Citric Acid Anhydrous and 13c Urea

IDkit Hp ® One and IDkit Hp ® Two are indicated for use as a diagnostic aid in the initial diagnosis and post-treatment monitoring of Helicobacter pylori (H. pylori) infection in adults and pediatric patients 3 years of age and older. IDkit Hp One and IDkit Hp Two are to be administered only by trained personnel as ordered by a licensed healthcare practitioner using the BreathID ® system device as identified in the BreathID ® system device labeling. IDkit Hp One and IDkit Hp Two are indicated for use as a diagnostic aid in the initial diagnosis and post-treatment monitoring of Helicobacter pylori (H. pylori) infection in adults and pediatric patients 3 years of age and older. ( 1 ) IDkit Hp One and IDkit Hp Two are to be administered only by trained personnel as ordered by a licensed healthcare practitioner using the BreathID ® system device as identified in the BreathID ® system device labeling. ( 1 )

IDkit Hp One and IDkit Hp Two consists of a 13 C-urea tablet for oral solution co-packaged with Citrica (citric acid) for oral solution along with other materials for use with the BreathID system device [see How Supplied/Storage and Handling ( 16 )] . 13 C-urea tablet for oral solution is supplied as a white, biconvex round tablet with “U” debossed on one side. Each tablet contains 75 mg 13 C-urea. Citrica (citric acid) for oral solution is supplied as a white to off-white powder. Each pouch contains 4 grams of citric acid. 75 mg 13 C-urea tablet for oral solution co-packaged with 4g Citrica (citric acid) for oral solution. ( 3 )

IDkit Hp One and IDkit Hp Two are contraindicated in patients with a known hypersensitivity to the 13 C-urea, Citrica (citric acid) or to any of the excipients [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.2 )] . Hypersensitivity to the 13 C-urea, Citrica (citric acid) or to any of the excipients in the drug. ( 4 )

Hypersensitivity Reactions: Hypersensitivity reactions, including anaphylaxis, have been reported in patients using IDkit Hp. Institute appropriate supportive measures if an allergic reaction occurs. ( 5.1 ) Phenylketonuria: Citrica (citric acid) for oral solution, a component in the IDkit Hp, contains phenylalanine which can be harmful to patients with phenylketonuria. ( 5.2 )

5.1 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported in patients who have used the IDkit Hp One and IDkit Hp Two for H. pylori diagnostic testing [see Adverse Reactions ( 6.2 )] . The IDkit Hp One and IDkit Hp Two are contraindicated in patients with known history of hypersensitivity to 13 C-urea, Citrica (citric acid) or the excipients [see Contraindications ( 4 )] . Before administering the IDkit Hp One or IDkit Hp Two, carefully inquire about previous hypersensitivity reactions.

5.2 Risks in Patients with Phenylketonuria Phenylalanine can be harmful to patients with phenylketonuria (PKU). In IDkit Hp One and IDkit Hp Two, the Citrica (citric acid) for oral solution contains phenylalanine, a component of aspartame. Each 4 g packet of Citrica (citric acid) for oral solution contains 84 mg of phenylalanine. Before prescribing IDkit Hp One or IDkit Hp Two to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including IDkit Hp One or IDkit Hp Two.

5.1 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported in patients who have used the IDkit Hp One and IDkit Hp Two for H. pylori diagnostic testing [see Adverse Reactions ( 6.2 )] . The IDkit Hp One and IDkit Hp Two are contraindicated in patients with known history of hypersensitivity to 13 C-urea, Citrica (citric acid) or the excipients [see Contraindications ( 4 )] . Before administering the IDkit Hp One or IDkit Hp Two, carefully inquire about previous hypersensitivity reactions.

5.2 Risks in Patients with Phenylketonuria Phenylalanine can be harmful to patients with phenylketonuria (PKU). In IDkit Hp One and IDkit Hp Two, the Citrica (citric acid) for oral solution contains phenylalanine, a component of aspartame. Each 4 g packet of Citrica (citric acid) for oral solution contains 84 mg of phenylalanine. Before prescribing IDkit Hp One or IDkit Hp Two to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including IDkit Hp One or IDkit Hp Two.

The following clinically significant adverse reactions are discussed in the Warning and Precautions section of the labeling: Hypersensitivity Reactions [see Warning and Precautions ( 5.1 )] Adult Patients: The most common adverse reactions (incidence >0.3%) using the IDkit Hp included nausea, throat burning, and lightheadedness. ( 6.1 ) Pediatric Patients: The most common adverse reactions (incidence >1.5%) using the IDkit Hp included vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Meridian Bioscience Corporation at 1-800-543-1980 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience and Adverse Reactions in Adult Patients The safety of the IDkit Hp was evaluated in 465 adult patients who participated in two clinical trials (Trial 1 and Trial 2). All patients used the IDkit Hp Two kit for initial diagnosis and post-treatment monitoring of H. pylori infection. The most commonly observed adverse reactions associated with the use of the IDkit Hp were nausea (0.6%), throat burning (0.4%), and lightheadedness (0.4%). Clinical Trials Experience and Adverse Reactions in Pediatric Patients The safety of the IDkit Hp was evaluated in one multi-center, non-randomized, open-label study (Trial 3). A total of 53 pediatric patients, 3 to less than 18 years of age, were enrolled in the study and used the IDkit Hp Two. The only adverse reaction reported was vomiting (2%).

