CLINICAL PHARMACOLOGY/BIOPHARMACEUTICS REVIEW

NDA: 21-236

Submission Dates: January 2, 2001

April 25, 2001

May 2, 2001

May 30, 2001

June 7, 2001

Drug Name: IntraDose (Cisplatin/Epinephrine Injectable Gel)

Applicant: Matrix Pharmaceuticals, Inc.

Fremont, CA

Reviewer: Sophia Abraham, Ph.D.

Submission Type: Review of an Original NDA

________________________________________________________________

  1. EXECUTIVE SUMMARY

This is a review of an NDA filed for IntraDose (cisplatin/ epinephrine, CDDP/epi) Injectable Gel. The Applicant seeks approval for the use of IntraDose in the treatment of patients with recurrent squamous cell carcinoma of the head and neck (SCCHN) whose tumors considered incurable with surgery or radiotherapy. The proposed dosing schedule is 0.25 ml IntraDose per cm3 of tumor volume to a maximum of 10 ml (40 mg cisplatin) to be administered weekly for up to six treatments (one cycle). In support of the proposed indication (i.e., use of IntraDose in the treatment of SCCHN), the Applicant submitted two prospective, randomized, multicenter, double-blind, placebo-controlled Phase III studies (Studies 414-94-2 and 514-94-2). A total of 178 patients with tumor volumes up to 20 cm3 were enrolled and randomized (2:1) to receive IntraDose or placebo (collagen gel only). The primary clinical endpoints were objective response of a target tumor and the attainment of clinical benefit. The pharmacokinetics (PK) of total and free platinum (Pt) in patients with head and neck cancer were assessed following intratumoral administration of IntraDose in the pivotal Study MP #516-99-PK.

IntraDose was granted an Orphan Drug Designation for this indication on April 3, 2000. No other approved therapy is available for the proposed indication (i.e., SCCHN). Foscan is a competing product under development for the treatment of SCCHN.

 

 

(A) OVERALL RECOMMENDATION

The NDA 21-238 filed for the use of IntraDose in the treatment of patients with recurrent squamous cell carcinoma of the head and neck appears to be acceptable from the Clinical Pharmacology and Biopharmaceutics perspectives. High variability in cisplatin pharmacokinetics after IntraDose administration needs further investigation. The Applicant should incorporate the changes made in the Clinical Pharmacology/ Pharmacokinetic section of the package insert as outlined under section "I.B" of this review.

Please forward the Overall Recommendation (section I.A.), Labeling Recommendations (section I.B.), and Comments 1 and 2 (section I.C.) to the firm. Comments 3-5 are to the Medical Reviewer (section I.C.).

 

(B) LABELING RECOMMENDATIONS

Please incorporate the changes made in the CLINICAL PHARMACOLOGY/ PHARMACOKINETICS section of the package insert for IntraDose as outlined below:

[Note: Statements added are in italic and bold. Statements deleted are strikeout]

 

CLINICAL PHARMACOLOGY

Pharmacokinetics

In a pharmacokinetic study of IntraDose administered intratumorally to sixteen subjects Study 516-99-PK (total of 20 treatments) with squamous cell carcinoma of the head and neck, platinum levels were monitored in plasma (total Pt), and plasma ultrafiltrate (free Pt). The pharmacokinetics of both total and free platinum were determined in 16 patients with squamous cell carcinoma of the head and neck following intratumor administration of IntraDose. Patients received 0.25 mL gel/cm3 of tumor volume, corresponding to cisplatin doses of 6.8-16.4 mg/m2 10.5 to 25.6 mg (averaging approximately 10 mg/m2) body surface area. After the first dose, the peak maximum average total Pt platinum concentration in the plasma was reached at a median (range) tmax value of 1.5 (0.08-24) hours was observed reached at 9.8 hours. Over the dosing this dose range administered, average observed total Pt platinum peak plasma concentration (Cmax) averaged (" standard deviation) 250" 85 ng/mL was 252 ng/ml and decreased slowly over time with an average t2 elimination half-life of 12.5" 10 days. There was little increase or No accumulation in of total Pt platinum was observed after multiple weekly treatments. After the first dose, the peak appearance of free Pt concentration in plasma was reached at delayed from the time of administration with an average tmax value of 0.80" 0.43 hours 45 min. The Cmax averaged 103" 50 ng/ml and decreased over time with a t2 of 8.9" 8.1 hours was variable, ranging from 15 to 229 ng/mL with an average of 95 ng/mL that fell below the detection limits (5 ng/mL) after 4 hours. The peak free Pt levels in plasma were transient and much lower than the sustained exposure of 1.5 to 2.0 F g/mL normally considered the lower threshold for nephrotoxicity. Systemic exposure to free platinum as measured by The estimated AUC (t0 to t4 ) for free Pt ranged from 204-4310 ngC h/mL 0.2 to 4.3 F gC h/mL. Systemic Apparent clearance and apparent volume of distribution of free platinum averaged 632" 758 573" 155 mL/h/kg and 3.7" 2.1 L/kg, respectively. the apparent volume of distribution during the elimination phase (Vz) was 200 L for free Pt. These observations are consistent with local sequestration of Pt at the injection site and delayed release into the systemic circulation.

(C) COMMENTS

  1. A considerably high variability is observed in all pharmacokinetic parameters for both total and free platinum following intratumor administration of IntraDose (%CV=34-176%) (Study #516). This variability could not be explained by differences in age, gender, and dose administered. Please explain what are the reasons for the high variability of cisplatin pharmacokinetics after IntraDose Administration?
  2. It is noted that the median tmax values for total platinum after intratumoral administration of Intradose in Study #516 were comparable to that after intravenous administration of cisplatin Injection in Johnson’s Study, 1.5 (0.08-24) hours versus 1.2 (1.0-1.4) hours, respectively. You have mentioned that when IntraDose gel is administered intratumorally, cisplatin is retained at or near the site of injection and its local decay into the systemic circulation is prolonged. Only a few patients had prolonged tmax value in the study supporting your hypothesis; 3/16 patients had a tmax value of 24 hours. In the remaining 13 patients tmax ranged from 0.08-6.0 hours,

demonstrating a highly variable retention of cisplatin at the tumor site. Please

explain why only few patients(3 out of 16) retained the drug at the site of injection

after IntraDose administration as demonstrated by the prolonged Tmax value of

24 hours for total platinum?

  1. The Applicant claims that maximum platinum plasma levels (Cmax) are much lower following IntraDose administration than that following intravenous cisplatin. Dose-normalized Cmax (normalized to 1 mg/m2 platinum dose) is significantly lower after intratumor administration of IntraDose than that after intravenous cisplatin, by about 1.6- and 2.8-fold lower for total and free platinum, respectively (Study 516). Exposure to IntraDose is comparable or even higher to that after intravenous cisplatin. Dose-normalized AUC0-4 (normalized to 1 mg/m2 platinum dose) after IntraDose administration is 1.8-fold higher for total platinum and 1.1-fold lower for free platinum than after intravenous cisplatin. These differences are not statistically significant.
  1. It is noted from the pooled PK data from the three studies (Studies 516, 43, and Johnson’s) following IntraDose administration that there is a trend for systemic clearance of both total and free platinum to decrease as age increases (CL=7.7-

0.06C Age, r=0.217 and CL=935-9.7C Age, r=0.285, respectively). Systemic

clearance was comparable between male and female patients for total platinum

[CL=4.2 ml/ hr/m2 and 4.4 ml/hr/m2, respectively], but was 30% lower in female than

male patients for free platinum [CL=255 ml/hr/m2 (74%) versus 377 ml/hr/m2 (82%),

respectively]. In addition, the kinetics of free platinum are dose-dependent and may

accumulate more in elderly and female patients. A precaution statement may need

to be added to the package insert for the use of IntraDose in elderly and female

patients.

