without mucositis. For patients with Grade 2 and
`more severe mucositis, fentanyl sublingual spray should be avoided. Dose reduction
`should be done for the patients with Grade 1 mucositis.
`
`
` Question Based Review
`
` 2
`
`
`
`2.1 General Attributes of the Drug
`
`
`1. What are the highlights of the chemistry and physical-chemical properties of the drug
`substance, and the formulation of the drug product?
`
`
`
`Table 1 Physical-Chemical Properties of Fentanyl Drug Substance
`Drug Name
`Fentanyl
`Chemical Name N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]propanamide
`Structure
`
`Molecular
`Formula
`Molecular
`Weight
`Solubility
`
`
`
`C22H28N2O
`
`336.47
`
`Aqueous – practically insoluble; non-aqueous – freely soluble in
`ethanol and methanol; soluble in dilute acids and in methylene
`chloride
`
`
`Fentanyl Sublingual Spray is a clear, colorless solution in a clear, colorless glass single-
`dose stoppered vial assembled into a delivery device to be used as a sublingual spray.
`The Fentanyl Sublingual Spray is packaged as a unit dose spray device designed to
`deliver
` of fentanyl solution containing fentanyl doses 100 mcg, 200 mcg, 400
`mcg, 600 mcg, and 800 mcg. The composition of fentanyl sublingual spray is shown in
`Table 2.
`
`
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`Reference ID: 3051528
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`5
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`(b) (4)
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`

`

`Sponsor stated that throughout clinical development, the composition of the fentanyl
`
`solution formulation has remained unchanged. It was also stated that the to—be—marketed
`
`formulation is identical to the formulations used in all the clinical studies.—
`. The remaining studies used the
`
`unit-dose spray device.
`
`Table 2 Composition of Fentanyl Sublingual Spray, 100. 200, 400, 600, and 800 mcg
`
`Quantity per 100 pL
`
`Quality
`component Standard
`
`1 mg/mL 2 mg/mL 4 mg/mL 6 mg/mL 8 mg/mL
`(100 pg
`(200 pg
`(400 pg
`(600 pg
`(800 pg
`dose)
`dose)
`dose)
`dose)
`dose)
`
`
`
`A t'
`
`100 pg
`
`200 pg
`
`400 pg
`
`600 pg
`
`800 pg
`
`Fentanyl base
`
`Dehydrated
`
`Propylene
`glycol
`
`L-Menthol
`
`water
`
`2. What are the proposed mechanism(s) of action and therapeutic indication(s)?
`
`Fentanyl is a pure opioid agonist whose principal therapeutic acfion is analgesia.
`
`It is indicated for the management of breakthrough wncer pain in patients—
`— who are already receiving and who are tolerant to opioid therapy
`
`for their underlying persistent cancer pain. Patients must remain on around-the-clock
`
`opioids when taking fentanyl sublingual spray.
`
`3. What are the proposed dosage(s) and route(s) of administration?
`
`Reference ID: 3051528
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`

