DRUGS & SUPPLEMENTS

Medication: Adprazole

advertisement
What are the side effects you encounter while taking this medicine?

Adprazole uses

WARNINGS AND PRECAUTIONS

Bone Fracture (5.3)

09/2010
WARNINGS AND PRECAUTIONS

Diminished anti-platelet activity of clopidogrel (5.4)

01/2011
WARNINGS AND PRECAUTIONS

Hypomagnesemia (5.7)

06/2011
WARNINGS AND PRECAUTIONS

Concomitant Use of Adprazole Delayed-Release Capsules with St. John's Wort or rifampin (5.8)

Interactions with Diagnostic Investigations for Neuroendocrine Tumors (5.9)

06/2011

1 INDICATIONS AND USAGE

Adprazole Delayed-Release Capsules are a proton pump inhibitor indicated for:

  • Treatment in adults of duodenal ulcer and gastric ulcer (1.2).
  • Treatment in adults and children of gastroesophageal reflux disease (GERD) (1.3) and maintenance of healing of erosive esophagitis (1.4).

The safety and effectiveness of Adprazole Delayed-Release Capsules in pediatric patients < 1 year of age have not been established (8.4).

1.1 Duodenal Ulcer (adults)

Adprazole Delayed-Release Capsules are indicated for short-term treatment of active duodenal ulcer in adults. Most patients heal within four weeks. Some patients may require an additional four weeks of therapy.

Adprazole Delayed-Release Capsules in combination with clarithromycin and amoxicillin, are indicated for treatment of patients with H. pylori infection and duodenal ulcer disease (active or up to 1-year history) to eradicate H. pylori in adults.

Adprazole Delayed-Release Capsules in combination with clarithromycin are indicated for treatment of patients with H. pylori infection and duodenal ulcer disease to eradicate H. pylori in adults.

Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence [see Clinical Studies (14.1) and Dosage and Administration (2)].

Among patients who fail therapy, Adprazole Delayed-Release Capsules with clarithromycin is more likely to be associated with the development of clarithromycin resistance as compared with triple therapy. In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted. [see Microbiology section (12.4 )], and the clarithromycin package insert, Microbiology section.

1.2 Gastric Ulcer

Adprazole Delayed-Release Capsules are indicated for short-term treatment (4-8 weeks) of active benign gastric ulcer in adults [see Clinical Studies (14.2)].

1.3 Treatment of Gastroesophageal Reflux Disease (adults and pediatric patients)

Symptomatic GERD

Adprazole Delayed-Release Capsules are indicated for the treatment of heartburn and other symptoms associated with GERD in pediatric patients and adults.

Erosive Esophagitis

Adprazole Delayed-Release Capsules are indicated for the short-term treatment (4-8 weeks) of erosive esophagitis that has been diagnosed by endoscopy in pediatric patients and adults [see Clinical Studies (14.4)].

The efficacy of Adprazole Delayed-Release Capsules used for longer than 8 weeks in these patients has not been established. If a patient does not respond to 8 weeks of treatment, an additional 4 weeks of treatment may be given. If there is recurrence of erosive esophagitis or GERD symptoms (e.g., heartburn), additional 4-8 week courses of Adprazole may be considered.

1.4 Maintenance of Healing of Erosive Esophagitis

Adprazole Delayed-Release Capsules are indicated to maintain healing of erosive esophagitis in pediatric patients and adults.

Controlled studies do not extend beyond 12 months [see Clinical Studies ( 14.4 )].

1.5 Pathological Hypersecretory Conditions

Adprazole Delayed-Release Capsules are indicated for the long-term treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome, multiple endocrine adenomas and systemic mastocytosis) in adults.

advertisement

2 DOSAGE AND ADMINISTRATION

Adprazole Delayed-Release Capsules should be taken before eating. In the clinical trials, antacids were used concomitantly with Adprazole Delayed-Release Capsules.

Patients should be informed that the Adprazole Delayed-Release Capsules should be swallowed whole.

For patients unable to swallow an intact capsule, alternative administration options are available [see Dosage and Administration ].