  1. The results from Study 43 and Johnson’s Study are irrelevant to this NDA submission. First, these studies did not validate the assay methods used for determination of total and free platinum in plasma samples. Secondly, the patient population (i.e., patients with hepatocellular carcinoma) enrolled in these studies is not the relevant population for which IntraDose is indicated (i.e., patients with SCCHN). Therefore, any Pharmacokinetic information obtained in these studies should not be included in the package insert for IntraDose.

 

(D) Briefing on , 2001: (Attendees: Drs.: )

 

_____________________________ _____________________________

Team Leader: Atiqur Rahman, Ph.D. Reviewer: Sophia Abraham, Ph.D.

Division of Pharmaceutical Evaluation I Division of Pharmaceutical Evaluation I

cc: NDA: 21-236

HFD-150/Division file

HFD-150/Spillman, Williams, Frykman

HFD-860/Mehta, Rahman, Abraham

CDR/Biopharm

 

 

 

 

 

 

 

 

 

 

 

 

Table of Contents Page #

  1. Executive Summary

(A) Overall Recommendation ……………………………. 2

(B) Labeling Recommendations ………………………………. 2

(C) Comments

(D) Briefing, Signatures, and "cc" List……………………… 4

II. Table of Contents………………………………………………… 5

III. List of Abbreviations………………………………………………. 6

  1. Background………………………………………………………… 6
  2. Question-Based Review

Appendix 1: Firm’s Proposed Package Insert

Attachment 1: Firm’s Formulations

Attachment 2: Firm’s Results for Study MP #516-99-PK

Attachment 3: Firm’s Results for Study MP # 43-92-P-PK

Attachment 4: Firm’s Results for Johnson’s Study

Attachment 5: Firm’s Analytical Methodology and Validation

 

 

 

 

 

 

 

 

 

 

 

 

 

III. LIST OF ABBREVIATIONS

AUC0-4 Area under plasma concentration/time curve from time zero to infinity

CDDP Cisplatin

Cmax Peak plasma concentration

Cm2 Squared centimeter

Cm3 Cubic centimeter

CL Systemic Clearance

%CV Coefficient of variation [%CV=(standard deviation/mean) x 100]

Epi Epinephrine

HC Hepatocellular carcinoma

hr Hour

IV Intravenous

MRT Mean residence time

NDA New Drug Application

PDR® Physician’s Desk Reference®

PK Pharmacokinetics

Pt Platinum

SCCHN Squamous cell carcinoma of the head and neck

tmax Time to reach Cmax

t2 Elimination half-life

Vz Apparent volume of distribution

IV. BACKGROUND

IntraDose (cisplatin/epinephrine, CDDP/epi) Injectable Gel is a novel drug delivery system intended for intratumoral administration. IntraDose contains the antineoplastic agent, cisplatin (CDDP), and the local vasoconstrictor, epinephrine (epi), in a viscous biodegradable aqueous matrix of purified bovine collagen. Epinephrine and collagen both help to limit the spread of cisplatin outside of the site of injection.

Cisplatin is a heavy metal complex containing a central atom of platinum surrounded by two chloride atoms and two ammonia molecules in the cis position.

Cisplatin, an alkylating agent, binds intracellularly with DNA, RNA, or other macromolecules at two sites to form interstrand and intrastrand links. These intrastrand links account for > 90% of the platinum binding to DNA. Cisplatin causes cell cycle arrest in the G2-phase and then induces programmed cell death or apoptosis. The recommended cisplatin doses are 50-70 mg/m2 IV per cycle once every 3 to 4 weeks as a single agent for the treatment of advanced bladder cancer, 20 mg/m2 IV daily for

5 days per cycle in combination with other approved chemotherapeutic agents for the treatment of testicular cancer, and 75-100 mg/m2 IV per cycle once every 4 weeks in combination with cyclophosphamide for the treatment of metastatic ovarian tumors (PDR®).

Epinephrine is an endogenous sympathomimetic catecholamine that has many therapeutic applications.

Endogenous epinephrine is produced primarily from norepinephrine in the adrenal medulla. Epinephrine can be administered by injection, inhalation, or administered topically to the eye; the effects of exogenous epinephrine are identical to those of the endogenous hormone. Epinephrine is administered subcutaneously (SC), intramuscul-arly (IM), or intravenously (IV) at recommended doses of 0.3-0.5 mg SC, 0.3-0.5 mg IM, or 0.1-0.25 mg IV (PDR®).

The proposed indication in the present NDA submission is the use of CDDP/epi gel in the treatment of patients with recurrent squamous cell carcinoma of the head and neck (SCCHN) whose tumors considered incurable with surgery or radiotherapy. The CDDP/epi gel is prepared immediately prior to use from sterile and nonpyrogenic components supplied in kit form. The kit includes a vial of IntraPlatinJ (CDDP Injectable suspension, 11 mg), a vial of IntraEpiJ (epi solution, 0.152 mg/ml), and a syringe of IntraGelJ (aqueous collagen gel, 6.5%). Each kit will provide 2 ml of IntraDose after mixing. Each 1-ml of IntraDose contains 4-mg cisplatin, 0.1-mg epinephrine, and 20-mg purified bovine collagen (see Attachment 1 for details).

  1. QUESTION-BASED REVIEW

! What is the rationale for the proposed dosing regimen provided in the

NDA?

No attempt was made to correlate exposure to IntraDose and response rate. The proposed dosing schedule of 0.25 ml IntraDose per cm3 of tumor volume administered weekly (one cycle) was selected on the basis of clinical experience. The 0.25 ml dose per cm3 of tumor volume in Phase III studies showed optimum risk/benefit ratio for patients. The weekly administration of IntraDose in earlier trials was both tolerable and feasible for the routine management of patients with advanced head and neck cancer.

! Has the Applicant adequately characterized the pharmacokinetics (PK) of

total and free Platinum from IntraDose in the target population (i.e., head and neck cancer patients)?

Study MP #516-99-PK assessed the pharmacokinetics (PK) of total and free platinum (Pt) in patients with head and neck cancer following intratumoral administration of IntraDose. The report of this study was included in the 4-month Safety Update for IntraDose in the Submission of May 2, 2001.

The Human Pharmacokinetics and Bioavailability section of the NDA submission (Submission of January 2, 2001) included two other studies which also assessed the PK of total and free platinum but in patients with advanced liver cancer. One study was sponsored by Matrix Pharmaceuticals as part of an early phase II study (Study MP #43-92-P-PK) and the other was conducted independently by one of the investigators (Dr. Philip Johnson) in some of his patients in the Matrix Study No. 417-96-2.

Unbound Plasma Platinum Levels in Patients Receiving Cisplatin/Epinephrine

(CDDP/epi) Injectable Gel Intratumorally for Recurrent or Refractory

Squamous Cell Carcinoma of the Head and Neck".

Study MP #516-99-PK evaluated the PK of total and free platinum (Pt) in 16 patients with SCCHN (13 males/3 females, 40-67 years of age). Patients were treated by direct intratumor injection of 2.6-6.4 ml of IntraDose gel (depending on tumor size) every week for 6 weeks. CDDP doses from the gel ranged from 12-25.6 mg (6.8-16.4 mg/m2). Plasma samples were collected pre-dose and at 0.08, 0.33, 0.67, 1, 2, 4, 4.5, 24, and 48 hours after the first dose in all patients and also after the third dose in six of 16 patients. Total as well as free Pt plasma levels were determined by atomic absorption spectrophotometry. The assay was adequately validated. Calibration curves were linear over the concentration range of 150-5000 ng/ml for total Pt and 30-600 ng/ml for free Pt. The lower limit of quantitation was 150 ng/ml for total Pt and 30 ng/ml for free Pt. Intra- and inter-day assay precision, as expressed by percent relative standard deviation (%RSD), was less than 10% for quality control data for both total and free Pt. Separation of free Pt fraction was carried out by ultrafiltration. The formulation gel for marketing was used in this study (see Attachment 1). Results of this study are presented in Attachment 2. The assay methodology and validation are presented in Attachment 5.