`

`The dosage is sublingual spray for sublingual transmucosal absorption.
`
`2.2 General Clinical Pharmacology
`
`
`
`1. What is known about the PK characteristics of fentanyl in general?
`
`Fentanyl is highly lipophilic. The plasma protein binding is 80-85%. The main binding
`protein is alpha-1-acid glycoprotein, but both albumin and lipoproteins contribute to
`some extent. Fentanyl is metabolized in the liver and in the intestinal mucosa to
`norfentanyl by cytochrome P450 3A4. Norfentanyl was not found to be
`pharmacologically active in animal studies. Fentanyl is primarily (more than 90%)
`eliminated by biotransformation to N-dealkylated and hydroxylated inactive metabolites.
`Less than 7% of the dose is excreted unchanged in the urine, and only about 1% is
`excreted unchanged in feces. The metabolites are mainly excreted in the urine.
`
`2. Were the active moieties in the plasma appropriately identified and measured to
`assess pharmacokinetics?
`
`The activity is primarily due to the parent compound fentanyl. Fentanyl concentrations
`were measured in all the clinical pharmacology studies.
`
`3. Is the Dose Proportionality of Fentanyl Sublingual Spray established?
`
`The fentanyl pharmacokinetics of five different strengths including 100 mcg, 200 mcg,
`400 mcg, 600 mcg, and 800 mcg were determined in a single dose crossover study in
`healthy subjects under fasted conditions (Study INS-06-004 Part A). The fentanyl
`concentration-time profiles are shown in Figure 1 and pharmacokinetic parameters
`along with statistical analysis results are shown in Table 3.
`
`Fentanyl plasma concentration-time profiles exhibited similar shape for all strengths. The
`systemic exposure of fentanyl increased in an approximate dose proportional manner
`over the 100 mcg – 800 mcg range under fasting condition based on the ANOVA and
`linear regression of the dose-normalized Cmax, AUClast, and AUCinf values. When
`each lower strength (100 mcg, 200 mcg, 400 mcg, and 600 mcg) was compared to the
`
`
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`Reference ID: 3051528
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`7
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`

`

`highest strength 800 mcg, ANOVA analysis showed that for Cmax/Dose, all the 90%
`confidence interval fell within the 80-125% range except for the 600 mcg strength (lower
`bound of the 90% confidence interval was 79.47%). For AUCinf/Dose, all 90%
`confidence interval fell within the 80-125% limit except for the 100 mcg strength (lower
`bound of the 90% confidence interval was 77.44%). For AUClast/Dose, the 90%
`confidence intervals for the 400 mcg and 600 mcg fell within the 80-125% while the
`lower bounds for the 100 mcg and 200 mcg were 67.95% and 76.95%, respectively.
`
`Linear regression results showed that the slopes for Cmax/Dose and AUCinf/Dose were
`not significant different from 0. The value of slope for AUClast/Dose (2.89 E-04) was
`significant different from zero, however, it is very close to zero. Therefore, the linear
`regression results confirmed the approximate dose proportionality among different doses
`from 100 mcg to 800 mcg.
`
`Figure 1 Mean Fentanyl Concentration-Time Profiles after Administration of Single
`Doses of Fentanyl Sublingual Spray 100 mcg (Treatment A), 200 mcg (Treatment B),
`400 mcg (Treatment C), 600 mcg (Treatment D), and 800 mcg (Treatment E) from Study
`INS-06-004
`
`
`
`
`
`A: fentanyl sublingual spray 100 mcg; B: fentanyl sublingual spray 200 mcg; C: fentanyl sublingual spray 400 mcg; D:
`fentanyl sublingual spray 600 mcg; E: fentanyl sublingual spray 800 mcg
`
`
`
`
`
`Reference ID: 3051528
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`8
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`

