Pranactin Citric

Dosage Form: powder, for solution

Introduction and Test Instructions

Note: This “Introduction and Test Instructions” contains information for:

Test Collection Kit	Breath Test Instrument
BreathTek™ UBT for H. pylori	1. UBiT®-IR 300 Infrared Spectrophotometer
	2. POCone™ Infrared Spectrophotometer

I. Intended Use

The BreathTek™ UBT Collection Kit is intended for use in the qualitative detection of urease associated with Helicobacter pylori in the human stomach and as an aid in the initial diagnosis and post-treatment monitoring of Helicobacter pylori infection in adult patients. The test may be used for monitoring treatment if used at least four (4) weeks following completion of therapy. For these purposes, the system utilizes an Infrared Spectrophotometer for the measurement of the ratio of 13CO2 to 12CO2 in breath samples.

For administration by health care professionals. To be administered under a physician’s supervision.

II. Summary and Explanation

Since the isolation of the spiral urease-producing Helicobacter pylori bacteria (H. pylori) in 1983 by Drs. Marshall and Warren1, a significant body of evidence has accumulated indicating that the bacteria is an important pathogen in the upper GI tract of humans.2.3 The causal relationship between H. pylori and chronic active gastritis, duodenal ulcer, and gastric ulcer is well documented.4.5 Methods available for detecting current infection of the human stomach by H. pylori are generally divided into two (2) general types: Invasive and Non-invasive.

Invasive methods are so named because they include, as a first step, an esophagogastroduodenoscopy (“EGD”) with collection of gastric biopsies. These biopsies are then examined by one or more detection methods: histological examination of stained tissue, microbiological culture of the organism, or direct detection of urease activity in the tissue (for example, the CLOtest®). Biopsy based methods are expensive, entail some patient risk and discomfort and may give false negative results due to sampling errors when colonization of the gastric mucosa is patchy.6

The non-invasive, non-radioactive method for detecting current H. pylori infection is based on the BreathTek™ UBT which is described in the next section. Several serological tests that detect serum antibodies to H. pylori are commercially available. A positive result with these tests cannot distinguish between current infection and past exposure to infection and, therefore, is not a conclusive indicator of current gastrointestinal colonization by H. pylori.

III. Principle of the BreathTek™ UBT for H. pylori

1. Description of the Pranactin®-Citric Diagnostic Drug Component
   
   The diagnostic drug component of the kit is 13C-urea, a synthetic urea contained in a granulated powder (Pranactin®-Citric) for reconstitution with potable water to provide a clear solution for oral administration. The carbon in the drug component is predominantly Carbon-13, a stable, naturally occurring, non-radioactive isotope of carbon; the relative abundance of Carbon-13 is greater than or equal to 99%. Each three (3) gram dose of Pranactin®-Citric is supplied in a polyethylene-lined foil pouch and contains 75 mg of 13C-urea, citric acid7, aspartame and mannitol. 13C-urea is the diamide of 13C-carbonic acid and is highly soluble in water (1 gram per mL at 25°C). It has the following chemical formula: 13CH4N2O. An average adult body normally contains about 9 grams of urea, which is a product of protein metabolism. Urea in the body is referred to as natural isotopic abundance urea since it is composed of 98.9% 12C-urea and 1.1% 13C-urea.
   
   


2. Principle of the Test
   
   Pranactin®-Citric drug product is a component of the BreathTek™ UBT for H. pylori kit. Three (3) g of reconstituted Pranactin®-Citric containing 75 mg of 13C-urea is ingested by the patient. In the presence of urease associated with gastric H. pylori, 13C-urea is decomposed to 13CO2 and NH4 + according to the following equation:
   
   
   
   
   
   
   
   

   (NH2)213CO + H2O + 2H+	HP Urease	13CO2 + 2NH4+13C-urea
   	→

   
   The 13CO2, is absorbed in the blood, then exhaled in the breath. This results in an increase in the ratio of 13CO2 to 12CO2 in a POST-DOSE breath sample taken after the Pranactin®-Citric solution was consumed, compared to a BASELINE sample taken before the Pranactin®-Citric solution was consumed. Analysis of the breath samples is performed by UBiT®-IR300 Infrared Spectrophotometer or POCone™ Infrared Spectrophotometer [located at your testing laboratory, physician office or hospital].
   
   The BreathTek™ UBT can detect very low levels of H. pylori colonization and, by assessing the entire gastric mucosa, avoids the risk of sampling errors inherent in biopsy based methods. In the absence of gastric H. pylori, the 13C-urea does not produce 13CO2 in the stomach. The ratio of 13CO2 in the POST-DOSE breath sample remains essentially the same as the BASELINE.

IV. Warnings and Precautions

1. For in vitro diagnostic use only. The Pranactin®-Citric drug solution is taken orally as part of the diagnostic procedure.


2. Phenylketonurics: Contains Phenylalanine (one of the protein components of Aspartame), 84 mg per dosage unit. (For reference, 12 ounces of typical diet cola soft drinks contain approximately 80 mg of Phenylalanine.)


3. A negative result does not rule out the possibility of Helicobacter pylori infection. False negative results do occur with this procedure. If clinical signs are suggestive of H. pylori infection, retest with a new sample or an alternate method.


4. Antimicrobials, proton pump inhibitors, and bismuth preparations are known to suppress H. pylori. Ingestion of these within two (2) weeks prior to performing the BreathTek™ UBT may give false negative results.


5. A false positive test may occur due to urease associated with other gastric spiral organisms observed in humans such as Helicobacter heilmannii.


6. Premature POST-DOSE breath collection time can lead to a false negative diagnosis for a patient with a marginally positive BreathTek™ UBT result.


7. A false positive test could occur in patients who have achlorhydria.8


8. If particulate matter is visible in the reconstituted Pranactin®-Citric solution after thorough mixing, the solution should not be used.

V. Shelf Life and Storage

The BreathTek™ UBT Collection Kit should be stored at 15°-30°C (59°-86°F). Pranactin®-Citric has an expiration date. Do not use beyond the expiration date stated on the label.

VI. Patient Preparation

1. Remind the patient that Pranactin®-Citric contains phenylalanine (one of the protein components of Aspartame). Phenylketonurics restrict dietary phenylalanine.


2. The patient should have fasted at least one (1) hour before administering the BreathTek™ UBT.


3. The patient should not have taken antimicrobials, proton pump inhibitors, or bismuth preparations within two (2) weeks prior to administering the BreathTek™ UBT.

VII. Procedure for Collecting Breath Samples Using BreathTek™ UBT Kit, for Analysis by Infrared Spectrophotometer

A.

Materials

1. Materials provided
   
   Each sealed single-patient BreathTek™ UBT Collection Kit contains:
   
   • One (1) plastic kit tray containing
     

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     One (1) “How To” guide

     
     

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     Test instructions

     
     

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     One (1) pouch of Pranactin®-Citric powder (3 g)

     
     

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     A set of four (4) self-adhesive bar-code stickers. All bar-codes should bear the same number.

     
     

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     Two (2) breath collection bags, one (1) blue bag for the BASELINE sample and one (1) pink bag for the POST-DOSE sample.

     
     

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     One (1) sample transport bag

     
     

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     One (1) plastic straw

     
     

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     One (1) plastic drinking cup

     
     

   
   


2. Materials needed but not provided
   
   • A timer capable of timing an interval up to fifteen (15) minutes.
   
   
   • Scissors for opening the Pranactin®-Citric pouch.
   
   

Note: An Infrared Spectrophotometer (UBiT®-IR3000 or POCone™, Otsuka Pharmaceutical Co., Ltd.) is required for analysis of breath samples.