Study MP #43-92-P-PK evaluated the PK of total and free platinum in eight patients

(4 males/4 females, 37-75 years of age). Of the eight patients, two had hepatocellular carcinoma and the six others had a variety of tumor types (colorectal adenocarcinoma, pancreatic, gall bladder adenocarcinoma, small bowel leiomyosarcoma, and gastric leiomyosarcoma) metatstatic to the liver. The volume of IntraDose administered ranged from 4.8-25 ml depending on tumor size. The gel was administered intralesionally by ultrasound-guided injection every other week for 8 weeks. CDDP doses from the gel ranged from 19-100 mg (10-63 mg/m2). Plasma samples were collected pre-dose and at 0.08, 0.33, 0.67, 1, 2, 6, 24, 48, 72, and 96 hours after first dose in all patients and also after second dose in four of eight patients. Six-hour urine samples were collected from

7 of 8 patients. Total as well as unbound platinum levels in plasma and total platinum levels in urine were determined by atomic absorption spectrophotometry (NOT validated, Submission of April 25, 2001). Separation of free Pt fraction was carried out by precipitation. A prototype CDDP/epi gel formulation was used in this study (see Attachment 1). Results of this study are presented in Attachment 3.

In Johnson’s Study, the PK of total and unbound platinum were assessed after intralesional injection of CDDP/epi gel or after intravenous infusion of CDDP in cirrhotic patients with unresectable hepatocellular carcinoma. Six patients (4 males/2 females, 48-75 years of age) received 2.5-10 ml CDDP/epi gel weekly or biweekly over 6-week period. CDDP doses from the gel ranged from 10-40 mg (6-23 mg/m2). For comparison, another four male patients (52-68 years of age) received 100 mg (75 mg/m2) CDDP intravenously (IV) over 1-hour infusion. Plasma samples were collected pre-dose and at 0.083, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 21, 24, 48, 72, 168, and 336 hours from patients receiving the CDDP/epi gel and pre-dose and at 0.083, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 21, 24, 48, 72, 96, 168, and 384 hours from patients receiving the CDDP infusion. Urine samples were collected to 336 hours from patients receiving the CDDP/epi gel post-infusion and up to 148 hours from patients receiving the CDDP infusion. Total as well as unbound platinum levels in plasma and total platinum levels in urine were determined by atomic absorption spectrophotometry (NOT validated, Submission of April 25, 2001). Separation of unbound platinum fraction was carried out by ultrafiltration. The formulation gel for marketing was used in this study (see Attachment 1). Results of this study are presented in Attachment 4.

Note: In the studies submitted, no attempt was made to compare the PK parameters of CDDP in the presence or absence of epinephrine (epi) after intratumor administration. However, no drug interaction is expected to occur between CDDP and epinephrine since both drugs have different metabolic pathways. Epinephrine is rapidly and extensively metabolized by the enzymes, catechol-O-methyltransferase and monoamine oxidase, in the liver and in other tissues to inactive metabolites. Cisplatin, due to its unique chemical structure, its chlorine atoms are more subject to chemical displacement reactions by nucleophiles, such as water or sulfahydryl groups, than to enzyme-catalyzed metabolism.

Overall Results:

The overall results from the above PK studies are reported in Table 1 as mean (%CV) PK parameters for total and free Pt after the first dose (Cycle 1). Table 2 (a and b) shows the effect of treatment cycle, as measured by comparing dose-normalized Cmax and AUC0-4 values between the first and third dose in Study 516 (n=4) and in Johnson’s Study (n=5) and between the first and second dose in Study 43 (n=4). Table 3 shows the effect of tumor type (SCCHN versus HC) on dose-normalized Cmax and AUC0-4 following the first cycle of IntraDose treatment. Figures 1-5 show various analyses made on overall data set.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 1. Mean (%CV) PK Parameters After the First Dose

Study #

MP #516-99-PK

MP #43-92-P-PK

Johnson’s Study

No. of Patients

16

8

6

4

Route of Administration

Intratumor

Intralesional

Intralesional

1-Hour

Infusion

Dosage Form

IntraDoseõ

IntraDosex

IntraDoseõ

Cisplatin Solution

Tumor Type

SCCHN

HC

HC

HC

Tumor size

10.5-25.5 cm3

37-3164 cm3

*NR

--

Volume of IntraDose administered

2.6-6.4 ml

4.8-25 ml

2.5-10 ml

--

CDDP Dose (mean, range)

10 mg/m2

6.8-16.4 mg/m2

45 mg/m2

10-63 mg/m2

  1. mg/m2

6-23 mg/m2

76.6 mg/m2

75.1-77.4 mg/m2

Pt Dose (mean, range)

6.8 mg/m2

4.4-10.7 mg/m2

29.2 mg/m2

6.5-38.2 mg/m2

10.5 mg/m2

3.9-15.2 mg/m2

49.8 mg/m2

48.8-50.3 mg/m2

Mean (%CV) PK

Parameter

Total

Pt

Free

Pt

Total

Pt

Free

Pt

Total

Pt

Free

PtŠ

Total

Pt

Free

Pt

Cmax

(ng/ml)

250

(34%)

103

(49%)

781

(65%)

472

(83%)

465

(43%)

345

(62%)

3130

(15%)

2210

(21%)

ç Cmax/Dose

(ng/ml/mg/m2)

38.7

(42%)

15.7

(42%)

27

(65%)

19.8

(83%)

46

(24%)

32

(62%)

62.9

(16%)

44

(21%)

Š p-value (T-test)

0.0038

0.0029

0.0007

0.0046

0.0236

0.165

--

--

& tmax (hr)

1.5

(0.08-24)

0.67

(0.08-1)

6.0

(0.33-24)

0.66

(0.33-1)

0.825

(0.43-48)

0.65

(0.26-0.83)

1.2

(1-1.4)

1.2

(1-1.4)

AUC0-4

(ng.hr/ml)

71687

(102%)

823

(136%)

234200

(147%)

5313

(73%)

78483

(83%)

1705

(114%)

338650

(21%)

7760

(27

ç AUC0-4 /Dose

( ng.hr/ml/mg/m2)

11453

(108%)

118

(115%)

7650

(120%)

178

(61%)

7276

(75%)

134

(87%)

6817

(23%)

156

(29%)

Š p-value (T-test)

0.061

0.186

0.405

0.317

0.427

0.376

--

--

CL (ml/hr/kg)

4.1

(80%)

632

(120%)

7.4

(95%)

217

(73%)

4.7

(38%)

386

(100%)

4.03

(16%)

180

(48%)

Vz (L/kg)

1.05

(55%)

3.7

(59%)

1.3

(43%)

18.7

(55%)

1.06

(37%)

15.2

(23%)

1.1

(13%)

11.4

(45%)

MRT (hr)

376

(74%)

17.5

(147%)

482

(167%)

143

(109%)

250

(54%)

56.2

(109%)

281

(9.6%)

38

(53%)

t1/2 (days)

299

(81%)

8.9

(91%)

334

(167%)

108

(103%)

176

(53%)

52.2

(94%)

193

(14%)

45.0

(46%)

% of Total Pt dose excreted in urine

#ND

#ND

' 3.7%

(58%)

#ND

, 4.25% (14%)

#ND

, 33% (13%)

#ND

õ Commercial formulation

x Prototype formulation

*NR (Not Reported)

& Median (range)

Š Data are available from 4 patients

ç Normalized to 1-mg/m2 Pt dose

Š T-Test for 1-tailed distribution and two samples with unequal variance for IntraDose compared to IV cisplatin

#ND (Not Determined)

' Over the first 6 hours

, Over 72 hours

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 2a. Effect of Treatment Cycle (For Total Pt)

PK Parameter

Total Pt

Study 516

(n=4)

Study 43

(n=4)

Johnson’s Study

(n=5)

Cycle #

1st

3rd

1st

2nd

1st

3rd

Pt Dose (mg/m2)

5.5

(4.4-6.2)

5.5

(4.4-6.2)

31.9

(24-40.6)

29.8

(7.2-57.8)

9.5

(3.9-14.9)

10.4

(4.7-14.9)

Cmax

(ng/ml)

275

(33%)

257

(34%)

1150

(39%)