Indication Adprazole Dose Frequency
Treatment of Active Duodenal Ulcer (2.1)

20 mg

Once daily for 4 weeks. Some patients may require an additional 4 weeks
H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence (2.2)
Triple Therapy:
Adprazole Delayed-Release Capsules 20 mg Each drug twice daily for 10 days
Amoxicillin 1000 mg
Clarithromycin 500 mg
Dual Therapy:
Adprazole Delayed-Release Capsules 40 mg Once daily for 14 days
Clarithromycin 500 mg Three times daily for 14 days
Gastric Ulcer (2.3) 40 mg Once daily for 4 to 8 weeks
GERD (2.4) 20 mg Once daily for 4 to 8 weeks
Maintenance of Healing of Erosive Esophagitis (2.5) 20 mg Once daily
Pathological Hypersecretory Conditions (2.6) 60 mg (varies with individual patient) Once daily

Pediatric Patients (2 to 16 years of age) (2.7)

GERD

And Maintenance of Healing of Erosive Esophagitis


Weight

10 < 20 kg ≥ 20 kg


Dose

10 mg

20 mg


Once daily

2.1 Short-Term Treatment of Active Duodenal Ulcer

The recommended adult oral dose of Adprazole Delayed-Release Capsules is 20 mg once daily. Most patients heal within four weeks. Some patients may require an additional four weeks of therapy.

2.2 H. pylori Eradication for the Reduction of the Risk of Duodenal Ulcer Recurrence

Triple Therapy — The recommended adult oral regimen is Adprazole Delayed-Release Capsules 20 mg plus clarithromycin 500 mg plus amoxicillin 1000 mg each given twice daily for 10 days. In patients with an ulcer present at the time of initiation of therapy, an additional 18 days of Adprazole Delayed-Release Capsules 20 mg once daily is recommended for ulcer healing and symptom relief.

Dual Therapy (Omeprazole Delayed-Release Capsules /clarithromycin) — The recommended adult oral regimen is Adprazole Delayed-Release Capsules 40 mg once daily plus clarithromycin 500 mg three times daily for 14 days. In patients with an ulcer present at the time of initiation of therapy, an additional 14 days of Adprazole Delayed-Release Capsules 20 mg once daily is recommended for ulcer healing and symptom relief.

2.3 Gastric Ulcer

The recommended adult oral dose is 40 mg once daily for 4-8 weeks.

2.4 Gastroesophageal Reflux Disease

The recommended adult oral dose for the treatment of patients with symptomatic GERD and no esophageal lesions is 20 mg daily for up to 4 weeks. The recommended adult oral dose for the treatment of patients with erosive esophagitis and accompanying symptoms due to GERD is 20 mg daily for 4 to 8 weeks.

2.5 Maintenance of Healing of Erosive Esophagitis

The recommended adult oral dose is 20 mg daily [see Clinical Studies ].

2.6 Pathological Hypersecretory Conditions

The dosage of Adprazole Delayed-Release Capsules in patients with pathological hypersecretory conditions varies with the individual patient. The recommended adult oral starting dose is 60 mg once daily. Doses should be adjusted to individual patient needs and should continue for as long as clinically indicated. Doses up to 120 mg three times daily have been administered. Daily dosages of greater than 80 mg should be administered in divided doses. Some patients with Zollinger-Ellison syndrome have been treated continuously with Adprazole Delayed-Release Capsules for more than 5 years.

2.7 Pediatric Patients

For the treatment of GERD and maintenance of healing of erosive esophagitis, the recommended daily dose for pediatric patients 2 to 16 years of age is as follows:

Patient Weight Adprazole Daily Dose
10 < 20 kg 10 mg
≥ 20 kg 20 mg

On a per kg basis, the doses of Adprazole required to heal erosive esophagitis in pediatric patients are greater than those for adults.

Alternative administrative options can be used for pediatric patients unable to swallow an intact capsule [see Dosage and Administration ].

2.8 Alternative Administration Options

Adprazole Delayed-Release Capsule is available as a delayed-release capsule.

For patients who have difficulty swallowing capsules, the contents of an Adprazole Delayed-Release Capsule can be added to applesauce. One tablespoon of applesauce should be added to an empty bowl and the capsule should be opened. All of the microtablets inside the capsule should be carefully emptied on the applesauce. The microtablets should be mixed with the applesauce and then swallowed immediately with a glass of cool water to ensure complete swallowing of the microtablets. The applesauce used should not be hot and should be soft enough to be swallowed without chewing. The microtablets should not be chewed or crushed. The microtablets/applesauce mixture should not be stored for future use.

2.9 Use with clopidogrel

Avoid concomitant use of clopidogrel and Adprazole. Co-administration of clopidogrel with 80 mg Adprazole, a proton pump inhibitor that is an inhibitor of CYP2C19, reduces the pharmacological activity of clopidogrel if given concomitantly or if given 12 hours apart [see Warnings and Precautions (5.4) and Drug Interactions (7.3) ].

advertisement

3 DOSAGE FORMS AND STRENGTHS

Adprazole Delayed-Release Capsules, 10 mg, are opaque white cap and opaque white body capsules imprinted with "KU" and "114" in black ink.