B.

Step-By-Step Procedure

 

Time intervals listed in the following step-by-step procedure are critical. They are highlighted by the timer icon:

1. Verify that the patient has been prepared for the test as specified in Section VI.


2. Open the BreathTek™ UBT Collection Kit, which should contain all the materials listed in Step VII. Slide out the kit tray. Label each breath collection bag to maintain patient identification using the bar-code labels provided, or according to your laboratory or office procedure.


3. Collect the BASELINE breath sample according to the following procedure:
   
   1. Remove the blue breath collection bag from the kit tray.
   
   
   2. Remove the pull-off cap from the mouthpiece of the breath collection bag.
   
   
   3. Instruct the patient to: (1) breathe normally; (2) take a deep breath then pause momentarily; (3) exhale into the mouthpiece of the bag.
   
   
   4. Replace the cap firmly until it clicks on the mouthpiece of the bag.
   
   


4. Prepare the Pranactin®-Citric solution no more than sixty (60) minutes before administering it to the patient. Urea slowly decomposes in water.
   
   1. Remove the Pranactin®-Citric pouch from the kit tray. Tap the upright packet of Pranactin®-Citric to settle the contents in the bottom half.
   
   
   2. With clean scissors, cut off the top of the packet and carefully empty the contents into the drinking cup provided, making sure to transfer all of the contents by tapping on the bottom of the pouch.
   
   
   3. Add potable water to the fill line indicated on the outside of the cup by a raised plastic ridge.
   
   
   4. Replace the lid securely and swirl the mixture for up to two (2) minutes to dissolve the packet contents; typically, only one (1) minute is required for complete dissolution. The resulting solution should be clear with no particulate matter. If particulate matter is present after thorough mixing, the solution should not be used.
   
   


5. Instruct the patient to drink all of the solution with the straw provided, without stopping. Advise the patient NOT to ‘rinse’ the inside of his/her mouth with the solution before swallowing. Discard the straw.


6. Set the timer for fifteen (15) minutes. The patient should sit quietly and should not eat, drink or smoke during the fifteen (15) minute interval.


7. After fifteen (15) minutes have elapsed, remove the pink breath collection bag from the kit tray. Collect the POST-DOSE breath sample according to the procedure described in Steps VII B.3.b through B.3.d.


8. Store the specimens at 15°-30°C (59°-86°F) until analysis is performed.


9. Perform breath sample analysis within seven (7) days of breath sample collection. If desired, use the plastic sample transport bag for transport of the breath samples.

VIII. Quality Control

Complete operating information, including self-diagnostic instrument routines and user maintenance procedures, is provided in the Instruction Manuals for the UBiT®-IR300 Spectrophotometer, the UBiT®-AS10 Autosampler and the POCone™ Spectrophotometer, respectively. Additionally, each office laboratory or test facility should follow its own internal procedures for quality control.

IX. Test Results

1. The Test Method
   
   The ratio of 13CO2 to 12CO2 in breath samples is determined by Infrared Spectrophotometer, (i.e., UBiT®-IR300 or POCone™).


2. Calculation of Results
   
   The result of the BreathTek™ UBT is provided as the Delta Over Baseline. No calculations are required by the user. Delta Over Baseline is the difference between the ratio (13CO2 / 12CO2) in the POST-DOSE sample and the corresponding ratio in the BASELINE sample.


3. Determination of the Cutoff Point
   
   The cutoff point is the level of BreathTek™ UBT result used to discriminate between H. pylori infected and uninfected individuals. For the BreathTek™ UBT, the Delta Over Baseline cutoff point was determined to be 2.4 in a controlled study of twenty-six (26) infected, and twenty-three (23) uninfected adult volunteers. Test subjects were judged to be in acceptable health based on the results of a medical history and physical examination and demonstrated no uncontrolled clinically significant abnormality other than, for some, symptoms of peptic ulcer. The previous version of the Meretek urea breath test, the Meretek UBT® was used as the reference standard. The cutoff point was calculated by determining the BreathTek™ UBT result level at which negative and positive subjects were best distinguished by co-optimization of relative sensitivity and specificity. The 2.4 cutoff point for the BreathTek™ UBT was verified in an independent study by retrospective analysis of Clinical Field Trial data collected on 145 H. pylori negative and 105 H. pylori positive test subjects, again using the original Meretek UBT® as reference. Asymptomatic subjects and those with dyspepsia were included in the validation study. Figure 1a depicts graphically the BreathTek™ UBT Delta Over Baseline cutoff point which distinguishes H. pylori positive and negative subjects. For the Meretek UBT® Breath Test, the Delta Over Baseline cutoff point was determined to be 2.4 in a controlled study of sixty-six (66) infected and fifty-three (53) uninfected asymptomatic, apparently healthy volunteers. Histological examination of biopsy tissue was used as the reference standard. The cutoff point was evaluated by determining the Meretek UBT® Breath Test result level at which histologically negative and positive subjects were best distinguished. Figure 1b graphically depicts the Meretek UBT® Breath Test Delta Over Baseline cutoff point which distinguishes histologically positive and negative subjects. Note that in Figures 1a and 1b, the Delta Over Baseline scales are logarithmic.
   
   
   


4. Interpretation of Results
   
   For the BreathTek™ UBT, a result greater than or equal to 2.4 Delta Over Baseline is interpreted as diagnostically positive indicating the presence of urease associated with H. pylori. A BreathTek™ UBT result less than 2.4 Delta Over Baseline is interpreted as diagnostically negative indicating the absence of urease associated with H. pylori. The 2.4 Delta Over Baseline cutoff point applies to both initial diagnosis and post-treatment monitoring of H. pylori infection.

X. Limitations of the Test

1. The BreathTek™ UBT should not be used until four (4) weeks or more after the end of treatment for the eradication of H. pylori as earlier post-treatment assessment may give false negative results.


2. The performance characteristics for persons under the age of eighteen (18) have not been established for this test.


3. The specimen integrity of breath samples and reference gases stored in breath bags under ambient conditions has not been determined beyond seven (7) days.


4. A correlation between the number of H. pylori organisms in the stomach and the BreathTek™ UBT result has not been established.


5. The predicate device (Meretek UBT®) was standardized in asymptomatic healthy volunteers and subsequently validated in clinical trials limited to patients with documented duodenal ulcer disease.

XI. Expected Values

Delta Over Baseline values for the BreathTek™ UBT were determined in a controlled clinical study of twenty-six (26) infected and twenty-three (23) uninfected adult volunteers. The Meretek UBT® Breath Test was used as the reference method in the diagnosis of infection. The range of BreathTek™ UBT Delta Over Baseline values for the uninfected group was determined to be 0.0 to 1.0. A histogram for the distribution of Delta Over Baseline values from the uninfected subjects is shown in Figure 2a.

Values for the Meretek UBT® Breath Test were determined in a controlled clinical study of sixty-six (66) infected and fifty-three (53) uninfected asymptomatic, apparently healthy volunteers. Histological examination of biopsy tissue was used as the reference method in the determination of infection in this study. The range of Meretek UBT® Delta Over Baseline values for the uninfected group was determined to be 0.0 to 2.2. A histogram for the distribution of Delta Over Baseline values from the uninfected subjects is shown in Figure 2b.

XII. Performance Characteristics

1. Performance Characteristics for the UBiT®-IR300 Spectrophotometer. Refer to the Instruction Manual for the instrument.