1147

(82%)

396

(30%)

400

(41%)

Cmax/Pt Dose

(ng/ml.mg/m2)

49.01

(26%)

46.1

(27%)

38.5

(50%)

39.1

(29%)

45.1

(27%)

41.4

(38%)

*p-value

0.377

0.480

0.355

AUC0-4

(ng.hr/ml)

94875

(112%)

126800

(70%)

381950

(122%)

162625

(28%)

74820

(111%)

146220

(38%)

AUC0-4 /Pt Dose

(ng.hr/ml.mg/m2)

16162

(103%)

23014

(73%)

11095

(113%)

10627

(90%)

7474

(91%)

12651

(32%)

*p-value

0.292

0.477

0.132

*T-Test for 1-tailed distribution and two samples with unequal variance

 

 

Table 2b. Effect of Treatment Cycle (For Free Pt)

PK Parameter

Free Pt

Study 516

(n=4)

Study 43

(n=4)

Johnson’s Study

(n=3)

Cycle #

1st

3rd

1st

2nd

1st

3rd

Pt Dose (mg/m2)

5.5

(4.4-6.2)

5.5

(4.4-6.2)

31.9

(24-40.6)

29.8

(7.2-57.8)

11.03

(5.9-14.9)

12.3

(8.2-14.9)

Cmax

(ng/ml)

120

(32%)

60

(83%)

735

(56%)

640

(145%)

253

(52%)

437

(107%)

Cmax/Pt Dose

(ng/ml.mg/m2)

21.6

(21%)

10.6

(74%)

24.5

(64%)

14.3

(96%)

29.5

(80%)

37.2

(90%)

*p-value

0.031

0.178

0.383

AUC0-4

(ng.hr/ml)

1183

(93%)

691

(86%)

80485

(129%)

3207

(88%)

736

(46%)

763

(75%)

AUC0-4 /Pt Dose

(ng.hr/ml.mg/m2)

205

(83%)

120

(77%)

2251

(113%)

110

(48%)

79

(59%)

68

(73%)

*p-value

0.211

0.095

0.407

*T-Test for 1-tailed distribution and two samples with unequal variance

 

 

 

 

 

Table 3. Effect of Tumor Type

PK Parameter

Total Pt

Free Pt

SCCHN

HC#

SCCHN

HC#

N

16

14

16

12

Cmax/Pt Dose

(ng/ml.mg/m2)

38.7

35.3

15.7

23.9

p-value*

0.293

0.075

AUC0-4 /Pt Dose

(ng.hr/ml.mg/m2)

11453

7488

118

164

p-value*

0.112

0.169

*T-Test for 1-tailed distribution and two samples with unequal variance for IntraDose after the first dose

#Data from Study #43 and Johnson’s Study were combined.

From the Tables and Figures above, it is noted that:

    • A considerably high variability is observed in all PK parameters for both total and free Pt following IntraDose administration (either intratumor or intralesional) (%CV=34-176%). This variability could not be explained by differences in age, gender, and dose administered. Analysis of pooled data from the three studies following IntraDose administration (n=30, 21 males, 9 females) shows that there is a trend for systemic clearance for both total and free Pt to decrease as age increases (Figures 2a and 2b). Male and female patients have comparable systemic clearance for total Pt, CL=4.2 ml/hr/m2 (62%) and 4.4 ml/hr/m2 (82%), respectively. For free Pt, systemic clearance is 30% lower in female patients than in male patients [CL=255 ml/hr/m2 (74%) versus 377 ml/hr/m2 (82%), respectively] (Figures 3a and 3b). Nonlinearity is observed in the kinetics of free Pt (Fig. 4a and 4b); this is also reported in PDR®. Variability following the 1-hour IV cisplatin infusion (Johnson’s Study) is much lower, and is lower for total Pt (%CV=9.6-23%) than free Pt (%CV=21-53%).
    • The median tmax values for total Pt are 1.5 hours, 6 hours, and 0.825 hours in Studies 516, 43, and Johnson’s, respectively, compared to 1.2 hours after IV cisplatin infusion. The Applicant claims that when IntraDose gel is administered intratumorally, the drug is retained at or near the site of injection and its availability to the systemic circulation is prolonged. Only few patients had shown to have a prolonged tmax value for total Pt; 3/16 patients in Study 516 had a tmax value of 24 hours, 2/8 patients in Study 43 had tmax values of 24 and 20 hours, and 2/6 patients in Johnson’s Study had tmax values of 23.7 and 48 hours. This demonstrates highly variable retention of cisplatin at the tumor site.
    • Dose-normalized Cmax (normalized to 1 mg/m2 Pt dose) following IntraDose administration is significantly lower than that after the 1-hour IV cisplatin infusion for both total and free Pt (p < 0.05, Table 1). For total Pt, dose-normalized Cmax is about 1.6-, 2.3- and 1.4-fold lower after IntraDose than IV cisplatin in Studies 516, 43, Johnson’s, respectively; the corresponding values for free Pt are 2.8-, 2.2- and 1.3-fold lower, respectively.
    • Exposure to IntraDose, as expressed by dose-normalized AUC0-4 (normalized to 1 mg/m2 Pt dose), is not significantly different from that after IV cisplatin for both total and free Pt (p > 0.05, Table 1). Dose-normalized AUC0-4 values for total and free Pt after IntraDose administration are comparable to that after IV cisplatin administration, except in Study 516, dose-normalized AUC0-4 it for total Pt after IntraDose administration is 1.8-fold higher than that after cisplatin IV administration.

    • Figures 5a and 5b show that mean dose-normalized plasma concentration/time profiles for total and free Pt are comparable after intraDose and IV cisplatin administrations. These profiles are even superimposable for free Pt, the pharmacologically active species of cisplatin.
    • For both total and free Pt, no significant differences are observed in dose-normalized Cmax and AUC0-4 either between the first and second dose in Study 43 or between the first and third dose in Study 516 and Johnson’s Study (p > 0.05, Table 2, a and b). The difference observed in Cmax/dose for free Pt in Study 516 (p=0.031) may be due an artifact. This means that total and free Pt do not accumulate upon weekly administration of IntraDose.

However, this contradicts with the mean t2 value of 299, 334, 176 hours for total Pt (12.5, 14, 7.3 days, Table 1) at which accumulation of total pt is expected upon weekly administration of IntraDose. The t2 may be overestimated.

    • Finally, tumor type has not effect on in dose-normalized Cmax and AUC0-4 for both total and free Pt following IntraDose administration (p >0.05, Table 3).

In conclusion, the data submitted are considerably variable. The results demonstrated that IntraDose as a novel drug delivery system did not appear to achieve the goal of targeting cisplatin directly into tumor tissues with much slower rate of appearance of platinum in systemic circulation. Although dose-normalized Cmax for both total and free Pt was significantly lower after IntraDose than after IV cisplatin, exposure to both moieties was comparable between the two treatments. Mean dose-normalized plasma concentration/time profiles for free platinum (the pharmacologically active species for cisplatin) are superimposable after IntraDose and IV cisplatin administrations. No accumulation of platinum occurred upon weekly administration of IntraDose. Tumor has no effect on PK parameters of both total and free platinum.

 

 

 

APPENDIX 1

 

Labeling Text

NDA Cross Reference
Volume/Page

Rx only

 

 

DESCRIPTION

IntraDoseÒ (cisplatin/epinephrine) Injectable Gel is a viscous, opaque, pale yellow gel containing the antineoplastic agent, cisplatin, and the vasoconstrictor, epinephrine, in an aqueous matrix of purified bovine collagen. It is intended only for intratumoral administration. The drug product is provided as a single-use kit containing one single-use vial of IntraPlatinÔ (cisplatin for injectable suspension), one single-use vial of IntraEpiÔ (epinephrine solution, 0.152 mg/mL), and one single-use syringe of IntraGelÔ (6.5% collagen gel). The product is prepared shortly before use. Each kit will provide 2 mL of IntraDose after mixing.