`

`Table 3 Mean (%CV) Pharmacokinetic Parameters of Fentanyl following the administration of
`single doses of 100 mcg, 200 mcg, 400 mcg, 600 mcg, and 800 mcg sublingual spray (Study
`INS-06-004)
`
`
`Parameter
`
`Treatment A:
`100 mcg
`Mean
`(%CV)
`1.25
`(0.17, 2.05)
`0.202
`(28.35)
`
`n
`
`42
`
`42
`
`Treatment B:
`200 mcg
`Mean
`(%CV)
`1.25
`(0.17, 2.03)
`0.378
`(29.69)
`
`n
`
`45
`
`45
`
`Treatment C:
`400 mcg
`Mean
`(%CV)
`1
`(0.17, 2.03)
`0.800
`(27.66)
`
`n
`
`42
`
`42
`
`Treatment D:
`600 mcg
`Mean
`(%CV)
`0.67
`(0.083, 2)
`1.17
`(32.48)
`
`n
`
`46
`
`46
`
`Treatment E:
`800 mcg
`Mean
`(%CV)
`0.69
`(0.17, 4)
`1.61
`(37.22)
`
`n
`
`44
`
`44
`
`Tmax (hr)*
`
`Cmax
`(ng/mL)
`AUClast(ng/
`mL.hr)
`AUCinf
`(ng/mL.hr)
`T1/2 (hr)
`
`42
`
`38
`
`0.9776
`(49.82)
`
`1.245
`(53.82)
`
`45
`
`42
`
`1.985
`(40.93)
`
`2.475
`(46.48)
`
`42
`
`42
`
`38
`
`5.25 (89.92)
`
`42
`
`8.45 (77.94)
`
`42
`
`4.643
`(44.53)
`
`5.342
`(44.16)
`
`11.03
`(62.20)
`24 (12, 36)
`
`46
`
`45
`
`45
`
`46
`
`6.682
`(32.46)
`
`7.446
`(31.54)
`
`10.64
`(41.73)
`36 (24, 36)
`
`44
`
`44
`
`44
`
`44
`
`9.450
`(36.62)
`
`10.38
`(35.60)
`
`11.99
`(32.15)
`36 (24, 36)
`
`Tlast (hr)*
`
`42
`
`10 (2, 36)
`
`45
`
`16 (8, 36)
`
`42
`
`Statistical Analysis: Geometric Mean Ratio % (Test/Reference) (90% CI)
`Ln (Cmax/D)
`100.9
`98.27
`99.26
`92.70
`(92.03, 110.62)
`(90.59, 106.60)
`(88.15, 111.78)
`(79.47, 108.14)
`76.49
`83.74
`94.82
`100.28
`(67.95, 86.10)
`(76.95, 91.13)
`(83.93, 107.12)
`(87.95, 114.33)
`
`86.12
`(77.44, 95.77)
`
`92.31
`(85.58, 99.57)
`
`100.33
`(88.39, 113.87)
`
`100.58
`(88.58, 114.21)
`
`Ln
`(AUClast/D)
`Ln
`(AUCinf/D)
`*median (min, max)
`
`
`Reference
`
`Reference
`
`Reference
`
`2.3
`
`Intrinsic Factors
`
`
`1. What is the pediatric plan?
`
`
`
`
`
`
`Reference ID: 3051528
`
`
`
`
`
`
`
`
`
`
`
`9
`
`(b) (4)
`
`

`

`
`2. How do oral mucositis affect the pharmacokinetics of fentanyl sublingual spray?
`
`The effect of oral mucositis was assessed by comparing fentanyl pharmacokinetics of a
`single 100 mcg dose of fentanyl sublingual spray in opioid tolerant cancer patients with
`or without oral mucositis (Study INS-09-011). Fentanyl plasma concentration-time
`profiles are shown in Figure 2 and fentanyl pharmacokinetics and statistical analysis
`results are summarized in Table 4.
`
`In opioid tolerant cancer patients with Grade 1 mucositis (N = 7), mean fentanyl Cmax
`and AUClast values were 73% and 52% greater than the patients without mucositis (N =
`8) following the administration of 100 mcg fentanyl sublingual spray. In the two patients
`with Grade 2 mucositis (subjects 804 and 910), fentanyl Cmax values were 7-fold and 4-
`fold greater than the mean Cmax values obtained in patients without mucositis for
`subject 804 and subject 910, respectively. The corresponding fentanyl AUClast values
`were 17-fold and 3-fold higher than the values in patients without mucositis. For patients
`with Grade 2 and more severe mucositis, fentanyl sublingual spray should be avoided.
`Dose reduction should be done for the patients with Grade 1 mucositis.
`
`
`Figure 2. Fentanyl plasma concentration-time profiles in subjects without mucositis (left panel)
`and subjects with mucositis Grade 1 or 2 (right panel) from Study INS-09-011
`
`
`
`
`
`
`Reference ID: 3051528
`
`
`
`10
`
`