2. Performance Characteristics for the POCone™ Spectrophotometer. Refer to the Instruction Manual for the instrument.


3. Method Comparisons in Clinical Trials
   
   1. Comparison of the BreathTek™ UBT with the Meretek UBT®
      
      1. Experimental Design
         
         The method comparison data presented here were collected from a prospective, cross-over clinical field trial designed to validate the BreathTek™ UBT test procedure and to examine the effect of pre-test fasting time on test performance. The study included two hundred fifty-two (252) adult test subjects from Houston and Galveston, Texas. Subjects were judged to be in acceptable health based on the results of a medical history and physical examination and demonstrated no uncontrolled clinically significant abnormality other than, for some, symptoms of dyspepsia. Test subjects were tested for H. pylori infection using the Meretek UBT® Breath Test according to established procedure and with the BreathTek™ UBT under differing conditions of pre-test fasting times. Otherwise, no special instructions were given to subjects beyond those listed in the step-by-step procedures for administration of the Meretek UBT® and BreathTek™ UBT®. To minimize potential bias due to test order, the sequence of urea breath tests administered to each subject was randomized. All breath tests were administered to a given individual within fourteen (14) days of one another, most often and at a minimum, on successive days.
      
      
      2. Results
         
         It was demonstrated in the field trial that the BreathTek™ UBT may be administered at any time beyond one (1) hour after consuming solid and/or liquid food.
         
         
         Method comparison results are presented in a two-way contingency table on the following page (Table 1).
         
         
         Point estimates of Percent Agreement of the BreathTek™ UBT with Meretek UBT® positive and negative results are listed in the contingency table (Table 1). The comparative method for determining the true diagnosis was the predicate device (Meretek UBT®) rather than endoscopic methods. The exact binomial distribution was used to calculate the lower and upper limits of the 95% confidence intervals of the performance statistics. The confidence intervals are entered in parentheses following the point estimate of the statistic.
         
         
         
         
         
         
         
         
         
         
         
         
         
         
         
         
         
         
         
         
         

         Table 1. Comparison of BreathTek™ UBT (≥ 1-hour fast) with Meretek UBT®

         	BreathTek™ UBT Results
         Meretek UBT®	Positive	Negative	Total
         Positive	105	1	106
         Negative	1	145	146
         Total	106	146	252

         
         
         Percent Agreement with Meretek UBT® positive subjects: 99.1 % [95% CI: (94.9, 1.00.0)]
         
         Percent Agreement with Meretek UBT® negative subjects: 99.3% [95% CI: (96.2, 100.0)]
         
         
      
      
   
   
   2. Comparison of Gas Isotope Ratio Mass Spectrometry (GIRMS) and UBiT®-IR300 Infrared Spectrophotometry Method
      
      A multi-center prospective clinical trial was conducted to compare the UBiT®-IR300 method with the traditional GIRMS method. The study included a total of three hundred twenty (320) adult test subjects enrolled at four (4) physicans’ office laboratory (POL) settings and at a clinical laboratory. The results of the clinical trial are provided in the Instructional Manual for the UBiT®-IR300 Infrared Spectrophotometer (refer to the Application Note, 13C-Urea Breath Test using the UBiT®-IR300 Infrared Spectrophotometry System).
      
      
      Table 2 shows the percent agreement of the UBiT®-IR300 results as compared to the GIRMS method. Overall agreement was excellent at 99.06 percent.
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      

      Table 2. Agreement of UBiT®-IR300 and GIRMS for 13C urea breath test

      	GIRMS Results
      UBiT®-IR 300 Results	Positive	Negative	Total
      Positive	115	1	116
      Negative	2	202	204
      Total	117	203	320

      
      %Overall Agreement: 99.06% [95% CI: (97.35, 99.74)]
      
      %Positive Agreement: 98.29% [95% CI: (94.26, 99.70)]
      
      %Negative Agreement: 99.51% [95% CI: (97.49, 99.97)]
      
      
   
   
   3. Comparison of UBiT®-IR300 and POCone™ Infrared Spectrophotometry Methods
      
      
      A multi-center, prospective study was conducted to compare the POCone™ Infrared Spectrophotometer to the UBiT®-IR300 Infrared Spectrophotometer for measuring 13CO2 enrichment in breath. The study included a total of two hundred twenty (220) adult test subjects enrolled at five (5) physicians’ office laboratory (POL) and point of care (POC) settings. The results of the clinical trial are provided in the Instruction Manual for the POCone™ Infrared Spectrophotometer (refer to the Application Note, 13C-Urea Breath Test using the POCone™ Infrared Spectrophotometry System).
      
      
      Table 3 shows the percent agreement of the POCone™ results with the UBiT®-IR300 results. Overall agreement was 99.55 percent
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      

      Table 3. Agreement of POCone™ and UBiT®-IR300 for the 13C urea breath test

      	UBiT ® -IR 300 Results
      POCone™Results	Positive	Negative	Total
      Positive	86	1	87
      Negative	0	133	133
      Total	86	134	220

      
      
      %Overall Agreement: 99.55% [95% CI: (97.67, 99.98)]
      
      %Positive Agreement: 100.00% [95% CI: (95.90, 100.00)]
      
      %Negative Agreement: 99.25% [95% CI: (96.27, 99.96)]
      
      
   
   
   4. Comparison of Meretek UBT® with Endoscopic Methods
      
      1. Experimental Design
         
         The method comparison data presented here were collected from two (2) independent double blind clinical field trials which involved treatment of H. pylori infection. The studies included four hundred ninety-nine (499) adult patients with duodenal ulcer disease at seventy-five (75) clinical sites in the United States. Patients were tested for H. pylori infection initially (using histopathology, microbiological culture, CLOtest®, and the Meretek UBT®), and at various post-treatment intervals through out the study (using histopathology, microbiological culture, and the Meretek UBT®). In these clinical trials, patients were treated with various combinations of clarithromycin, omeprazole and placebo. Note, however, that there is no evidence that differing treatment regimens affect the performance of the Meretek UBT®.
         

         1)

         
         

         Histopathology
         
         Biopsy specimens, fixed with 10% buffered formalin were cut into 4-mm sections, stained with Genta stain and examined by an experienced pathologist.

         
         

         2)

         
         

         Microbiologic culture
         
         Culture was performed using fresh blood-based media, both selective and non-selective, at 37°C in 12% CO2 in air with 98% humidity. H. pylori were identified by Gram stain, typical colony morphology, and biochemical properties (production of oxidase, catalase and urease).

         
         

         3)

         
         

         CLOtest® (Delta West, Limited, Bently, West Australia)
         
         A biopsy specimen was tested for urease activity with the CLOtest® according to the instructions in its package insert.

         
         

         4)

         
         

         The Meretek UBT® Breath Test for H. pylori
         
         The diagnostic Meretek UBT® Breath Test was performed in accordance with procedures described in its package insert.

         
         

      
      
      2. Results
         
         Method comparison results are presented in two-way contingency tables. In Tables 4, 5, and 6, the Meretek UBT® Breath Test results are compared with the CLOtest®, histology, and with the combined endoscopic method results (CLOtest®, histology, and culture) for the initial patient visit9. In Table 7, the Meretek UBT® Breath Test results are compared with the combined endoscopic method results (histology and culture) for the post-treatment visits which occurred four (4) weeks or more after end of treatment. The exact binomial distribution was used to calculate the lower and upper limits of the 95% confidence intervals of the performance statistics. The confidence intervals are entered in parentheses following the point estimate of the statistic.
         