Adprazole Delayed-Release Capsules, 20 mg, are opaque white cap and opaque gold body capsules imprinted with "KU" and "118" in black ink.

Adprazole Delayed-Release Capsules, 40 mg, are opaque gold cap and opaque gold body capsules imprinted with "KU" and "136" in black ink.

Adprazole Delayed-Release Capsules, 10 mg, 20 mg and 40 mg (3)

4 CONTRAINDICATIONS

Adprazole Delayed-Release Capsules are contraindicated in patients with known hypersensitivity to substituted benzimidazoles or to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, and urticaria [see Adverse Reactions ( 6 )].

Known hypersensitivity to any component of the formulation or substituted benzimidazoles (angioedema and anaphylaxis have occurred) (4)

5 WARNINGS AND PRECAUTIONS

  • Symptomatic response does not preclude the presence of gastric malignancy.
  • Atrophic Gastritis: has been noted with long-term therapy (5.2).
  • Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increaded risk for osteoporosis-related fractures of the nip, wrist, or spine (5.3).
  • Diminished anti-platelet activity of clopidogrel due to impaired CYP2C19 function by 80 mg Adprazole (5.4).
  • Triple therapy for H. pylori – there are risks due to antibiotics; see separate prescribing information for individual antibiotics (5.5, 5.6).
  • Hypomagnesemia has been reported rarely with prolonged treatment with PPIs (5.7).
  • Avoid concomitant use of Adprazole Delayed-Release Capsules with St. John's Wort or rifampin due to the potential reduction in Adprazole concentrations (5.8, 7.3).
  • Interactions with diagnostic investigations for Neuroendocrine Tumors: Increases in intragastric pH may result in hypergastrinemia and enterochromaffin-like cell hyperplasia and increased Chromogranin A levels which may interfere with diagnostic investigations for neuroendocrine tumors (5.9, 12.2).

5.1 Concomitant Gastric Malignancy

Symptomatic response to therapy with Adprazole does not preclude the presence of gastric malignancy.

5.2 Atrophic Gastritis

Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with Adprazole.

5.3 Bone Fracture

Several published observational studies suggest that proton pump inhibitor therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines [see Dosage and Administration ( 2 ) and Adverse Reactions (6.3)].

5.4 Diminished Anti-platelet Activity of clopidogrel due to Impaired CYP2C19 Function by Adprazole

Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as Adprazole, that interfere with CYP2C19 activity. Avoid concomitant use of clopidogrel and Adprazole. Co-administration of clopidogrel with 80 mg Adprazole, a proton pump inhibitor that is an inhibitor of CYP2C19, reduces the pharmacological activity of clopidogrel if given concomitantly or if given 12 hours apart [see Drug Interactions (7) ].

5.5 Combination Use of Adprazole Delayed-Release Capsules with Amoxicillin

Serious and occasionally fatal hypersensitivity reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. Before initiating therapy with amoxicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other allergens. If an allergic reaction occurs, amoxicillin should be discontinued and appropriate therapy instituted. Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous steroids and airway management, including intubation, should also be administered as indicated.

Pseudomembranous colitis has been reported with nearly all antibacterial agents and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of "antibiotic-associated colitis."

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

5.6 Combination Use of Adprazole Delayed-Release Capsules with Clarithromycin

Clarithromycin should not be used in pregnant women except in clinical circumstances where no alternative therapy is appropriate. If pregnancy occurs while taking clarithromycin, the patient should be apprised of the potential hazard to the fetus.

Co-administration of Adprazole and clarithromycin has resulted in increases in plasma levels of Adprazole, clarithromycin, and 14-hydroxy-clarithromycin [see Clinical Pharmacology (12)].

Concomitant administration of clarithromycin with cisapride or pimozide, is contraindicated.

5.7 Hypomagnesemia

Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia, health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions (6.3) ].

5.8 Concomitant Use of Adprazole Delayed-Release Capsules with St. John's Wort or rifampin

Drugs which induce CYP2C19 or CYP3A4 (such as St. John's Wort or rifampin) can substantially decrease Adprazole concentrations [see Drug Interactions (7.3) ]. Avoid concomitant use of Adprazole Delayed-Release Capsules with St. John's Wort or rifampin.