`

`Table 4 Mean (%CV) PK parameters of fentanyl in cancer patients with mucositis and without
`mucositis following the administration of a single 100 mcg dose of Fentanyl Sublingual Spray
`(Study INS-09-011)
`PK Parameter
`
`Non-mucositis
`(n=8)
`
`Mucositis Grade 1
`(n=7)
`
`Mucositis Grade 2
`(N = 2)
`Subject 804
`Subject 910
`0.5
`0.25
`1.81
`1.07
`15.78
`2.56
`
`0.38 (0.25, 2.00)
`0.26 (55.94)
`0.91 (14.67)
`
`0.25 (0.25, 2.00)
`0.45 (96.26)
`1.38 (44.80)
`
`Tmax*(hr)
`Cmax (ng/mL)
`AUClast (ng/mL.hr)
`*: median (min, max)
`
`Reviewer’s Comments:
`
`Fentanyl is mainly metabolized by CYP3A4 and inhibition of CYP3A4 will result in an
`increase in the systemic exposure of fentanyl. In Study INS-09-011, concomitant
`medications (prescription, over-the-counter, vitamin, or herbal substances) were
`prohibited for the duration of the study. As was expected for this patient population, all
`patients were taking one or more concomitant medications/supplements. For example,
`subject 804 (with Grade 2 mucositis) was taking calcium, ensure, erbitux, morphine,
`vitamin D and carboplatin taxotere. However, these medications/supplements are not
`known CYP3A4 inhibitors. Therefore, available data did not suggest that the increased
`exposure of fentanyl in this patient was due to the inhibition of CYP3A4. The only
`reported adverse events were mild burning sensation in the oral mucosa in two subjects
`(subject 904 with Grade 1 mucositis and subject 910 with grade 2 mucositis).
`
`2.4 Extrinsic Factors
`
`
`
`1. Does the pretreatment of oral cavity with hot or cold water affect the absorption of
`fentanyl from sublingual spray?
`
`
`The effects of temperature of the oral cavity on the pharmacokinetics of fentanyl
`sublingual spray 200 mcg was analyzed by comparing the fentanyl PK parameters
`obtained following pretreatment with a cold or hot water to the fentanyl PK parameters
`for the reference treatment (sublingual dosing following no pretreatment) (Study INS-06-
`004 Part B). The cold water was cooled to the temperature of refrigerated ice water. The
`
`
`
`Reference ID: 3051528
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`11
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`

`

`hot water was heated to the temperature of hot coffee or tea. Fentanyl pharmacokinetic
`parameters and statistical analysis results are summarized in Table 5.
`
`The pretreatment of oral cavity with hot water did not affect the PK of fentanyl sublingual
`spray. The Cmax, AUClast, AUCinf values after pretreatment with hot water were
`bioequivalent to the reference (no pretreatment) based on the 90% confidence interval
`(81.70% – 114.76% for Cmax; 83.71% – 113.03% for AUClast; 85.87% – 119.38% for
`AUCinf) falling within the 80-125% limits. The cold water decreased the AUC values of
`fentanyl by 5 to 8% and had no effect on fentanyl Cmax values. The point estimate of
`the geometric mean ratio (cold water/no pretreatment) for Cmax, AUClast and AUCinf
`are 100.08%, 94.78%, and 92.23%, respectively. The corresponding 90% confidence
`intervals are 83.07% – 120.58%, 75.95% – 118.29%, and 73.38% – 115.93%,
`respectively.
`
`Table 5 Mean (%CV) Pharmacokinetic Parameters of Fentanyl after Administration of
`200 mcg of Fentanyl Sublingual Spray after Pretreatment of the Oral Cavity with Cold
`Water (Test), Hot Water (Test), and no Pretreatment (Reference) (Study INS-06-004)
`PK Parameter
`Fentanyl Sublingual
`Fentanyl Sublingual
`Fentanyl Sublingual
`Spray 200 mcg
`Spray 200 mcg
`Spray 200 mcg
`(no pretreatment)
`(pretreatment with cold
`(pretreatment with hot
`water)
`water)
`
`
`
`Mean (%CV)
`Mean (%CV)
`
`n
`
`n
`
`n
`
`Mean (%CV)
`
`Tmax (hr)*
`
`11
`
`11
`
`1.5 (0.33, 4)
`
`12
`
`1.22 (0.17, 1.5)
`
`0.325 (30.00)
`
`1.983 (33.14)
`
`11
`
`11
`
`2.468 (43.60)
`
`11
`
`11
`
`11
`
`11
`
`9
`
`9
`
`Cmax (ng/mL)
`
`AUClast
`(ng/mL.hr)
`AUCinf (ng/mL.hr)
`
`T1/2 (hr)
`
`Ln (Cmax)
`
`
`
`Reference ID: 3051528
`
`0.324 (39.50)
`
`2.005 (34.36)
`
`2.459 (37.11)
`
`8.43 (58.76)
`9.90 (72.84)
`
`
`Statistical Analysis: Geometric Mean Ratio (Test/Reference) (90% CI)
`100.08 [83.07, 120.58]
`96.88 [81.79, 114.76]
`Reference
`
`12
`
`12
`
`10
`
`10
`
`1.375 (0.33, 2)
`
`0.336 (26.24)
`
`1.997 (35.20)
`
`2.427 (40.49)
`
`8.00 (65.21)
`
`12
`
`