         
      
      
   
   


4. Performance Characteristics For Initial Diagnosis
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   

   Table 4. Comparison with CLOtest® for Initial Visit

   	Meretek™ UBT Results
   CLOtest® Results	Positive	Negative	Total
   Positive	397	31	428
   Negative	1	16	17
   Total	398	47	445

   
   Relative Sensitivity: 92.8% [95% CI: (90, 95)]
   
   Relative Specificity: 94.1% [95% CI: (71, l00)]
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   

   Table 5. Comparison with Histology for Initial Visit

   	Meretek™ UBT Results
   Histology	Positive	Negative	Total
   Positive	394	20	414
   Negative	3	27	30
   Total	397	47	444

   
   Sensitivity: 95.2% [95% CI: (93, 97)]
   
   Relative Specificity: 90.0% [95% CI: (74, 98)]
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   

   Table 6. Comparison with Combined Endoscopic Methods for Initial Visit

   Combined endoscopic methods used were CLOtest®, histology, and culture per DAIDP guidelines8 for pre-treatment diagnosis.
   	Meretek™ UBT Results
   Endoscopy	Positive	Negative	Total
   Positive	395	20	414
   Negative	3	26	29
   Total	398	46	444

   
   Sensitivity: 95.2% [95 % CI: (93, 97)]
   
   Specificity: 89.7% [95% CI: (73, 98)]
   
   
   E. Performance Characteristics for Post-Treatment Monitoring
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   

   Table 7. Comparison with Combined Endoscopic Methods* for Post-Treatment Visits (four weeks or more after End of Treatment (EOT))

   	Meretek UBT® Breath Test Results
   	1 Month EOT		3 Months EOT		6 Months EOT		1-6 Months ComBined
   Endoscopy	Pos	Neg	Pos	Neg	Pos	Neg	Pos	Neg
   Positive	187	6	123	8	91	5	401	19
   Negative	5	97	4	87	2	80	11	264
   Sensitivity (95% CI)	96.9 (93, 99)		93.9 (88, 97)		94.8 (88, 98)		95.5 (93, 97)
   Specificity (95% CI)	95.1 (89, 98)		95.6 (89, 99)		97.6 (92, 100)		96.0 (93, 98)
   *Combined endoscopic methods used were histology and culture per DAIDP guidelines8 for post-treatment monitoring.

   
   
   
   Please note that the post-treatment performance characteristics at 1, 3 and 6 months after therapy are not statistically different. Therefore, the single best estimates of sensitivity and specificity are presented in the 1-6 Months Combined column.
   
   
   Negative Predictive Value (NPV) for Post-Treatment Monitoring
   
   
   Given the post-treatment sensitivity (95.5%) and specificity (96.0%) observed in these studies, and assuming a treatment efficacy of 90% (10% prevalence of residual H. pylori infection), the NPV of the Meretek UBT® is greater than 99%. When efficacy of treatment drops to 50%, the NPV is still greater than 95%.

XIII. Bibliography

1. Marshall, B.J., Warren, J.R. Unidentified curved bacilli on gastric epithelium in active chronic gastritis, Lancet, June 4: 1273-1275; 1983.


2. Northfield T.C., Mendall M., Goggin P.M., (Eds), Helicobacter pylori infection. Pathophysiology, Epidemiology and Management. Kluwer Academic Publisher (1993).


3. Rathbone B.J., Heatley R.V., (Eds) Helicobacter pylori and Gastroduodenal Disease, Blackwell Scientific Publications, 2nd edition (1992).


4. Helicobacter pylori in Peptic Ulcer Diseases, Program and Abstracts. NIH Consensus Development Conference, February 7-9, 1994, Bethesda, MD.


5. NIH Consensus Development Panel, H. pylori in Peptic Ulcer Disease, JAMA, July 6, 1994 - Vol. 272, No.1, 65-69.


6. Reference 2, page 113.


7. Graham, D.Y., Runke, D., Anderson, S., Malaty, H.M., and Klein, P.D. Citric Acid as the Test Meal for the 13C-Urea Breath Test. American Journal of Gastroenterology, 5, 1214-1217; 1999.


8. Borriello, S.P., Reed, P.J., Dolby, J.M., Barclay, F.E. and Webster, A.D.B. Microbial and metabolic profile of achlorhydric stomach: comparison of pernicious anemia and hypogammaglobulinaemia. J. Chin. Pathol. 38, 946-953; 1985.


9. FDA, Center for Drug Evaluation and Research, Division of Anti-Infective Drug Products, DAIDP Points to consider document - Helicobacter pylori-associated Peptic Ulcer Disease. Indication #25. (March 1995 Addendum to March 15, 1995 Draft).

XIV. Name and Place of Business

The BreathTek™ UBT for H. pylori Collection Kit is manufactured for Meretek Diagnostics Group of Otsuka America Pharmaceutical, Inc., 2440 Research Boulevard, Rockville, MD 20850.

XV. Labeling Revision Information

Revision: September 2008

Print Code: 0508L-0177

Part Number: 002215AC

Directions For Use:

The PranactinR-Citric in this container

is intended for use only as a

componet of a BreathTekTM UBT for

H. pylori. See package insert for

instructions on how to prepare the

solution and directions for use.


Phenylketonurics: Contains

Phenylalanine, 84 mg Per Pouch


Part No. 002201AA

Print Code: 0508L-0155

US PATENT 4,830,010



NDC 59148-023-33


PranactinR-Citric


Contains: 13C-Urea, 75mg


For in vitro diagnostic use only.

The PranactinR-Citric drug is

taken orally as part of the

BreathTekTM UBT for H. pylori.


Store at 15o-30oC (59o-86oF)


Manufactured for

Otsuka America Pharmaceutical, Inc.

Rockville, MD 20850


002204AA

PRANACTIN-CITRIC  urea c-13  powder, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 59148-023 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength UREA C-13 (UREA C-13) UREA C-13 75 mg  in 3000 mg

Inactive Ingredients Ingredient Name Strength ANHYDROUS CITRIC ACID 2000 mg  in 3000 mg MANNITOL 775 mg  in 3000 mg ASPARTAME 150 mg  in 3000 mg

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 59148-023-33 75 mg In 1 KIT None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA020586	05/10/2001

Labeler - Otsuka America Pharmaceutical (008314390)

Registrant - Otsuka America Pharmaceutical (008314390)

Revised: 08/2009Otsuka America Pharmaceutical

ProQuad

Pronunciation: MEE-zills, mumps, rue-BELL-a, ver-i-SELL-a
Generic Name: Measles, Mumps, Rubella, and Varicella Vaccine
Brand Name: ProQuad

ProQuad is used for:

Preventing measles, mumps, rubella, and varicella (chickenpox).

ProQuad is a vaccine. It stimulates the body to produce antibodies against infection of measles, mumps, rubella, or chickenpox.

Do NOT use ProQuad if:

• you are allergic to any ingredient in ProQuad, including gelatin


• you have had a severe allergic reaction (eg, severe rash, hives, difficulty breathing, dizziness) to neomycin


• you have a weakened immune system (eg, advanced HIV, AIDS, decreased gamma globulin levels, decreased white blood cell levels), blood problems, cancer affecting the blood or bone marrow (eg, leukemia), fever, or active or untreated tuberculosis (TB)


• you are pregnant


• you are taking an immunosuppressant (eg, cyclosporine) or a salicylate (eg, aspirin)

Contact your doctor or health care provider right away if any of these apply to you.

Before using ProQuad:

Some medical conditions may interact with ProQuad. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are planning to become pregnant or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you are allergic to eggs


• if you have an infection, a tumor, HIV, low blood platelet levels, a history of seizures or head injury, or a family history of seizures or immune system weakness


• if you have had a recent blood or plasma transfusion or have received immune globulin or a tuberculin test


• if you have been exposed to measles, mumps, rubella, or chickenpox


• if you have a history of tuberculosis

Some MEDICINES MAY INTERACT with ProQuad. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Corticosteroids (eg, prednisone) or immunosuppressants (eg, cyclosporine) because the effectiveness of ProQuad may be decreased


• Salicylates (eg, aspirin) because the risk of side effects may be increased

This may not be a complete list of all interactions that may occur. Ask your health care provider if ProQuad may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use ProQuad:

Use ProQuad as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• ProQuad is administered as an injection at your doctor's office, hospital, or clinic. Ask your doctor any questions that you may have about ProQuad.