5.9 Interactions with Investigations for Neuroendocrine Tumors

Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Providers should temporarily stop Adprazole treatment before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.

advertisement

6 ADVERSE REACTIONS

Adults: Most common adverse reactions in adults are

  • Headache, abdominal pain, nausea, diarrhea, vomiting, and flatulence (6)

Pediatric patients (2 to 16 years of age):

  • Safety profile similar to that in adults, except that respiratory system events and fever were the most frequently reported reactions in pediatric studies (8.4).

To report SUSPECTED ADVERSE REACTIONS, contact UCB, Inc. (1-866-822-0068) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials Experience with Adprazole Delayed-Release Capsules Monotherapy

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 data described below reflects exposure to Adprazole Delayed-Release Capsules in 3096 patients from worldwide clinical trials (465 patients from US studies and 2,631 patients from international studies). Indications clinically studied in US trials included duodenal ulcer, resistant ulcer, and Zollinger-Ellison syndrome. The international clinical trials were double blind and open-label in design. The most common adverse reactions reported (i.e., with an incidence rate ≥ 2%) from Adprazole Delayed-Release Capsules-treated patients enrolled in these studies included headache (6.9%), abdominal pain (5.2%), nausea (4.0%), diarrhea (3.7%), vomiting (3.2%), and flatulence (2.7%).

Additional adverse reactions that were reported with an incidence ≥1% included acid regurgitation (1.9%), upper respiratory infection (1.9%), constipation (1.5%), dizziness (1.5%), rash (1.5%), asthenia (1.3%), back pain (1.1%), and cough (1.1%).

The clinical trial safety profile in patients greater than 65 years of age was similar to that in patients 65 years of age or less.

The clinical trial safety profile in pediatric patients who received Adprazole Delayed-Release Capsules was similar to that in adult patients. Unique to the pediatric population, however, adverse reactions of the respiratory system were most frequently reported in the 2 to 16 year age group (18.5%). Similarly, accidental injuries were reported frequently in the 2 to 16 year age group (3.8%) [see Use in Specific Populations ( 8.4 )].

6.2 Clinical Trials Experience with Adprazole Delayed-Release Capsules in Combination Therapy for H. pylori Eradication

In clinical trials using either dual therapy with Adprazole Delayed-Release Capsules and clarithromycin, or triple therapy with Adprazole Delayed-Release Capsules, clarithromycin, and amoxicillin, no adverse reactions unique to these drug combinations were observed. Adverse reactions observed were limited to those previously reported with Adprazole, clarithromycin, or amoxicillin alone.

Dual Therapy

Adverse reactions observed in controlled clinical trials using combination therapy with Adprazole Delayed-Release Capsules and clarithromycin (n = 346) that differed from those previously described for Adprazole Delayed-Release Capsules alone were taste perversion (15%), tongue discoloration (2%), rhinitis (2%), pharyngitis (1%) and flu-syndrome (1%). (For more information on clarithromycin, refer to the clarithromycin prescribing information, Adverse Reactions section).

Triple Therapy (Omeprazole Delayed-Release Capsules/clarithromycin/amoxicillin)

The most frequent adverse reactions observed in clinical trials using combination therapy with Adprazole Delayed-Release Capsules, clarithromycin, and amoxicillin (n = 274) were diarrhea (14%), taste perversion (10%), and headache (7%). None of these occurred at a higher frequency than that reported by patients taking antimicrobial agents alone. (For more information on clarithromycin or amoxicillin, refer to the respective prescribing information, Adverse Reactions sections).

6.3 Post-marketing Experience

The following adverse reactions have been identified during post-approval use of Adprazole Delayed-Release Capsules. Because these reactions are voluntarily. reported from a population of uncertain size, it is not always possible to reliably estimate their actual frequency or establish a causal relationship to drug exposure.

Body As a Whole: Hypersensitivity reactions including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, urticaria, (see also Skin below); fever; pain; fatigue; malaise;

Cardiovascular: Chest pain or angina, tachycardia, bradycardia, palpitations, elevated blood pressure, peripheral edema

Endocrine: Gynecomastia

Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, stomatitis, abdominal swelling, dry mouth. During treatment with Adprazole, gastric fundic gland polyps have been noted rarely. These polyps are benign and appear to be reversible when treatment is discontinued. Gastroduodenal carcinoids have been reported in patients with ZE syndrome on long-term treatment with Adprazole Delayed-Release Capsules. This finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors.