`

`Ln (AUClast)
`Ln (AUCinf)
`*median (min, max)
`Statistical analysis based on n=11 for Cmax and AUClast for both cold and hot beverage and n = 9 for AUCinf for cold
`beverage and n = 10 for AUCinf for hot beverage
`
`94.78 [75.95, 118.29]
`92.23 [73.38, 115.93]
`
`97.27 [83.71, 113.03]
`101.25 [85.87, 119.38]
`
`Reference
`Reference
`
`
`
`2. Does the pretreatment of oral cavity with low and high pH beverages affect the
`absorption of fentanyl from sublingual spray?
`
`The effects of pH of the oral cavity on the pharmacokinetics of fentanyl sublingual spray
`200 mcg was analyzed by comparing the fentanyl PK parameters obtained following
`pretreatment with low or high pH beverages to the fentanyl PK parameters for the
`reference treatment (sublingual dosing following no pretreatment) (Study INS-06-004
`Part B). The low pH beverage was a commercially available carbonated drink i.e., Coca-
`Cola or Sprite. The high pH beverage was from a solution of ½ tsp of sodium
`bicarbonate dissolved in 4 ounces of room temperature water. Fentanyl pharmacokinetic
`parameters and statistical analysis results are summarized in Table 6.
`
`The pretreatment of oral cavity with low pH beverage decreased fentanyl Cmax by 17%
`but had no effect on the AUC values. The point estimate of the geometric mean ratio
`(low pH/no pretreatment) for Cmax, AUClast, and AUCinf are 83.26%, 91.93%, and
`95.68%, respectively. The corresponding 90% confidence intervals are 70.81% -
`97.90%, 81.70% - 103.44%, and 84.39% - 108.49%, respectively. The pretreatment of
`oral cavity with high pH beverage increased fentanyl Cmax, AUClast, and AUCinf by
`23%, 19%, and 18%, respectively.
`
`
`
`
`Table 6 Mean (%CV) Pharmacokinetic Parameters of Fentanyl after Administration of
`200 mcg of Fentanyl Sublingual Spray after Pretreatment of the Oral Cavity with Low pH
`Beverage (Test), High pH Beverage (Test), and no Pretreatment (Reference) (Study
`INS-06-004)
`PK Parameter
`
`Fentanyl Sublingual
`Spray 200 mcg
`
`Fentanyl Sublingual
`200 mcg
`
`Fentanyl Sublingual
`Spray 200 mcg
`
`
`
`Reference ID: 3051528
`
`13
`
`