 

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When prepared as directed, 1 mL of IntraDose contains: cisplatin (4 mg), epinephrine (0.1 mg), mannitol (40 mg), sodium chloride (37 mg), purified bovine collagen (20 mg), sodium phosphate dibasic (2.1 mg), sodium phosphate monobasic (1.8 mg), polysorbate 80 (0.7 mg), acetic acid (0.3 mg), sodium metabisulfite (0.1 mg), sodium acetate (0.1 mg) and edetate disodium (0.07 mg). The pH of the mixed gel is approximately 6.2.

Vol. 2.1/pg. 59

Kit Components

Each vial of IntraPlatin contains 11 mg cisplatin formulated with mannitol (110 mg) and sodium chloride (99 mg) as a sterile lyophilized powder. Hydrochloric acid and/or sodium hydroxide may be added during manufacture to adjust pH.

Vol. 2.1/pg. 60

IntraEpi is a sterile aqueous solution containing epinephrine (0.152 mg/mL), polysorbate 80 (1 mg/mL), glacial acetic acid (0.49 mg/mL), sodium metabisulfite (0.2 mg/mL), sodium acetate (0.15 mg/mL), and edetate disodium dihydrate (0.1 mg/mL). Hydrochloric acid and/or sodium hydroxide may be added during manufacture to adjust pH. IntraEpi differs significantly from other commercial preparations of epinephrine and is specifically designed for IntraDose preparation.

Vol. 2.1/pg. 60

IntraGel is a sterile aqueous collagen gel formulation containing purified bovine collagen (65 mg/g); dibasic sodium phosphate, heptahydrate (17.9 mg/g); monobasic sodium phosphate, monohydrate (4.6 mg/g); and sodium chloride (2.6 mg/g).

Vol. 2.1/pg. 61

Active Ingredients

Cisplatin (cis-diamminedichloroplatinum) is a heavy metal complex containing a central atom of platinum surrounded by two chloride atoms and two ammonia molecules in the cis position, and has the molecular formula Cl2H6N2Pt and a molecular weight of 300.1. It exists as a yellow to yellow-orange microcrystalline powder or crystals. It is slightly soluble in water, sparingly soluble in dimethyl formamide, practically insoluble in ethanol. It has the following structure:

Vol. 2.1/pg. 52

Epinephrine is (R)-4-[1-hydroxy-2-(methylamino)ethyl]-1,2-benzenediol, C9H13NO3 (molecular weight of 183.21). Epinephrine as the free base is very slightly soluble in water and in alcohol. Epinephrine is freely soluble in water at neutral or acid pH. It has the following structure:

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CLINICAL PHARMACOLOGY

Cisplatin is a cytotoxic agent with a long history of use in treating solid tumors when administered intravenously. Although its mechanism of action is not fully understood, it is believed to form inter- and intrastrand DNA crosslinks which interfere with DNA function, inducing cell death through the apoptotic cascade. Cisplatin also forms DNA-protein crosslinks and interacts with other cell components, such as glutathione. Epinephrine is a well-known catecholamine, active at - and -receptors. One of its pharmacological activities is to cause arteriolar vasoconstriction. IntraDose is designed to provide local delivery and retention of cisplatin within solid tumors by direct intratumoral injection, achieving much higher local concentrations of the drug within the tumor and for longer periods of time than can be achieved with either systemic or local administration of cisplatin solutions. The epinephrine is believed to aid tumor retention of the cisplatin by restricting local blood flow.

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In a pharmacokinetic study of IntraDose administered intratumorally to sixteen subjects (total of 20 treatments) with squamous cell carcinoma of the head and neck, platinum levels were monitored in plasma (total Pt), and plasma ultrafiltrate (free Pt). Patients received 0.25 mL gel/cm3 of tumor volume, corresponding to cisplatin doses of 10.5 to 25.6 mg, averaging approximately 10 mg/m2 body surface area. The maximum average total Pt concentration in the plasma (tmax) was observed at 9.8 hours. Over this dose range, average observed total Pt peak plasma concentration (Cmax) was 252 ng/mL and decreased slowly over time with a t1/2 of 12.5 days. There was little increase or accumulation in total Pt after multiple weekly treatments. The appearance of free Pt in plasma was delayed from the time of administration with an average tmax of 45 min. The Cmax was variable, ranging from 15 to 229 ng/mL with an average of 95 ng/mL that fell below the detection limits (5 ng/mL) after 4 hours. The peak free Pt levels in plasma were transient and much lower than the sustained exposure of 1.5 to 2.0 µg/mL normally considered the lower threshold for nephrotoxicity. The estimated AUC (t0 to t¥ ) for free Pt ranged from 0.2 to 4.3 m g· h/mL. Systemic clearance of free Pt was 573 ± 155 mL/h/kg and the apparent volume of distribution during the elimination phase (Vz) was 200 L for free Pt. These observations are consistent with local sequestration of Pt at the injection site and delayed release into the systemic circulation.

Study 516-99-PK

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In studies in tumor-bearing mice, intratumoral administration of IntraDose resulted in tumor platinum concentrations 40 to 80 times higher, and kidney levels three times lower, than were observed after intravenous administration of similar doses of cisplatin. Platinum levels in tumors after intratumoral injection of IntraDose remained in excess of 15 µg/g (approximately 75 µM) for up to 6 days after injection.

Study TB-1616
Vol. 4.5/pg. 55

 

CLINICAL STUDIES

A total of 396 patients with a variety of solid tumors have been treated in IntraDose clinical studies. The widest experience with IntraDose is in the treatment of squamous cell carcinoma of the head and neck (SCCHN), metastatic breast cancer, malignant melanoma and esophageal cancer. The clinical development program for SCCHN included two prospective, randomized, placebo-controlled studies in patients with recurrent or refractory SCCHN and two open-label, single-arm studies in patients with metastatic or recurrent tumors from a variety of primary sites.

 

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Study 414-93-2

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Study 514-94-2

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Study 403-93-2

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Study 503-93-2

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Study 39-92-P

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Head and Neck Cancer

Two prospective, randomized, multicenter, double-blind, placebo-controlled studies support the use of IntraDose in the treatment of SCCHN. A total of 178 patients with tumors up to 20.0 cm3 were enrolled and randomized 2:1 to receive IntraDose or placebo. The primary endpoints were objective response of a target tumor and the attainment of clinical benefit.

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One study enrolled and treated 86 patients in North America (62 IntraDose, 24 placebo); the second study enrolled and treated 92 patients in Europe (57 IntraDose, 35 placebo). Most patients (99%) were previously treated for their head and neck cancer; most (89%) had been heavily pretreated with multiple prior treatment modalities including surgery, radiotherapy and/or chemotherapy. Most tumors were located in the cervical, oral, facial or laryngopharyngeal regions. The treatment regimen consisted of up to 6 weekly injections of IntraDose or placebo (collagen gel only) within 8 weeks to one or more tumors. The dose administered in these studies was 0.25-0.5 mL/cm3.

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ISE Section 3.1.2.1

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Target Tumor
In the two controlled studies conducted in North America and Europe, patients could receive IntraDose treatment to more than one tumor. However, a single target tumor was selected as a measure of objective tumor response. The target tumor was defined as the single most symptomatic, threatening or distressful to the patient or the largest tumor if a single tumor could not be identified as the most troublesome. The difference in response rate between IntraDose- and placebo-treated patients was statistically significant. This positive response to IntraDose treatment was demonstrated in patients who were heavily pretreated with multiple prior therapies and who had a low expectation of response to further treatment. These data are shown in the following table:

ISE Section 3.1.2.1

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Response of Target Tumor
(Blinded Phase)

North America Europe

IntraDose Placebo IntraDose Placebo
(n= 62) (n= 24) (n=57) (n= 35)

No. (%) of responses

Complete response (CR) 14 (23%) 0 (0%) 9 (16%) 1 (3%)

Partial response (PR) 7 (11%) 0 (0%) 5 (9%) 0 (0%)
Overall response 21 (34%) 0 (0%) 14 (25%) 1 (3%)
(CR + PR)

95% Confidence Interval (22-47%) (0-14%) (14-38%) (0.072-15%)

p value 0.001 0.007

____________________________

Complete response (100% decrease in tumor volume sustained for at least 28 days)

Partial response (>50% < 100% decrease in tumor volume sustained for at least 28 days)

 

 

 

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Study 514-94-2
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The overall response rate (CR + PR) for target tumors in the two studies combined was 29% (95% CI:21-38%); the overall complete response rate was 19%. In patients who responded, the median duration of response for the combined studies was 78 days (range 30 to 554+ days) and the median time to response was 21 days, after a median of two IntraDose treatments.