Hepatic: Liver disease including hepatic failure (some fatal), liver necrosis (some fatal), hepatic encephalopathy hepatocellular disease, cholestatic disease, mixed hepatitis, jaundice, and elevations of liver function tests [ALT, AST, GGT, alkaline phosphatase, and bilirubin]

Metabolic/Nutritional: Hypoglycemia, hypomagnesemia, hyponatremia, weight gain

Musculoskeletal: Muscle weakness, myalgia, muscle cramps, joint pain, leg pain, bone fracture

Nervous System/Psychiatric: Psychiatric and sleep disturbances including depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, apathy, somnolence, anxiety, and dream abnormalities; tremors, paresthesia; vertigo

Respiratory: Epistaxis, pharyngeal pain

Skin: Severe generalized skin reactions including toxic epidermal necrolysis (some fatal), Stevens-Johnson syndrome, and erythema multiforme; photosensitivity; urticaria; rash; skin inflammation; pruritus; petechiae; purpura; alopecia; dry skin; hyperhidrosis

Special Senses: Tinnitus, taste perversion

Ocular: Optic atrophy, anterior ischemic optic neuropathy, optic neuritis, dry eye syndrome, ocular irritation, blurred vision, double vision

Urogenital: Interstitial nephritis, hematuria, proteinuria, elevated serum creatinine, microscopic pyuria, urinary tract infection, glycosuria, urinary frequency, testicular pain

Hematologic: Agranulocytosis (some fatal), hemolytic anemia, pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia, leucocytosis

advertisement

7 DRUG INTERACTIONS

  • Atazanavir and nelfinavir: Adprazole Delayed-Release Capsules reduce plasma levels of atazanavir and nelfinavir. Concomitant use is not recommended.
  • Saquinavir: Adprazole Delayed-Release Capsules increase plasma levels of saquinavir. Monitor for toxicity and consider dose reduction of saquinavir (7.1).
  • May interfere with drugs for which gastric pH affects bioavailability (e.g., ketoconazole, iron salts, ampicillin esters, and digoxin). Patients treated with Adprazole Delayed-Release Capsules and digoxin may need to be monitored for increases in digoxin toxicity (7.2).
  • Co-administration of clopidogrel with 80 mg Adprazole may reduce the pharmacological activity of clopidogrel if given concomitantly or if given 12 hours apart (7).
  • Cilostazol: Adprazole Delayed-Release Capsules increase systemic exposure of cilostazol and one of its active metabolites. Consider dose reduction of cilostazol (7.3).
  • Drugs metabolized by cytochrome P450 (e.g., diazepam, warfarin, phenytoin, cyclosporine, disulfiram, benzodiazepines): Adprazole Delayed-Release Capsules can prolong their elimination. Monitor and determine need for dose adjustments (7.3).
  • Patients treated with proton pump inhibitors and warfarin may need to be monitored for increases in INR and prothrombin time (7.3).
  • Combined inhibitor of CYP 2C19 and 3A4 (e.g., voriconazole) may raise Adprazole levels (7.3).
  • Tacrolimus: Adprazole Delayed-Release Capsules may increase serum levels of tacrolimus (7.4).

7.1 Interference with Antiretroviral Therapy

Concomitant use of atazanavir and nelfinavir with proton pump inhibitors is not recommended. Co-administration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and may result in a loss of therapeutic effect and the development of drug resistance. Coadministration of saquinavir with proton pump inhibitors is expected to increase saquinavir concentrations, which may increase toxicity and require dose reduction.

Adprazole has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions are not always known. Increased gastric pH during Adprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP 2C19.

Reduced concentrations of atazanavir and nelfinavir

For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with Adprazole. Following multiple doses of nelfinavir (1250 mg, twice daily) and Adprazole (40 mg daily), AUC was decreased by 36% and 92%,

Cmax by 37% and 89% and Cmin by 39% and 75% respectively for nelfinavir and M8. Following multiple doses of atazanavir (400 mg, daily) and Adprazole (40 mg, daily, 2 hr before atazanavir), AUC was decreased by 94%, Cmax by 96%, and Cmin by 95%. Concomitant administration with Adprazole and drugs such as atazanavir and nelfinavir is therefore not recommended.

Increased concentrations of saquinavir

For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported, with an increase in AUC by 82%, in Cmax by 75%, and in Cmin by 106%, following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with Adprazole 40 mg daily co-administered days 11 to 15. Therefore, clinical and laboratory monitoring for saquinavir toxicity is recommended during concurrent use with Adprazole Delayed-Release Capsules. Dose reduction of saquinavir should be considered from the safety perspective for individual patients.