• If you miss a dose of ProQuad, contact your doctor to set up a new dosing schedule.

Ask your health care provider any questions you may have about how to use ProQuad.

Important safety information:

• ProQuad may cause drowsiness or dizziness. Do not drive, operate machinery, or do anything else that could be dangerous until you know how you react to ProQuad. Using ProQuad alone, with certain other medicines, or with alcohol may lessen your ability to drive or perform other potentially dangerous tasks.


• ProQuad may decrease the effectiveness of tuberculin tests. If you are scheduled to have a tuberculin test within 6 weeks after receiving this vaccination, contact your doctor. You may need to reschedule your tuberculin test.


• Avoid contact with individuals with weakened immune systems, pregnant women who have not had chickenpox, and newborns whose mothers have not had chickenpox for 6 weeks after receiving this vaccination.


• Avoid use of salicylates (eg, aspirin) for 6 weeks after receiving this vaccination.


• Keep written documentation of all vaccinations received to help avoid unnecessary doses. Be sure that your doctor knows the dates that you have received other vaccinations.


• This vaccine may not guarantee protection against measles, mumps, rubella, or chickenpox. Discuss any questions or concerns with your doctor.


• Adult women may experience joint pain 2 to 4 weeks after receiving this injection. This usually lasts only a short time. However, these symptoms have persisted for months or, rarely, years.


• ProQuad contains albumin, which comes from human blood. There is an extremely rare risk of developing a viral disease, or a central nervous system disease called Creutzfeldt-Jakob disease. No cases of viral diseases or Creutzfeldt-Jakob disease from albumin have been identified.


• Use ProQuad with extreme caution in CHILDREN younger than 12 months of age. Safety and effectiveness in this age group have not been confirmed.


• PREGNANCY and BREAST-FEEDING: Do not use ProQuad if you are pregnant. If you suspect that you could be pregnant, contact your doctor immediately. After receiving ProQuad, do not become pregnant for at least 3 months without checking with your doctor. It is unknown if ProQuad is excreted in breast milk. Do not breast-feed while using ProQuad.

Possible side effects of ProQuad:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Diarrhea; dizziness; fever; general unwell feeling; headache; irritability; mild rash; muscle or joint ache or pain; nausea; pain, tenderness, soreness, or swelling at the injection site; tiredness; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); fainting; loss of coordination; mental or mood changes; numbness or tingling in the fingers or toes; red, swollen, blistered, or peeling skin; seizures; unusual bruising or bleeding; vision or hearing changes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: ProQuad side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of ProQuad:

ProQuad is usually handled and stored by a health care provider. If you are using ProQuad at home, store ProQuad as directed by your pharmacist or health care provider. Keep ProQuad out of the reach of children and away from pets.

General information:

• If you have any questions about ProQuad, please talk with your doctor, pharmacist, or other health care provider.


• ProQuad is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about ProQuad. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More ProQuad resources

• ProQuad Side Effects (in more detail)
• ProQuad Use in Pregnancy & Breastfeeding
• ProQuad Drug Interactions
• ProQuad Support Group
• 0 Reviews for ProQuad - Add your own review/rating

• ProQuad Prescribing Information (FDA)


• ProQuad Advanced Consumer (Micromedex) - Includes Dosage Information


• ProQuad Consumer Overview

Compare ProQuad with other medications

• Measles Prophylaxis
• Mumps Prophylaxis
• Rubella Prophylaxis
• Varicella-Zoster, Prophylaxis

Provenge

sipuleucel-t

Dosage Form: injection
FULL PRESCRIBING INFORMATION

Indications and Usage for Provenge

Provenge® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

Provenge Dosage and Administration

For Autologous Use Only.

For Intravenous Use Only. Do Not Use a Cell Filter.

Do Not Initiate Infusion of Expired Product.

Dose and Schedule

Each dose of Provenge contains a minimum of 50 million autologous CD54+ cells activated with PAP-GM-CSF [see Description (11)].

The recommended course of therapy for Provenge is 3 complete doses, given at approximately 2-week intervals. In controlled clinical trials, the median dosing interval between infusions was 2 weeks (range 1 to 15 weeks); the maximum dosing interval has not been established.

If, for any reason, the patient is unable to receive a scheduled infusion of Provenge, the patient will need to undergo an additional leukapheresis procedure if the course of treatment is to be continued. Patients should be advised of this possibility prior to initiating treatment.

Premedication

To minimize potential acute infusion reactions such as chills and/or fever, it is recommended that patients be premedicated orally with acetaminophen and an antihistamine such as diphenhydramine approximately 30 minutes prior to administration of Provenge [see Warnings and Precautions (5.1)].

Handling Precautions for Control of Infectious Disease

Provenge is not routinely tested for transmissible infectious diseases. Therefore, patient leukapheresis material and Provenge may carry the risk of transmitting infectious diseases to health care professionals handling the product. Employ universal precautions in handling leukapheresis material or Provenge. [See How Supplied/Storage and Handling (16).]

Storage

The Provenge infusion bag must remain within the insulated polyurethane container until the time of administration. Do not remove the insulated polyurethane container from the outer cardboard shipping box. [See How Supplied/Storage and Handling (16).]

Confirm Product Release Before Infusion

Do not infuse Provenge until confirmation of product release has been received from Dendreon. Dendreon will send a Cell Product Disposition Form containing the patient identifiers, expiration date and time, and the disposition status (approved for infusion or rejected), to the infusion site. [See How Supplied/Storage and Handling (16).]

Preparation for Infusion

See How Supplied/Storage and Handling (16) for full handling instructions.

Confirm Patient Identity

Provenge is intended solely for autologous use. Confirm the proper product has been received according to the label on the outside of the insulated polyurethane container. Prior to Provenge infusion, match the patient's identity with the patient identifiers on the Cell Product Disposition Form and the Provenge infusion bag.

Inspect the Infusion Bag

Remove the infusion bag from the insulated polyurethane container and inspect the bag for signs of leakage. Do not administer if the bag leaks.

Contents of the bag will be slightly cloudy, with a cream-to-pink color. Gently mix and re-suspend the contents of the bag, inspecting for clumps and clots. Small clumps of cellular material should disperse with gentle manual mixing. Do not administer if the bag leaks during handling or if clumps remain in the bag.

Administration

Infusion must begin prior to the expiration date and time indicated on the Cell Product Disposition Form and Product Label. Do not initiate infusion of expired Provenge.

Administer Provenge via intravenous infusion over a period of approximately 60 minutes. Do not use a cell filter. Provenge is supplied in a sealed, patient-specific infusion bag; the entire volume of the bag should be infused.

Observe the patient for at least 30 minutes following each infusion.

Administration Modification for Infusion Reactions

Acute infusion reactions such as chills, fatigue, fever, nausea, and joint ache were frequently observed in studies of Provenge. To mitigate such reactions, premedication, consisting of acetaminophen and an antihistamine such as diphenhydramine, was administered in clinical studies prior to infusion.

In the event of an acute infusion reaction, the infusion may be interrupted or slowed, depending on the severity of the reaction. Appropriate medical therapy should be administered as needed. In controlled clinical trials, symptoms of acute infusion reactions were treated with acetaminophen, intravenous H1 and/or H2 blockers, and low dose intravenous meperidine.