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The North American and European controlled studies included treatment of other tumors in addition to the target tumor. When all treated tumors in the two studies were assessed for response, the overall response rate (CR + PR) was 30% (68/227 treated tumors). For tumors that responded, the median response duration for individual treated tumors was 75 days.

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Patients who had received prior cisplatin or carboplatin therapy were as responsive to IntraDose treatment as those who had not been previously treated (29% and 30%, respectively).

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Clinical Benefit
Clinical benefit was assessed in terms of its impact on quality of life (QoL) as measured by the attainment of primary treatment goals that were related to the target tumor and chosen prospectively by the patient and physician. Patients could choose a palliative goal such as pain control, wound care, obstructive symptoms, physical appearance, ability to see, hear or smell, or mobility. Physicians could select one of the palliative goals or a preventive goal such as prevention of invasion or obstruction of a vital structure or blood vessel or break through to the skin of subcutaneous tumors. For the two controlled studies combined, 27% of IntraDose treated patients achieved a clinical benefit compared to 12% of placebo

patients (p=0.046).

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Tumor response and clinical benefit were significantly associated (p=0.006). Patients who had a response of the target tumor were nearly 2.5 times more likely to attain a clinical benefit from treatment than patients who did not have a response of the target tumor (46% versus 19%, respectively).

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Other Solid Tumors
Two open-label studies were conducted in 126 patients with solid tumors that were metastatic or recurrent from various primary sites. Cancers included breast cancer,

melanoma and esophageal cancer as well as a wide variety of other symptomatic cancers. Most of these patients (91%) had received previous treatment and the majority (73%) had received multiple prior therapies. Patients received weekly injections of 0.5 mL of IntraDose per cm3 of tumor for up to 6 weeks. Objective tumor response and clinical benefit were evaluated for the target tumor as described above for the placebo-controlled head and neck cancer studies. In patients with breast adenocarcinoma (n = 28), the response of the target tumor was 50% with a median duration of 82 days (29-211 days). Clinical benefit was attained in 39% of patients and there was a significant association with tumor response (p = 0.033). For patients with malignant melanoma (n = 27), the response rate was 33% with a median duration of 72.5 days (30-632 days). For esophageal cancer patients (n = 24), the response rate was 29% with a median duration of 84 days (29-120 days).

 

 

 

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ISE Section 3.2.3.2.2

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ISE Section 3.2.2

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The overall objective response rate (CR and PR) for the primary target tumor in the combined studies was 35%. The overall clinical benefit rate was 31%. Of those patients who had a response, 52% attained a clinical benefit. The association between clinical benefit and response of the target tumor was statistically significant (p=0.0001).

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ISE Section 3.2.3.4.2
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ISE Section 3.2.3.5
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INDICATIONS AND USAGE

IntraDoseÒ (cisplatin/epinephrine) Injectable Gel is indicated for the treatment of recurrent or refractory squamous cell carcinoma of the head and neck in patients who are not considered curable with surgery or radiotherapy. The safety and efficacy of IntraDose in the treatment of individual tumors >20 cm3 has not been established.

 

CONTRAINDICATIONS

IntraDose should not be used for the treatment of any tumor that directly involves or threatens to invade the carotid or vertebral artery. In these patients, the potential risk of cerebral vascular complications, including cerebral vascular accidents, outweighs the potential benefit from tumor regression.

Patients with known hypersensitivity to any of the components in IntraDose, including cisplatin, bovine collagen, epinephrine or sulfites, should not be treated.

 

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WARNINGS

Caution: IntraDose should only be administered by direct intratumoral injection. IntraDose MUST NOT be injected intravenously, intra-arterially, or intrathecally. Injection into or adjacent to a major blood vessel may cause bleeding, arterial vasospasm or vascular occlusion. In situations where there are complex anatomical relationships, use of imaging procedures to guide the injection of the drug may be advisable. Injection of IntraDose may involve a risk of damage to adjacent peripheral or cranial nerves (see PRECAUTIONS).

 

 

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ISS Section 19.10

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Local Reactions: Injection of IntraDose into tumors results in a high intratumoral concentration of cisplatin for an extended period of time. Expected local cytotoxic effects in the tumor and adjacent tissue may include erythema, swelling, erosion, ulceration, necrosis, eschar formation and/or bleeding. The incidence of local cytotoxic effects generally peaks 2 weeks after the start of treatment and resolves over the next 3-12 weeks. In clinical studies, many patients had these tissue conditions at baseline, although most of these were mild to moderate in severity. Following treatment with IntraDose, the overall incidence and severity of local cytotoxic reactions increased in the IntraDose group. However, most of these effects were mild to moderate and resolved with standard wound care measures.

ISS Section 7

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ISS Section 19.12

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Patients at risk for delayed wound healing due to prior surgery, radiation, poor nutrition or inadequate blood supply may be at higher risk for developing more severe local cytotoxic effects. In cases where administration of the next scheduled IntraDose treatment might be expected to intensify the severity of existing local cytotoxic effects, especially ulceration and necrosis, treatment with IntraDose should be delayed until there is adequate healing of the tumor or surrounding tissue (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

ISS Section 19.12

Vol. 4.13/pg. 314

Allergic Reactions: Anaphylactic-like reactions to platinum-containing products have been reported to occur within minutes of systemic administration in patients with prior exposure to similar compounds. The safety of IntraDose in patients with a history of anaphylaxis or a history of multiple severe allergies has not been demonstrated. Patients with a history of dietary beef allergy should be carefully evaluated before injection with products containing bovine collagen because such patients may be predisposed to allergic reaction to any bovine-derived product.

Platinol Package Insert

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IntraDose contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and severe or even life-threatening asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and is probably low. Sulfite sensitivity is more frequent in asthmatic than in nonasthmatic people.

21 CFR 201.22 (b)

Pregnancy: IntraDose should not be used in patients who are pregnant, lactating or breast feeding. Cisplatin can cause fetal harm when administered to a pregnant woman. Cisplatin has been shown to be mutagenic in bacteria and produces chromosome aberrations in animal cells in tissue culture. Patients should be advised to avoid becoming pregnant during IntraDose therapy. If IntraDose is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Platinol Package Insert

Vol. 4.160/pg. 135

PRECAUTIONS

General: Not for intravenous injection. IntraDose should only be administered by direct intratumoral injection and MUST NOT be injected intravenously, intra-arterially or intrathecally (see WARNINGS).

Physicians administering this product should be familiar with the local and surgical anatomy of the site of injection. Imaging studies such as computed tomography (CT) or magnetic resonance imaging (MRI) may be required prior to treatment with IntraDose in order to adequately define the local anatomy and to plan the approach and extent of the local injection. In some patients, imaging guidance with ultrasound or CT may assist needle placement at the site of injection.

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Local injection of IntraDose involves a risk of serious adverse experiences such as hemorrhage or cerebral vascular events, especially with tumors involving major vessels of the extracranial vascular system. Tissue damage, needle trauma to the artery, chemical irritation, mechanical pressure from a large injected volume, local inflammation and swelling or tumor progression alone or in combination with IntraDose may contribute to the occurrence of cerebral vascular events.

ISS Section 18

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Pain Management: A comprehensive pain management program should be planned for each patient prior to treatment. The physician should assess the patient’s pain prior to injection and anticipate the possibility that pain will be increased during and following the injection of IntraDose. Sufficient time should be allowed for any anesthetic or analgesia to take effect prior to administration of IntraDose. It may be valuable to obtain consultation from an anesthesiologist or other pain-management specialist. Topical and other local anesthetics, loco-regional nerve blocks and systemic analgesics may be used alone or in combination, as appropriate. If a local anesthetic is used, it should be injected around the tumor margins. Local anesthetics containing epinephrine are contraindicated.