`

`(Pretreatment with Low
`pH Beverage)
`
`n
`
`Mean (%CV)
`
`13
`
`13
`13
`
`2 (1, 2.07)
`
`0.291 (36.99)
`1.833 (54.79)
`
`(Pretreatment with
`High pH Beverage)
`
`Mean (%CV)
`
`1 (0.33, 2)
`
`n
`
`13
`
`13
`13
`
`0.409 (39.25)
`2.316 (44.08)
`
`(no pretreatment)
`
`
`n
`
`Mean (%CV)
`
`12
`
`12
`12
`
`1.375 (0.33, 2)
`
`0.336 (26.24)
`1.997 (35.20)
`
`12
`
`12
`
`2.746 (46.40)
`
`10
`
`Tmax (hr)*
`
`Cmax (ng/mL)
`AUClast
`(ng/mL.hr)
`AUCinf (ng/mL.hr)
`
`T1/2 (hr)
`
`2.427 (40.49)
`2.368 (56.62)
`
`
`8.00 (65.21)
`10
`8.60 (63.61)
`12
`8.19 (72.01)
`12
`Statistical Analysis: Geometric Mean Ratio % (Test/Reference) (90% CI)
`83.26 [70.81, 97.90]
`123.08 [107.98, 140.29]
`Reference
`91.93 [81.70, 103.44]
`119.08 [101.60, 139.58]
`Reference
`95.68 [84.39, 108.49]
`118.56 [104.16, 134.95]
`Reference
`
`Ln (Cmax)
`Ln (AUClast)
`Ln (AUCinf)
`*median (min, max)
`Statistical analysis based on n=12 for Cmax and AUClast for both low and high pH beverages and n=10 for AUCinf for low
`pH beverage and n=9 for AUCinf for high pH beverage
`
`
`2.5 General Biopharmaceutics
`
`
`1. Is the proposed to-be-marketed formulation the same as the clinical formulation?
`
`Throughout clinical development, the composition of the fentanyl solution formulation
`has remained unchanged.
` The proposed product is single-dose spray device with five strengths, 100, 200,
`400, 600, and 800 mcg. All five strengths were used in the clinical studies.
`
`2. What is the absolute bioavailability of fentanyl sublingual spray? Is the proposed
`fentanyl sublingual spray bioequivalent to the reference product, Actiq® transmucosal
`lozenge?
`
`The absolute bioavailability fentanyl sublingual spray 400 mcg to fentanyl citrate
`intravenous injection 100 mcg and the relative bioavailability to Actiq® 400 mcg were
`determined in a single dose crossover study in healthy subjects under fasted condition
`
`
`
`Reference ID: 3051528
`
`14
`
`(b) (4)
`
`