There are also some antiretroviral drugs of which unchanged serum levels have been reported when given with Adprazole.

7.2 Drugs for Which Gastric pH Can Affect Bioavailablity

Because of its profound and long lasting inhibition of gastric acid secretion, it is theoretically possible that Adprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability. The absorption of digoxin can increase during treatment with Adprazole. Concomitant treatment with Adprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects). Therefore patients may need to be monitored when digoxin is taken concomitantly with Adprazole. In the clinical trials, antacids were used concomitantly with the administration of Adprazole Delayed-Release Capsules.

7.3 Effects on Hepatic Metabolism/Cytochrome P-450 Pathways

Adprazole can prolong the elimination of diazepam, warfarin and phenytoin, drugs that are metabolized by oxidation in the liver. There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including Adprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin may need to be monitored for increases in INR and prothrombin time.

Although in normal subjects no interaction with theophylline or propranolol was found, there have been clinical reports of interaction with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, dandulfiram, benzodiazepines). Patients should be monitored to determine if it is necessary to adjust the dosage of these drugs when taken concomitantly with Adprazole Delayed-Release Capsules.

Concomitant administration of Adprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the Adprazole exposure. Dose adjustment of Adprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses up to 240 mg/day, dose adjustment may be considered. When voriconazole (400 mg Q12h x 1 day, then 200 mg x 6 days) was given with Adprazole (40 mg once daily x 7 days) to healthy subjects, it significantly increased the steady-state Cmax and AUC0-24 of Adprazole, an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4) respectively as compared to when Adprazole was given without voriconazole.

Adprazole acts as an inhibitor of CYP 2C19. Adprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in crossover study, increased Cmax and AUC of cilostazol by 18% and 26% respectively. Cmax and AUC of one of its active metabolites, 3,4-dihydro-cilostazol, which has 4-7 times the activity of cilostazol, were increased by 29% and 69% respectively. Co-administration of cilostazol with Adprazole is expected to increase concentrations of cilostazol and its above mentioned active metabolite. Therefore a dose reduction of cilostazol from 100 mg b.i.d. to 50 mg b.i.d. should be considered.

clopidogrel

Adprazole is an inhibitor of CYP2C19 enzyme. Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of Adprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogel and a reduction in platelet inhibition [see Warnings and Precautions (5.4) ].

In a crossover clinical study, 72 healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day) alone with Adprazole (80 mg at the same time as clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and Adprazole were administered together. The active metabolite of clopidogrel selectively and irreversibly inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor, thereby inhibiting platelet aggregation. The mean inhibition of platelet aggregation at 5 mcM ADP was diminished by 39% (Day 1) and 21% ( Day 5) when clopidogrel and Adprazole were administered together.

In another study, 72 healthy subjects were given the same doses of clopidogrel and 80 mg Adprazole but the drugs were administered 12 hours apart; the results were similar, indicating that administering clopidogrel and Adprazole at different times does not prevent their interaction [see Warnings and Precautions (5.4) ].

There are no adequate combination studies of a lower dose of Adprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.

7.4 Tacrolimus

Concomitant administration of Adprazole and tacrolimus may increase the serum levels of tacrolimus.

7.5 Interactions with Investigations of Neurodocrine Tumors

Drug-induced decrease in gastric acidity results in enterochromaffin-like cell hyperplasia and increased Chromogranin A levels which may interfere with investigations for neuroendocrine tumors.

8 USE IN SPECIFIC POPULATIONS

Patients with hepatic impairment:

  • Consider dose reduction, particularly for maintenance of healing of erosive esophagitis.

8.1 Pregnancy

Pregnancy Category C

Reproductive studies in rats and rabbits with Adprazole and multiple cohort studies in pregnant women with Adprazole use during the first trimester do not show an increased risk of congenital anomalies or adverse pregnancy outcomes. There are no adequate and well -controlled studies on the use of Adprazole in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. The vast majority of reported experience with Adprazole during human pregnancy is first trimester exposure and the duration of use is rarely specified, e.g., intermittent vs. chronic. An expert review of published data on experiences with Adprazole use during pregnancy by TERIS – the Teratogen Information System – concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (the quantity and quality of data were assessed as fair). Three epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used Adprazole during pregnancy with the frequency of abnormalities among infants of women exposed to H2–receptor antagonists or other controls. A population-based prospective cohort epidemiological study from the Swedish Medical Birth Registry, covering approximately 99% of pregnancies, reported on 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose mothers used Adprazole during pregnancy. In utero exposure to Adprazole was not associated with increased risk of any malformation (odds ratio 0.82, 95% CI 0.50–1.34), low birth weight or low Apgar score. The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in the normal population. The author concluded that both effects may be random.