6.2 Post-marketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during post-marketing use of the IDkit Hp One and IDkit Hp Two based on patient and test administrator reports. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal: Nausea, vomiting, abdominal pain, diarrhea General: Sweating, throat pain, malaise Immune: Anaphylactic reaction Neurologic: Dizziness, headache

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience and Adverse Reactions in Adult Patients The safety of the IDkit Hp was evaluated in 465 adult patients who participated in two clinical trials (Trial 1 and Trial 2). All patients used the IDkit Hp Two kit for initial diagnosis and post-treatment monitoring of H. pylori infection. The most commonly observed adverse reactions associated with the use of the IDkit Hp were nausea (0.6%), throat burning (0.4%), and lightheadedness (0.4%). Clinical Trials Experience and Adverse Reactions in Pediatric Patients The safety of the IDkit Hp was evaluated in one multi-center, non-randomized, open-label study (Trial 3). A total of 53 pediatric patients, 3 to less than 18 years of age, were enrolled in the study and used the IDkit Hp Two. The only adverse reaction reported was vomiting (2%).

6.2 Post-marketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during post-marketing use of the IDkit Hp One and IDkit Hp Two based on patient and test administrator reports. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal: Nausea, vomiting, abdominal pain, diarrhea General: Sweating, throat pain, malaise Immune: Anaphylactic reaction Neurologic: Dizziness, headache

No formal drug interaction studies were conducted. Information on drugs that may interfere with test results are listed in the Table 1. Table 1: Drugs That Interfere with Test Results Interfering Drug Clinical Effect Prevention or Management Antimicrobials, bismuth-containing preparations May suppress H. pylori or urease activity, leading to false negative results Avoid use within 2 weeks prior to testing. If used within 2 weeks, postpone testing until at least 2 weeks after discontinuation. Proton pump inhibitors (PPIs) May reduce urease activity or alter gastric conditions, potentially causing false negative results. A positive result during PPI use may still indicate H. pylori presence. Avoid use within 2 weeks prior to testing. If a negative result is obtained during PPI use, repeat the test 2 weeks after PPI discontinuation. Antimicrobials, Bismuth-containing preparations: Avoid use within 2 weeks prior to testing. ( 7 ) Proton pump inhibitors (PPIs): Avoid use within 2 weeks prior to testing. ( 7 )

Pediatric Use: The safety and effectiveness of IDkit Hp One and IDkit Hp Two has not been established in pediatric patients less than 3 years of age. ( 8.4 )

8.1 Pregnancy Risk Summary Published data from other single oral dose 13 C-urea breath test kits containing urea and citric acid have not demonstrated a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. There are no available data on the use of IDkit Hp One or IDkit Hp Two use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. There are no animal data that meet current standards for nonclinical developmental toxicity studies. Based on available literature, no significant developmental or reproductive toxicities were observed in nonclinical studies with urea or citric acid. A single oral dose of 13 C-urea and citric acid at the maximum recommended human dose (MRHD) are unlikely to pose a significant developmental or reproductive risk, since humans typically have higher circulating levels of urea, and citric acid exposure from the test is within the range of normal dietary intake. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

8.2 Lactation Risk Summary There are no data on the presence of the components of IDkit Hp One or IDkit Hp Two in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. A single oral dose of 13 C-urea and citric acid at the MRHD is unlikely to pose a risk in breastfed infants since humans typically have higher circulating levels of urea, and citric acid exposure from the test is within the range of normal dietary intake. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for IDkit Hp One or IDkit Hp Two and any potential adverse effects on the breastfed infant from IDkit Hp One or IDkit Hp Two or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of IDkit Hp One and IDkit Hp Two have been established in pediatric patients 3 years of age and older. Use of IDkit Hp One and IDkit Hp Two in pediatric patients is supported by two trials demonstrating clinical performance in adults along with a multi-center, non-randomized, open label study confirming the safety of the 13 C-urea substrate and the performance of the BreathID system device in pediatric patients [see Adverse Reaction ( 6.1 ) and Clinical Studies ( 14.1 )] . The safety and effectiveness of IDkit Hp One and IDkit Hp Two have not been established in pediatric patients less than 3 years of age.

8.5 Geriatric Use Of the total number of IDkit Hp One and IDkit Hp Two patients in clinical studies for detection of H. pylori , 74 (12%) were 65 to 74 years of age, and 38 (6%) were 75 years of age and older [see Clinical Studies ( 14 )] . No overall differences in safety or effectiveness were observed between patients 65 years of age and older and younger adult patients, and other reported clinical experience has not identified differences in responses between the elderly and younger adult patients.

8.6 Gastrectomy Data is insufficient for recommending the use of IDkit Hp One and IDkit Hp Two on patients with total or partial gastrectomy [see Clinical Pharmacology ( 12.3 )] .

IDkit Hp One and IDkit Hp Two are administered using the BreathID system device, a non-invasive breath test that analyzes a breath sample before and after ingestion of 13 C- urea and citric acid. 75 mg 13 C-urea and 4. g citric acid is dissolved in water and administered orally to the patient. The presence of citric acid creates an acidic environment in the stomach and delays the gastric emptying of the ingested solution to the duodenum. These two characteristics facilitate the decomposition of the urea by H. pylori , if present. Thus, in the presence of urease produced by gastric H. pylori , 13 C-urea is decomposed to 13 CO 2 and NH 3 according to the following equation: The 13 CO 2 formed is absorbed into the blood and then exhaled in breath, enabling detection of elevated 13 CO 2 in H. pylori-positive patients. In H. pylori-negative patients, no significant production of 13 CO 2 occurs in the stomach, as there are no human enzymes capable of hydrolyzing urea under gastric conditions. equ2