It should be assumed that narcotic-strength analgesia will be required at least for the first IntraDose administration procedure. Narcotic-strength analgesia with parenteral morphine sulfate, meperidine or fentanyl has been used in clinical trials of IntraDose, frequently in combination with lorazepam. An alternative regimen may involve local anesthesia with lidocaine and administration of midazolam hydrochloride. Provisions should be made to continue adequate analgesia for 24-48 hours following the procedure, during which time treatment with narcotic strength analgesics may be required. Subsequently, nonsteriodal anti-inflammatory drugs or acetaminophen may be adequate for pain management.

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Vol. 4.13/pg. 267

Wound Care: Local infection may occur, particularly in previously irradiated areas or in areas with pre-existing ulceration and necrosis, where facultative anaerobes and other pathogens may thrive. Cellulitis was reported infrequently in clinical studies. Management of local infection during IntraDose therapy, with local wound care or systemic antibiotics, may be necessary. The local cytotoxic effects of IntraDose on treated tumors may include erythema, swelling, erosion, ulceration, necrosis, eschar and/or bleeding (see WARNINGS). Patients at risk for delayed wound healing due to prior surgery, radiation, poor nutrition or inadequate blood supply may be at higher risk for developing more severe local cytotoxic effects.

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Renal Effects and Dehydration: The low systemic exposure to cisplatin released from IntraDose is not expected to produce direct renal toxicity. Nevertheless, patients with advanced head and neck cancer frequently have poor oral intake and may be both dehydrated and poorly nourished. This may be especially true for elderly patients, who are also more likely to have decreased renal function. Oral intake may be further compromised in the days following IntraDose treatment due to the local cytotoxic effects of the drug or from anorexia associated with concurrent narcotic analgesics. In these patients, the need for adequate hydration and/or intravenous fluid replacement should be considered.

Final report 43-93-P- PK
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Information for Patients: Patients should be informed of the expected effects of IntraDose, in particular, the likelihood of increased pain during and after injection. Patients should also be made aware that treatment may result in local skin reactions, such as erythema, swelling, erosion, ulceration, necrosis, eschar formation and/or bleeding or a worsening of these conditions that may be present before treatment with IntraDose. These effects occur within days of treatment and may become worse as treatments proceed before improvement is noted.

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ISS Section 6.1.2
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Drug Interactions: No formal drug interaction studies have been conducted. In addition, the short and long-term toxicity profiles of IntraDose, when given concurrently with radiation or systemic chemotherapy, have not been studied.

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Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic potential of IntraDose has not been studied. Cisplatin has been shown to be mutagenic in bacteria and produce chromosome aberrations in animal cells in tissue culture. In mice cisplatin is teratogenic and embryotoxic (see WARNINGS).

Platinol Package Insert

Vol. 4.160;pg. 135

Pregnancy: Category D. Safe use during human pregnancy has not been established
(see WARNINGS) .

Platinol Package Insert

Vol. 4.160;pg. 135

Nursing Mothers: The safety of IntraDose use in nursing mothers has not been established. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IntraDose, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

21 CFR.57(f)(8)

Pediatric Use: The safety and effectiveness of IntraDose in pediatric patients has not been established.

21 CFR 201.57(f)(9)

Geriatric Use: Of the total number of subjects in clinical studies of IntraDose, 37% percent were 65 and over, while 15% percent were 75 and over. No overall differences in safety or effectiveness were observed between these and younger subjects.

21 CFR 201.57(f)(10)

ADVERSE REACTIONS

The total safety database is comprised of 396 patients treated in five IntraDose clinical studies. Of these, 225 patients (150 IntraDose/75 placebo) were treated in the North American and European controlled studies; 171 patients were treated in open-label studies. Approximately 120 of these patients received 6 or more IntraDose treatments.

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The most frequent treatment-related adverse events in the North American and European placebo-controlled studies were either immediate injection effects (pain, tachycardia or hypertension) or local reactions at the treatment site (pain, facial edema, hemorrhage, infection, neck pain or pruritis). Overall, pain was the most frequent adverse event. Some patients randomized to IntraDose or placebo experienced transient elevation of blood pressure and pulse rate during the administration of the treatment. In a few cases, these were judged to be clinically significant hypertension or tachycardia, possibly due to the injected epinephrine or the result of anxiety that accompanied injection.

ISS Table S-20

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ISS Section 18

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The most clinically important adverse reactions observed in clinical studies with IntraDose were cerebrovascular events, cardiovascular events and significant tissue damage caused by the local cytotoxic effects of IntraDose.

ISS Section 18

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ISS Table S- 20

Vol. 4.128/pg. 1

The low systemic absorption of cisplatin after intratumoral injection of IntraDose formulation is evident in the small number of adverse events that are typically attributed to systemically administered cisplatin. The most frequently reported systemic events were nausea and vomiting, asthenia and headache. These adverse events were generally mild to moderate in severity and effectively managed with supportive measures. Treatment discontinuation or delay was usually not necessary.

 

ISS Section 19

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Adverse Events Occurring in ³ 5% of

Patients in the Placebo-Controlled Studies
(Treatment Related*)

Placebo
IntraDose (collagen gel only)
n = 150 n = 75

Pain 40% (60) 25% (19)

Within 15 min. of injection 25% (37) 19% (14)
Localized at treatment site 25% (37) 12% (9)

Face Edema 11% (17) 1% (1)

Hemorrhage 9% (13) 5% (4)

Infection 9% (13) 3% (2)

Nausea 8% (12) 3% (2)

Hypertension 8% (12) 5% (4)

Neck Pain 8% (12) 1% (1)

Vomiting 7% (10) 1% (1)
Headache 7% (10) 1% (1)

Pruritus 6% (9) 3% (2)

Tachycardia 6% (9) 3% (2)
Asthenia 5% (7) 1% (1)

*Patients may have experienced adverse events in more than one category and may be counted more than once.

ISS Section 20

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Selected treatment-related adverse reactions that occurred in 2-4% of patients in the two placebo-controlled studies are presented below in descending order of frequency. Included are clinically significant adverse reactions that occurred in 1% or less of patients regardless of relationship to treatment.

Body as a whole: Fever, cellulitis, chest pain, fistula, allergic reaction

Cardiovascular: Vasodilatation, palpitation, hypotension, vasospasm, cerebrovascular accident, arteriospasm, cerebral ischemia, cerebral infarct, heart arrest

Digestive: Anorexia, dysphagia, diarrhea, tongue edema

Hemic and Lymphatic: Anemia, leukocytosis

Metabolic and Nutritional: Edema, weight loss, hypomagnesemia, dehydration, hypercalcemia

Musculoskeletal: Joint disorder

Nervous: Dizziness, paresthesia, tremor, neuropathy, paralysis, facial paralysis, convulsion, hemiplegia

Respiratory: Dyspnea

Skin and appendages: Drainage, drainage serosanguinal, sweating

Special senses: Tinnitus, blindness, deafness

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ISS Table S-20

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Clinically important adverse events observed in patients treated in five IntraDose clinical studies (n=396) are described below:

 

Cerebrovascular Events: During the early portion of the North American placebo-controlled study, a total of six patients experienced a cerebrovascular event (5 IntraDose, 1 placebo). All of the events occurred during or shortly (within 1 to 2 hr) after treatment. These events were judged to be treatment related and most likely caused by carotid artery vasospasm. No events occurred after patients with tumors invading or threatening to invade the carotid artery were excluded from the study. The respective etiologies of these events have not been defined with certainty, and head and neck cancer itself, a known predisposing factor in cerebrovascular events, is listed among other possible causes that cannot be ruled out. Extreme care must be exercised when injecting IntraDose, particularly in areas where there are complex anatomical relationships (see CONTRAINDICATIONS and PRECAUTIONS).