A retrospective cohort study reported on 689 pregnant women exposed to either H2–blockers or Adprazole in the first trimester (134 exposed to Adprazole). The overall malformation rate was 4.4% (95% CI 3.6–5.3) and the malformation rate for first trimester exposure to Adprazole was 3.6% (95% CI 1.5–8.1). The relative risk of malformations associated with first trimester exposure to Adprazole compared with non-exposed women was 0.9 (95% CI 0.3–2.2).

The study could effectively rule out a relative risk greater than 2.5 for all malformations. Rates of preterm delivery or growth retardation did not differ between the groups.

A controlled prospective observational study followed 113 women exposed to Adprazole during pregnancy (89% first trimester exposures). The reported rates of major congenital malformations was 4% for the Adprazole group, 2% for controls exposed to non-teratogens, and 2.8% in disease-paired controls (background incidence of major malformations 1–5%). Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight did not differ between the groups. The sample size in this study has 80% power to detect a 5–fold increase in the rate of major malformation.

Several studies have reported no apparent adverse short-term effects on the infant when single dose oral or intravenous Adprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia.

Reproductive studies conducted with Adprazole on rats at oral doses up to 56 times the human dose and in rabbits at doses up to 56 times the human dose did not show any evidence of teratogenicity. In pregnant rabbits, Adprazole at doses about 5.5 to 56 times the human dose produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy loss. In rats treated with Adprazole at doses about 5.6 to 56 times the human dose, dose-related embryo/fetal toxicity and postnatal developmental toxicity occurred in offspring [see Animal Toxicology and/or Pharmacology (13.2)].

8.3 Nursing Mothers

Adprazole concentrations have been measured in breast milk of a woman following oral administration of 20 mg. The peak concentration of Adprazole in breast milk was less than 7% of the peak serum concentration. This concentration would correspond to 0.004 mg of Adprazole in 200 mL of milk. Because Adprazole is excreted in human milk, because of the potential for serious adverse reactions in nursing infants from Adprazole, and because of the potential for tumorigenicity shown for Adprazole in rat carcinogenicity studies, 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.

8.4 Pediatric Use

Use of Adprazole Delayed-Release Capsules in pediatric and adolescent patients 2 to 16 years of age for the treatment of GERD is supported by a) extrapolation of results, already included in the currently approved labeling, from adequate and well-controlled studies that supported the approval of Adprazole Delayed-Release Capsules for adults, and b) safety and pharmacokinetic studies performed in pediatric and adolescent patients. [see Clinical Pharmacology, Pharmacokinetics, Pediatric for pharmacokinetic information and Dosage and Administration ( 2 ), Adverse Reactions ( 6.1 ) and Clinicial Studies ( 14.6 )]. The safety and effectiveness of Adprazole Delayed-Release Capsules for the treatment of GERD in patients < 1 year of age have not been established. The safety and effectiveness of Adprazole Delayed-Release Capsules for other pediatric uses have not been established.

8.5 Geriatric Use

Adprazole was administered to over 2000 elderly individuals (≥ 65 years of age) in clinical trials in the U.S. and Europe. There were no differences in safety and effectiveness between the elderly and younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

Pharmacokinetic studies have shown the elimination rate was somewhat decreased in the elderly and bioavailability was increased. The plasma clearance of Adprazole was 250 mL/min (about half that of young volunteers) and its plasma half-life averaged one hour, about twice that of young healthy volunteers. However, no dosage adjustment is necessary in the elderly [see Clinical Pharmacology ( 12.3 )].

8.6 Hepatic Impairment

Consider dose reduction, particularly for maintenance of healing of erosive esophagitis .

8.7 Renal Impairment

No dosage reduction is necessary [see Clinical Pharmacology ( 12.3 )].

8.8 Asian Population

Consider dose reduction, particularly for maintenance of healing of erosive esophagitis [see Clinical Pharmacology ( 12.3 )].

10 OVERDOSAGE

Reports have been received of overdosage with Adprazole in humans. Doses ranged up to 2400 mg (120 times the usual recommended clinical dose). Manifestations were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, vomiting, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen in normal clinical experience [ see Adverse Reactions ( 6 )]. Symptoms were transient, and no serious clinical outcome has been reported when Adprazole Delayed-Release Capsules were taken alone. No specific antidote for Adprazole overdosage is known. Adprazole is extensively protein bound and is, therefore, not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive.