`

`(Study INS-06-003). Fentanyl pharmacokinetic parameters and statistical analysis
`results are shown in Table 7.
`
`The mean absolute bioavailability of Fentanyl Sublingual Spray 400 mcg was 72.1% and
`75.6% based dose normalized AUClast and AUCinf values, respectively. For the
`reference product Actiq®, the absolute bioavailability was 54.0% and 51.1% based on
`dose normalized AUClast and AUCinf, respectively.
`
`Single dose of the 1 x 400 mcg fentanyl sublingual spray exhibits 34% and 36% greater
`Cmax and AUCinf values as compared to Actiq® 1 x 400 mcg under fasting condition.
`The point estimates of the geometric mean ratio (Fentanyl Sublingual Spray 400
`mcg/Actiq® 400 mcg) for Cmax, AUClast, and AUCinf are 133.67%, 133.44% and
`136.27%, respectively. The corresponding 90% confidence intervals are 119.67 –
`149.31%, 121.47 – 146.58%, and 121.21 – 153.20%, respectively. Therefore, fentanyl
`sublingual spray is not bioequivalent to the reference product, Actiq®.
`
`Table 7 Mean (%CV) Pharmacokinetic Parameters of Fentanyl and Statistical Analysis
`(Study INS-06-003)
`PK Parameter
`
`400 mcg
`Fentanyl Sublingual
`Spray
`
`Mean (%CV)
`
`n
`
`400 mcg
`Actiq® (fentanyl citrate) oral
`transmucosal lozenge
`
`Mean (%CV)
`
`n
`
`100 mcg
`Fentanyl Citrate
`Injection
`
`n Mean (%CV)
`
`Tmax (hr)*
`
`21
`
`21
`
`2 (0.5, 2.12)
`
`
`
`1.5 (0.17, 2.00)
`
`0.813 (31.01)
`
`4.863 (35.12)
`
`21
`
`21
`
`--
`
`--
`
`
`
`21 1.688 (24.38)
`
`21
`
`21
`
`Cmax (ng/mL)
`
`AUClast
`(ng/mL.hr)
`AUCinf (ng/mL.hr)
`
`0.607 (30.55)
`
`3.677 (39.17)
`
`4.182 (39.93)
`
`7.89 (47.15)
`9.98 (44.14)
`
`
`Statistical Analysis: Geometric Mean Ratio (Fentanyl Sublingual spray/Actiq®) (90% CI)
`Cmax
`133.67 [119.67, 149.31]
`
`16
`
`5.761 (33.26)
`
`18
`
`16 1.758 (21.74)
`
`T1/2 (hr)
`
`16
`
`18
`
`16
`
`4.50 (43.02)
`
`
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`Reference ID: 3051528
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`15
`
`

`

`AUClast
`AUCinf
`* median (min, max)
`
`
`2.6 Analytical Section
`
`133.44 [121.47, 146.58]
`136.27 [121.21, 153.20]
`
`
`1. How is fentanyl measured in the plasma in the clinical pharmacology and
`biopharmaceutics studies?
`
` A
`
` validated LC-MS/MS method was used for the determination of fentanyl in human
`plasma. The established lower limit of quantitation (LLOQ) was 0.025 ng/mL.
`
`
`Table 8 Summary of the bioanalytical method for determination of plasma fentanyl
`concentration
`Study
`Method
`INS-06-
`LC-
`003
`MS/MS
`
`LLOQ
`0.025
`ng/mL
`
`INS-06-
`004
`
`LC/MS-
`MS
`
`INS-09-
`011
`
`LC/MS-
`MS
`
`0.025
`ng/mL
`
`0.025
`ng/mL
`
`QCs
`0.300,
`0.075,
`0.750, 1.50, and
`3.75 ng/mL
`0.249,
`0.075,
`0.498, 1.50, and
`3.75 ng/mL
`0.075
`ng/mL,
`0.300,
`0.750,
`1.50, and 3.75
`ng/mL
`
`Accuracy
`-4.3%
`0.3%
`
`to
`
`Precision
`2.1%
`8.3%
`
`-4.0%
`8.8%
`
`-1.1%
`3.3%
`
`to
`
`1.7%
`8.3%
`
`to
`
`2.2%
`4.6%
`
`to
`
`to
`
`to
`
`
`
` 3
`
` Detailed Labeling Recommendations
`
`(RED Strikeout text should be removed from labeling; Blue double underlined text should be
`added to labeling)
`
`The following labeling recommendations are preliminary. As of today (November 30, 2011),
`labeling negotiation with sponsor is still ongoing.
`
`
`
`
`
`
`16
`
`Reference ID: 3051528
`
`(b) (4)
`
`3 Page(s) of Draft Labeling has been Withheld in Full as B4 (CCI/TS)
`immediately following this page
`
`

`

`20
`
` Appendix
`
`4.1 Filing memo
`
`
`
`
`
`
` 4
`
`
`
`
`
`Reference ID: 3051528
`
`(b) (4)
`
`