If the infusion of Provenge must be interrupted, the infusion should not be resumed if the Provenge infusion bag will be held at room temperature for more than 3 hours. [See How Supplied/Storage and Handling (16).]

Dosage Forms and Strengths

Each dose of Provenge contains a minimum of 50 million autologous CD54+ cells activated with PAP-GM-CSF, suspended in 250 mL of Lactated Ringer's Injection, USP in a sealed, patient-specific infusion bag.

Contraindications

None.

Warnings and Precautions

Provenge is intended solely for autologous use.

Acute Infusion Reactions

Acute infusion reactions (reported within 1 day of infusion) included, but were not limited to, fever, chills, respiratory events (dyspnea, hypoxia, and bronchospasm), nausea, vomiting, fatigue, hypertension, and tachycardia. In controlled clinical trials, 71.2% of patients in the Provenge group developed an acute infusion reaction. The most common events (≥ 20%) were chills, fever, and fatigue. In 95.1% of patients reporting acute infusion reactions, the events were mild or moderate. Fevers and chills generally resolved within 2 days (71.9% and 89.0%, respectively).

In controlled clinical trials, severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the Provenge group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. The incidence of severe events was greater following the second infusion (2.1% vs. 0.8% following the first infusion), and decreased to 1.3% following the third infusion. Some (1.2%) patients in the Provenge group were hospitalized within 1 day of infusion for management of acute infusion reactions. No Grade 4 or 5 acute infusion reactions were reported in patients in the Provenge group.

Closely monitor patients with cardiac or pulmonary conditions. In the event of an acute infusion reaction, the infusion rate may be decreased, or the infusion stopped, depending on the severity of the reaction. Appropriate medical therapy should be administered as needed. [See Administration Modification for Infusion Reactions (2.8) and How Supplied/Storage and Handling (16).]

Handling Precautions for Control of Infectious Disease

Provenge is not routinely tested for transmissible infectious diseases. Therefore, patient leukapheresis material and Provenge may carry the risk of transmitting infectious diseases to health care professionals handling the product. Accordingly, health care professionals should employ universal precautions when handling leukapheresis material or Provenge. [See How Supplied/Storage and Handling (16).]

Concomitant Chemotherapy or Immunosuppressive Therapy

Use of either chemotherapy or immunosuppressive agents (such as systemic corticosteroids) given concurrently with the leukapheresis procedure or Provenge has not been studied. Provenge is designed to stimulate the immune system, and concurrent use of immunosuppressive agents may alter the efficacy and/or safety of Provenge. Therefore, patients should be carefully evaluated to determine whether it is medically appropriate to reduce or discontinue immunosuppressive agents prior to treatment with Provenge.

Product Safety Testing

Provenge is released for infusion based on the microbial and sterility results from several tests: microbial contamination determination by Gram stain, endotoxin content, and in-process sterility with a 2-day incubation to determine absence of microbial growth. The final (7-day incubation) sterility test results are not available at the time of infusion. If the sterility results become positive for microbial contamination after Provenge has been approved for infusion, Dendreon will notify the treating physician. Dendreon will attempt to identify the microorganism, perform antibiotic sensitivity testing on recovered microorganisms, and communicate the results to the treating physician. Dendreon may request additional information from the physician in order to determine the source of contamination.

Adverse Reactions

Clinical Trials Experience

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

The safety evaluation of Provenge is based on 601 prostate cancer patients in the Provenge group who underwent at least 1 leukapheresis procedure in four randomized, controlled clinical trials. The control was non-activated autologous peripheral blood mononuclear cells.

Almost all (98.3%) patients in the Provenge group and 96.0% in the control group reported an adverse event. The most common adverse events, reported in patients in the Provenge group at a rate ≥ 15%, were chills, fatigue, fever, back pain, nausea, joint ache, and headache. In 67.4% of patients in the Provenge group, these adverse events were mild or moderate in severity. Severe (Grade 3) and life-threatening (Grade 4) adverse events were reported in 23.6% and 4.0% of patients in the Provenge group compared with 25.1% and 3.3% of patients in the control group. Fatal (Grade 5) adverse events were reported in 3.3% of patients in the Provenge group compared with 3.6% of patients in the control group. The most common (≥ 2%) Grade 3-5 adverse events reported in the Provenge group were back pain and chills.

Serious adverse events were reported in 24.0% of patients in the Provenge group and 25.1% of patients in the control group. Serious adverse events in the Provenge group included acute infusion reactions [see Warnings and Precautions (5.1)], cerebrovascular events, and single case reports of eosinophilia, rhabdomyolysis, myasthenia gravis, myositis, and tumor flare.

Provenge was discontinued in 1.5% of patients in Study 1 due to adverse events. Some patients who required central venous catheters for treatment with Provenge developed infections, including sepsis. A small number of these patients discontinued treatment as a result. Monitoring for infectious sequelae in patients with central venous catheters is recommended.

Each dose of Provenge requires a standard leukapheresis procedure approximately 3 days prior to the infusion. Adverse events that were reported ≤ 1 day following a leukapheresis procedure in ≥ 5% of patients in controlled clinical trials included citrate toxicity (14.2%), oral paresthesia (12.6%), paresthesia (11.4%), and fatigue (8.3%).

Table 1 provides the frequency and severity of adverse events reported in ≥ 5% of patients in the Provenge group of randomized, controlled trials of men with prostate cancer. The population included 485 patients with metastatic castrate resistant prostate cancer and 116 patients with non-metastatic androgen dependent prostate cancer who were scheduled to receive 3 infusions of Provenge at approximately 2-week intervals. The population was age 40 to 91 years (median 70 years), and 90.6% of patients were Caucasian.

Table 1 Incidence of Adverse Events Occurring in ≥ 5% of Patients Randomized to Provenge