ISS Section 18

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Cardiovascular Events: Cardiovascular-related events, including tachycardia
(15), hypertension (23), palpitations (4) were reported in 58 (15%) IntraDose or placebo treated patients in five clinical studies. Of these events, only 12 (3%) were considered severe. One patient experienced a non-fatal cardiopulmonary arrest following injection with IntraDose. The etiology of this event has not been determined; however, the patient had a history of hypertension and peripheral vascular arteriosclerotic disease and a prior cardiac arrest of unknown etiology.

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Significant Tissue Damage: Local cytotoxic effects may result in erosion, ulceration, bleeding or fistula formation. Spontaneous hemorrhage occurred in 22 (6%) of patients. Most of these events were mild or moderate in severity. In 3 cases, the hemorrhage was severe and led to death of the patient. The possible etiologies of these events include necrosis of a tumor that involves a blood vessel (e.g. carotid artery) and tumor necrosis secondary to local cytotoxic effects of cisplatin. Caution is advised in treating tumors that are friable or bleeding. Breakdown of tumor tissue and disease progression affecting adjacent tissue can lead to superficial bleeding and fistula development. Fistulae were reported in 10 (3%) patients (9 IntraDose, 1 placebo).

 

 

ISS Table S-20

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ISS Section 10

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Allergic Reactions: Four patients treated with IntraDose had an allergic reaction. One patient had an anaphylactoid reaction following IntraDose treatment. A second patient had an anaphylactoid reaction to systemically administered cisplatin after completing local treatment with IntraDose and may have developed sensitivity to cisplatin following local treatment. Two other patients had immediate local allergic-like reactions limited to the site of injection. Because the causes of these allergic reactions are not known, the risk of allergic reaction to any component of IntraDose must be considered (See CONTRAINDICATIONS and WARNINGS).

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OVERDOSAGE

Caution should be exercised to prevent inadvertent overdosage with IntraDose. An overdosage may cause excess local cytotoxic effects and can lead to development of an ulcer or fistula. There is no known antidote for IntraDose overdosage. Management of overdosage should include general supportive care to sustain the patient through any period of toxicity that may occur. Supportive care may involve intravenous hydration and routine wound care measures for the management of any local cytotoxic effects in surrounding normal tissues.

Drug Abuse and Overdosage

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A 10-mL dose of IntraDose contains 1 mg epinephrine. Patients with cardiovascular disease may be at increased risk of adverse events attributable to epinephrine. Patients with pre-existing hypertension should have their blood pressure adequately controlled. Epinephrine overdosage may result in extremely elevated arterial pressure, increased risk of cerebrovascular accident, pulmonary edema, transient bradycardia followed by tachycardia, and potentially fatal cardiac arrhythmias, or ventricular premature contractions. Other reported effects may include extreme pallor and coldness of the skin, metabolic acidosis and kidney failure. Patients treated for epinephrine overdose should receive appropriate supportive care.

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DOSAGE AND ADMINISTRATION

Physicians administering this product should be familiar with the local and surgical anatomy of the site of injection. In addition, to reduce the possibility of cardiovascular complications, patient blood pressure and pulse should be monitored regularly during treatment.

Radiological imaging studies with CT, MRI, ultrasound or other specialized radiological techniques may be required to accurately identify the extent of local tumor involvement and to plan the treatment program for local tumor injection (see PRECAUTIONS).

 

Treat each tumor with 0.25 mL IntraDose per cm3 of tumor volume to a maximum of 10 mL of IntraDose administered at any one visit. One or more tumors may be treated on any one treatment day. IntraDose should be administered on a weekly basis for up to 6 treatments (one cycle). Estimate tumor volume by physical examination or imaging studies using the three tumor dimensions (length x width x height x 0.5). At each treatment visit, the tumor volume should be remeasured and the dose volume recalculated, as needed. Additional treatment cycles can be administered if the tumor progresses or as new tumors develop.

Tumors treated with IntraDose should be monitored on a weekly basis to assess the effect of treatment on tumor regression, as well as any local cytotoxic effects on the tumor and adjacent tissues (see WARNINGS). If needed, treatment should be delayed for one week or until there is adequate healing of any local cytotoxic effects in the tumor or surrounding tissue.

 

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ISE 3.1.2.1

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Preparation Instructions: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Aseptic techniques should be employed during preparation of IntraDose. Precautions appropriate for the handling of antineoplastic agents should be exercised including preparation under a laminar flow hood (see DOSAGE AND ADMINISTRATION; Storage and Handling).

Needles containing aluminum parts that may come in contact with IntraDose should not be used for preparation or administration. Aluminum reacts with cisplatin, causing precipitate formation and a loss of potency.

 

 

 

 

 

 

 

 

 

 

 

 

 

Platinol Package Insert

Vol. 4.160/pg. 135

No components of the kits should be substituted.

Components of IntraDose must not be substituted with other forms of lyophilized cisplatin, epinephrine solution or collagen gel, as the IntraDose components are each uniquely formulated for use in IntraDose. The use of other formulations of these components will result in a physically or chemically different product that could affect the efficacy or safety of the preparation.

Remove kit from refrigerator and allow to warm to room temperature for at least 5 minutes.

Attach the sterile 22-gauge needle provided in the kit to the empty sterile 3-cc syringe. Withdraw 1.7 mL of IntraEpi (epinephrine solution), and transfer into the vial of IntraPlatin (cisplatin for injectable suspension). Discard the IntraEpi vial and remaining contents.

Vol. 2.1/pg. 47

Swirl the IntraPlatin vial for 30 seconds to yield a homogeneous suspension. Invert the vial and, while gently swirling, withdraw 1.5 mL of the reconstituted IntraPlatin suspension into the 3-cc syringe. Remove and discard the needle upon completion of withdrawal.

Remove the IntraGel syringe from the kit, remove its rubber tip cap and attach the Luer-lock syringe connector.

Attach the syringe containing the IntraPlatin suspension on the syringe connector attached to the IntraGel syringe. Make sure the connections are secure and then slowly transfer the suspension into the IntraGel syringe. Pushing the plunger gently will eject the outer stopper from the IntraGel syringe. Affix the plunger rod into the IntraGel syringe by placing the threaded end into the syringe barrel and screwing it gently into the inner (remaining) rubber plunger. With both syringes securely fastened to the syringe connector, rapidly transfer the contents back and forth between syringes for 30 seconds (30 strokes forward and 30 strokes backward) to effect complete mixing.

Vol. 2.1/pg. 47

Complete the mixing with all the contents in the 3-cc (plastic) syringe. Remove and discard the empty glass syringe and Luer-lock syringe connector; then attach a suitable sterile administration needle to the 3-cc syringe containing the final mixed IntraDose Injectable Gel. The needle for patient injection is not included in the IntraDose kit.

Preparation as specified results in 2 mL of a viscous, opaque, pale yellow gel containing 8.0 mg of cisplatin and 0.2 mg of epinephrine.

NOTE: Discard 4 hours after mixing.

 

 

 

 

 

 

 

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Intratumoral Injection Technique: The precise anatomical localization of the tumor should be well defined by physical examination or pretreatment CT, MRI or x-ray studies. If the exact placement of injections cannot be performed by visual guidance and physical examination, imaging guidance and monitoring of the procedure with ultrasound or CT scan may be necessary. Imaging-guidance is recommended for injection of tumors that may be impinging on major arteries, especially when the local anatomy has been altered by surgery or radiation. Care should be taken in order to avoid unintentional injection of IntraDose into a blood vessel (See PRECAUTIONS).

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Using a small (22 to 25 gauge) needle attached to a Luer-lock syringe, insert the needle into the base of the tumor at approximately a 45-degree angle. Pull back gently on the plunger. If blood appears, withdraw the needle and repeat. If blood does not appear, proceed with administration. Depending on the size and location of the tumor, the injection may be done by tracking the product through the tumor from a single puncture site or by injecting the tumor from multiple sites in parallel rows approximately 0.5 to 1.0 cm apart.