`

`CLINICAL PHARVIACOLOGY AND BIOPHARV‘IACEITTICS
`
`FILING FOR.\-I/CHECKLIST FOR NDA/BLA or Supplement
`
`
`
`Office of Clinical Pharmacology
`
`Xew Drug Application Filing and Review Form
`General Information About the Submission
`
`Information
`Information
`
`NDArBLA Number
`zones
`Proposed Brand Name Sinsrsm
`
`OCP Division (I. II III. IV. V]
`II
`Generic Name
`Fentanvl Sublingual Sprav
`
`Medical Division
`DAAP
`Drug Class
`Opiod
`OCP Reviewer
`“'ei Qiu
`Indication(s)
`lIanagement of breakthrough cancer pain in
`patients with malignancies who are already
`receiving and who are tolerant to opioid therapy
`
`for their underlyina cancer
`OCP Team Leader Sublingual spray 100, 200. 400, 600. and SUI] mcg Yun Xu Dosage Form
`
`
`
`Dosing Regimen Initial dose of 100 mcg; titrate to a tolerable dose
`
`Pharmacometrics Reviewer
`
` Date of Submission March 4, 20]] Route of Sublingual spray for transmucosal delivery
`
`
`Administration
`SponsorNov 30, 2011Estimated Due Date of OCP Review Insys Therapeutics, Inc.
`
`
`
`
`Medical Division Due Date Standard
`Prio rity Classification
`PDUFA Due Date
`
`
`
`
`
` Jan 4, 2012
`
`
`
`
`
`
`
`
`NNNW
`
`
`C‘lin. Pharm. and Biopharm. Information
`“X" if included
`Numb er of
`Number of
`Critical Comments If any
`studies
`studies
`at filing
`
`submitted
`reviewed
`STI‘D ‘1’ TYPE
`94
`Table of Contents present and sufficient to
`
`locate reports, tables= data. etc.
`Tabular Listing of All Human rStudies
`
`HPK Suinmaij'
`Labeling
`Reference Bioanalytical and Analfitical
`KIethods
`I. Clinical Pharm ac olon'
`)Iass balance:
`Isozyme characterization:
`
`Blood-plasma ratio:
`Plasma protein binding:
`Pharmacokinetics (e.g., Phase I) ,
`
`Healthy Volunteers-
`single do a e'
`FAY—P4470, INS—Ufi-flflS.
`INS—064] D4
`multiple do 5 e'
`Patients-
`INS—094311
`single do a e:
`multiple dose:
`Dose proportionality —
`fasting non—fasting Single dose.
`fasting -' nonefasting multiple dose:
`
`Drua-drug interaction studies -
`Iii-rive effects on primary drng'
`In—vito effects of prnnary drug.
`Iii-Vino.
`Suhpopulation studies ,
`ethnicity"
`gender
`pediatrics.
`geriatrics:
`renal impamnent:
`hepatic iinpamnent'
`PD-
`Phase 2:
`
`Clinical Pharmacology and Biophannaceutics Filing Form-"Checklist for 1\DA_BLA 01'
`Supplement
`
`
`
`
`
`Reference ID: 3051528
`Reference ID: 3051528
`
`
`
`21
`21
`
`

`

`PK'PD -
`
`Phase 1 wide: 2‘ proof of concept:
`
`Phase 3 clinical uial
`Population Analyses -
`
`Data nch:
`Data sparse
`
`II. Biopharmaceutin
`
`Absolute bioavailability
`X
`155435003
`Relative bioavaihhilitv —
`
`solution as refumcc
`alternate formulation as reference: Same as above X
`
`
`‘wtlenee studies -
`Bioe-
`uadiuoual design. single ’ multi dose.
`r- hcate darn—u: single ‘ mulu dose:
`
`Food-drug interaction studies
`Bio-waiver request Inset! on BCS
`BCS class
`Dissolution study to evaluate alcohol induced
`dose—dum-'- -
`111. Other C'