	Provenge (N = 601)				Control* (N = 303)
	All Grades n (%)		Grade 3-5 n (%)		All Grades n (%)		Grade 3-5 n (%)
Any Adverse Event	591 (98.3)		186 (30.9)		291 (96.0)		97 (32.0)
* Control was non-activated autologous peripheral blood mononuclear cells.
Chills	319 (53.1)		13 (2.2)		33 (10.9)		0 (0.0)
Fatigue	247 (41.1)		6 (1.0)		105 (34.7)		4 (1.3)
Fever	188 (31.3)		6 (1.0)		29 (9.6)		3 (1.0)
Back pain	178 (29.6)		18 (3.0)		87 (28.7)		9 (3.0)
Nausea	129 (21.5)		3 (0.5)		45 (14.9)		0 (0.0)
Joint ache	118 (19.6)		11 (1.8)		62 (20.5)		5 (1.7)
Headache	109 (18.1)		4 (0.7)		20 (6.6)		0 (0.0)
Citrate toxicity	89 (14.8)		0 (0.0)		43 (14.2)		0 (0.0)
Paresthesia	85 (14.1)		1 (0.2)		43 (14.2)		0 (0.0)
Vomiting	80 (13.3)		2 (0.3)		23 (7.6)		0 (0.0)
Anemia	75 (12.5)		11 (1.8)		34 (11.2)		7 (2.3)
Constipation	74 (12.3)		1 (0.2)		40 (13.2)		3 (1.0)
Pain	74 (12.3)		7 (1.2)		20 (6.6)		3 (1.0)
Paresthesia oral	74 (12.3)		0 (0.0)		43 (14.2)		0 (0.0)
Pain in extremity	73 (12.1)		5 (0.8)		40 (13.2)		1 (0.3)
Dizziness	71 (11.8)		2 (0.3)		34 (11.2)		0 (0.0)
Muscle ache	71 (11.8)		3 (0.5)		17 (5.6)		0 (0.0)
Asthenia	65 (10.8)		6 (1.0)		20 (6.6)		2 (0.7)
Diarrhea	60 (10.0)		1 (0.2)		34 (11.2)		3 (1.0)
Influenza-like illness	58 (9.7)		0 (0.0)		11 (3.6)		0 (0.0)
Musculoskeletal pain	54 (9.0)		3 (0.5)		31 (10.2)		3 (1.0)
Dyspnea	52 (8.7)		11 (1.8)		14 (4.6)		3 (1.0)
Edema peripheral	50 (8.3)		1 (0.2)		31 (10.2)		1 (0.3)
Hot flush	49 (8.2)		2 (0.3)		29 (9.6)		1 (0.3)
Hematuria	46 (7.7)		6 (1.0)		18 (5.9)		3 (1.0)
Muscle spasms	46 (7.7)		2 (0.3)		17 (5.6)		0 (0.0)
Hypertension	45 (7.5)		3 (0.5)		14 (4.6)		0 (0.0)
Anorexia	39 (6.5)		1 (0.2)		33 (10.9)		3 (1.0)
Bone pain	38 (6.3)		4 (0.7)		22 (7.3)		3 (1.0)
Upper respiratory tract infection	38 (6.3)		0 (0.0)		18 (5.9)		0 (0.0)
Insomnia	37 (6.2)		0 (0.0)		22 (7.3)		1 (0.3)
Musculoskeletal chest pain	36 (6.0)		2 (0.3)		23 (7.6)		2 (0.7)
Cough	35 (5.8)		0 (0.0)		17 (5.6)		0 (0.0)
Neck pain	34 (5.7)		3 (0.5)		14 (4.6)		2 (0.7)
Weight decreased	34 (5.7)		2 (0.3)		24 (7.9)		1 (0.3)
Urinary tract infection	33 (5.5)		1 (0.2)		18 (5.9)		2 (0.7)
Rash	31 (5.2)		0 (0.0)		10 (3.3)		0 (0.0)
Sweating	30 (5.0)		1 (0.2)		3 (1.0)		0 (0.0)
Tremor	30 (5.0)		0 (0.0)		9 (3.0)		0 (0.0)

Cerebrovascular Events

In controlled clinical trials, cerebrovascular events, including hemorrhagic and ischemic strokes, were observed in 3.5% of patients in the Provenge group compared with 2.6% of patients in the control group.

Drug Interactions

No studies of drug interactions have been performed with Provenge.

USE IN SPECIFIC POPULATIONS

Geriatric

In controlled clinical trials, 72.9% of patients (438 of 601) in the Provenge group were ≥ 65 years of age. There were no apparent differences in the safety of Provenge between patients ≥ 65 years of age and younger patients.

In a survival analysis of the controlled clinical trials of Provenge in metastatic castrate resistant prostate cancer, 78.3% of randomized patients (382 of 488) were ≥ 65 years of age. The median survival of patients in the Provenge group ≥ 65 years of age was 23.4 months (95% confidence interval 22.0, 27.1), compared with 17.3 months in the control group (95% confidence interval: 13.5, 21.5).

Race

In controlled clinical trials, 90.6% of patients were Caucasian, 5.8% were African American, and 3.7% were “Other”. Due to the low numbers of non-Caucasian patients in the trials, no conclusions can be made regarding the safety or efficacy of Provenge by race.

Overdosage

Each Provenge infusion comprises the maximum number of cells that can be manufactured from a single leukapheresis procedure. The number of cells in Provenge does not exceed the number of cells collected from the leukapheresis. There are no known instances of overdosage from either a single infusion or a full course of therapy with Provenge.

Provenge Description

Provenge consists of autologous peripheral blood mononuclear cells, including antigen presenting cells (APCs), that have been activated during a defined culture period with a recombinant human protein, PAP-GM-CSF, consisting of prostatic acid phosphatase (PAP), an antigen expressed in prostate cancer tissue, linked to granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune cell activator. The patient's peripheral blood mononuclear cells are obtained via a standard leukapheresis procedure approximately 3 days prior to the infusion date. Due to the autologous nature of Provenge, it is important that the patient and physician adhere to the personalized leukapheresis and infusion schedules.

The active components of Provenge are autologous APCs and PAP-GM-CSF. During culture, the recombinant antigen can bind to and be processed by APCs into smaller protein fragments. The recombinant antigen is designed to target APCs, and may help direct the immune response to PAP. Minimal residual levels of the intact PAP-GM-CSF are detectable in the final Provenge product.

The cellular composition of Provenge is dependent on the composition of cells obtained from the patient's leukapheresis. In addition to APCs, the final product contains T cells, B cells, natural killer (NK) cells, and other cells. The number of cells present and the cellular composition of each Provenge dose will vary. Each dose of Provenge contains a minimum of 50 million autologous CD54+ cells activated with PAP-GM-CSF, suspended in 250 mL of Lactated Ringer's Injection, USP.

The potency of Provenge is in part determined by measuring the increased expression of the CD54 molecule, also known as ICAM-1, on the surface of APCs after culture with PAP-GM-CSF. CD54 is a cell surface molecule that plays a role in the immunologic interactions between APCs and T cells, and is considered a marker of immune cell activation.

Provenge - Clinical Pharmacology

Mechanism of Action

Provenge is classified as an autologous cellular immunotherapy. While the precise mechanism of action is unknown, Provenge is designed to induce an immune response targeted against PAP, an antigen expressed in most prostate cancers. During ex vivo culture with PAP-GM-CSF, APCs take up and process the recombinant target antigen into small peptides that are then displayed on the APC surface.

In Study 1, 237 out of the 512 patients randomized were evaluated for the development of humoral and T cell immune responses (proliferative and gamma-interferon (γIFN) ELISPOT) to the target antigens at Baseline, and at Weeks 6, 14, and 26. Antibody (IgM and IgG) responses against PAP-GM-CSF and PAP antigen alone were observed through the follow-up period in the Provenge group. Neutralizing antibody responses to GM-CSF were transient. T cell proliferative and γIFN ELISPOT responses to PAP-GM-CSF fusion protein were observed in cells collected from peripheral blood of patients through the follow-up period in the Provenge treatment group but not in controls. In some patients a response to PAP antigen alone was observed. No conclusions could be made regarding the clinical significance of the observed immune responses.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity or mutagenicity studies of Provenge in animals were conducted. No studies on the effects of Provenge on fertility have been conducted.

Clinical Studies

The effect of Provenge on patients with metastatic castrate resistant (hormone refractory) prostate cancer was studied in three similar randomized, double-blind, placebo-controlled, multicenter trials. Following randomization, patients from both treatment groups underwent a series of 3 leukapheresis procedures (at approximately Weeks 0, 2, and 4). Each leukapheresis was followed approximately 3 days later by infusion of Provenge or control. The control was autologous peripheral blood mononuclear cells that had not been activated [see Description (11)]. Following disease progression, patients were treated at the physician's discretion with other anti-cancer interventions.

Study 1

Study 1 was a randomized, double-blind, placebo-controlled, multicenter trial in patients with asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. Eligible patients had metastatic disease in the soft tissue and/or bone with evidence of progression either at these sites or by serial Prostate Specific Antigen (PSA) measurements. Exclusion criteria included visceral (liver, lung, or brain) metastases, moderate to severe prostate cancer-related pain, and use of narcotics for cancer-related pain.

A total of 512 patients were randomized in a 2:1 ratio to receive Provenge (n=341) or control (n=171). The median age was 71, and 90% of the patients were Caucasian. Thirty-five percent of patients had undergone radical prostatectomy, 54% had received local radiotherapy, and 82% had received combined androgen blockade. All patients had baseline testosterone levels < 50 ng/mL. Forty-eight percent of patients were receiving bisphosphonates and 18% had received prior chemotherapy, including docetaxel. Eighty-two percent of patients had an ECOG performance status of 0; 58% had primary Gleason scores of four or more; 44% had bone and soft tissue disease; 48% had bone-only disease; 7% had soft tissue-only disease; and 43% had greater than ten bony metastases.

Supportive Studies

Study 2 was a randomized, double-blind, placebo-controlled, multicenter trial in patients with metastatic castrate resistant prostate cancer and no cancer-related pain. The primary endpoint was time to disease progression; analysis of the primary endpoint did not reach statistical significance. All patients were to be followed for survival; however, the survival analysis was not pre-specified. A third study, similar in design to Study 2, was terminated prior to completion of planned accrual.

Summary of Study Results

Figure 1 and Table 2 present overall survival results observed in two randomized, Phase 3 studies of Provenge in men with metastatic castrate resistant prostate cancer. The survival findings were consistent across multiple subgroups. Analyses of time to disease progression did not meet statistical significance in any Phase 3 study of Provenge.

Figure 1 Kaplan-Meier Overall Survival Curve for Study 1

Table 2 Summary of Overall Survival (All Patients as Randomized)

a Hazard ratio and p-value based on the Cox Model adjusted for PSA (ln) and LDH (ln) and stratified by bisphosphonate use, number of bone metastases, and primary Gleason grade.
b Hazard ratio based on the unadjusted Cox Model (not pre-specified).
c p-value based on a log-rank test (not pre-specified).
Abbreviations: CI = confidence interval.
	Study 1		Study 2
	Provenge (N=341)	Control (N=171)	Provenge(N=82)	Control (N=45)
Overall Survival
Median, months      (95% CI)	25.8 (22.8, 27.7)	21.7 (17.7, 23.8)	25.9 (20.0, 32.4)	21.4 (12.3, 25.8)
Hazard Ratio      (95% CI)	0.775a (0.614, 0.979)		0.586b (0.388, 0.884)
p-value	0.032a		0.010c

How Supplied/Storage and Handling

Provenge IS INTENDED SOLELY FOR AUTOLOGOUS USE. Provenge is a 250 mL suspension containing a minimum of 50 million autologous CD54+ cells activated with PAP-GM-CSF in Lactated Ringer's Injection, USP, and supplied in an infusion bag labeled for the specific recipient. The identity of the patient must be matched with the patient identifiers on the infusion bag and the Cell Product Disposition Form prior to infusion. Provenge is not routinely tested for transmissible infectious diseases. Therefore, patient leukapheresis material and Provenge may carry the risk of transmitting infectious diseases to health care professionals handling the product. Accordingly, health care professionals should employ universal precautions when handling leukapheresis material or Provenge.

Handling Instructions:

1. Provenge is shipped directly to the infusing provider.


2. Provenge will arrive in a cardboard shipping box with a special insulated polyurethane container inside. The insulated container and gel packs within the container are designed to maintain the appropriate transportation and storage temperature of Provenge until infusion.


3. Upon receipt, the outer cardboard shipping box should be opened to verify the product and patient-specific labels located on the top of the insulated container. Do not remove this insulated container from the shipping box, or open the lid of the insulated container, until the patient is ready for infusion.


4. Do not infuse Provenge until confirmation of product release has been received from Dendreon. Dendreon will send a Cell Product Disposition Form containing the patient identifiers, expiration date and time, and the disposition status (approved for infusion or rejected), to the infusion site.


5. Infusion must begin prior to the expiration date and time indicated on the Cell Product Disposition Form and Product Label. Do not initiate infusion of expired Provenge. Once the Provenge infusion bag is removed from the insulated container, it should remain at room temperature for no more than 3 hours. Provenge should not be returned to the shipping container.


6. Once the patient is prepared for infusion and the Cell Product Disposition Form has been received, remove the Provenge infusion bag from the insulated container and inspect the bag for signs of leakage. Contents of the bag will be slightly cloudy, with a cream-to-pink color. Gently mix and re-suspend the contents of the bag, inspecting for clumps and clots. Small clumps of cellular material should disperse with gentle manual mixing. Do not administer if the bag leaks or if clumps remain in the bag.


7. Prior to Provenge infusion, match the patient's identity with the patient identifiers on the Cell Product Disposition Form and the Provenge infusion bag.

Patient Counseling Information

Inform the patient or caregiver about the following:

• The recommended course of therapy for Provenge is 3 complete doses. Each infusion of Provenge is preceded by a leukapheresis procedure approximately 3 days prior. It is important to maintain all scheduled appointments and arrive at each appointment on time because the leukapheresis and infusions must be appropriately spaced and the Provenge expiration time must not be exceeded.


• If the patient is unable to receive an infusion of Provenge, the patient will need to undergo an additional leukapheresis procedure if the treatment is to be continued.


• Counsel the patient on the importance of adhering to preparation instructions for the leukapheresis procedure, the possible side effects of leukapheresis, and post-procedure care.


• If the patient does not have adequate peripheral venous access to accommodate the leukapheresis procedure and infusion of Provenge, inform the patient about the need for a central venous catheter. Counsel the patient on the importance of catheter care. Instruct the patient to tell their doctor if they are experiencing fevers or any swelling or redness around the catheter site, because these symptoms could be signs of an infected catheter.


• Report signs and symptoms of acute infusion reactions such as fever, chills, fatigue, breathing problems, dizziness, high blood pressure, nausea, vomiting, headache, or muscle aches.


• Report any symptoms suggestive of a cardiac arrhythmia.


• Inform their doctor if they are taking immunosuppressive agents.

Dendreon toll-free number: 1-877-336-3736

Dendreon Corporation

3005 First Avenue

Seattle, Washington

98121

TRN-80010.01

LBS-76022.01

PATIENT LABELING

Patient Information about Provenge® (sipuleucel-T)

This leaflet is designed to help you understand treatment with Provenge (pronounced PROH-venj). The more you understand your treatment, the better you will be able to participate in your care. This leaflet does not take the place of talking with your doctor or healthcare professional about your medical condition or your treatment. If you have any questions, speak with your doctor.

What is Provenge?

Provenge is a prescription medicine that is used to treat certain patients with advanced prostate cancer. Provenge is made from your own immune cells.

What should I tell my doctor before getting Provenge?

Tell your doctor about all your medical problems, including:

• heart problems


• lung problems


• history of stroke

Tell your doctor about all the medicines you take, including prescription and nonprescription drugs, vitamins, and dietary supplements.

How will I get Provenge?

Since Provenge is made from your own immune cells, your cells will be collected approximately 3 days before each scheduled infusion of Provenge. You will need to go to a cell collection center for this collection. The collection is called “leukapheresis” (pronounced loo-kuh-fuh-REE-sis). Your collected cells are sent to a special manufacturing center where they are mixed with a protein to make them ready for your infusion.

You will get Provenge in 3 intravenous infusions (put into your veins), about 2 weeks apart. Each infusion takes about 60 minutes. Following each infusion, you will be monitored for at least 30 minutes.

Your doctor will give you a schedule for your cell collection and infusion appointments. It is very important that you arrive on time for your appointments. If you miss an appointment and cannot be infused, your Provenge dose will not be usable. Your doctor will work with you to schedule a new appointment at the cell collection center. You may also get a new infusion appointment.

What are the possible or reasonably likely side effects of Provenge?

The most common side effects of Provenge include:

chills	nausea