As with the management of any overdose, the possibility of multiple drug ingestion should be considered. For current information on treatment of any drug overdose, contact a Poison Control Center at 1-800-222-1222.

Single oral doses of Adprazole at 1350, 1339, and 1200 mg/kg were lethal to mice, rats, and dogs, respectively. Animals given these doses showed sedation, ptosis, tremors, convulsions, and decreased activity, body temperature, and respiratory rate and increased depth of respiration.

11 DESCRIPTION

The active ingredient in Adprazole Delayed-Release Capsules is a substituted benzimidazole, 5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl]-1H-benzimidazole, a compound that inhibits gastric acid secretion. Its empirical formula is C17H19N3O3S, with a molecular weight of 345.42. The structural formula is:

Adprazole is a white to off-white crystalline powder that melts with decomposition at about 155°C. It is a weak base, freely soluble in ethanol and methanol, and slightly soluble in acetone and isopropanol and very slightly soluble in water. The stability of Adprazole is a function of pH; it is rapidly degraded in acid media, but has acceptable stability under alkaline conditions.

Adprazole Delayed-Release Capsules meet USP Dissolution Test 2.

Adprazole Delayed-Release Capsules are supplied as delayed-release capsules for oral administration. Each delayed-release capsule contains either 10 mg, 20 mg, or 40 mg of Adprazole in the form of enteric-coated microtablets with the following inactive ingredients:  crospovidone, glyceryl behenate, hypromellose, lactose monohydrate, methacrylic acid copolymer dispersion, silicon dioxide, talc, titanium dioxide and triethyl citrate.  In addition, the capsule shells contain gelatin and may contain sodium lauryl sulfate.  In addition, the 20 mg and 40 mg capsule shells also contain yellow iron oxide.  The imprinting ink also contains ammonium hydroxide, butyl alcohol, black iron oxide, isopropyl alcohol, propylene glycol and shellac glaze.  The ink may also contain dehydrated alcohol.

structural formula

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Adprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid pump within the gastric mucosa, Adprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus. Animal studies indicate that after rapid disappearance from plasma, Adprazole can be found within the gastric mucosa for a day or more.

12.2 Pharmacodynamics

Antisecretory Activity

After oral administration, the onset of the antisecretory effect of Adprazole occurs within one hour, with the maximum effect occurring within two hours. Inhibition of secretion is about 50% of maximum at 24 hours and the duration of inhibition lasts up to 72 hours. The antisecretory effect thus lasts far longer than would be expected from the very short (less than one hour) plasma half-life, apparently due to prolonged binding to the parietal H+/K+ ATPase enzyme. When the drug is discontinued, secretory activity returns gradually, over 3 to 5 days. The inhibitory effect of Adprazole on acid secretion increases with repeated once-daily dosing, reaching a plateau after four days.

Results from numerous studies of the antisecretory effect of multiple doses of 20 mg and 40 mg of Adprazole in normal volunteers and patients are shown below. The "max" value represents determinations at a time of maximum effect (2-6 hours after dosing), while "min" values are those 24 hours after the last dose of Adprazole.

Adprazole 20 mg Adprazole 40 mg
Parameter Max Min Max Min
% Decrease in Basal Acid Output

78*


58–80


94*


80–93

% Decrease in Peak Acid Output

79*


50–59


88*


62–68

% Decrease in 24–hr Intragastric Acidity

80–97


92–94

* Single Studies

Single daily oral doses of Adprazole ranging from a dose of 10 mg to 40 mg have produced 100% inhibition of 24-hour intragastric acidity in some patients.

Serum Gastric Effects

In studies involving more than 200 patients, serum gastrin levels increased during the first 1 to 2 weeks of once-daily administration of therapeutic doses of Adprazole in parallel with inhibition of acid secretion. No further increase in serum gastrin occurred with continued treatment. In comparison with histamine H2-receptor antagonists, the median increases produced by 20 mg doses of Adprazole were higher (1.3 to 3.6 fold vs. 1.1 to 1.8 fold increase). Gastrin values returned to pretreatment levels, usually within 1 to 2 weeks after discontinuation of therapy.

Enterochromaffin-like (ECL) Cell Effects

Human gastric biopsy specimens have been obtained from more than 3000 patients treated with Adprazole in long-term clinical trials. The incidence of ECL cell hyperplasia in these studies increased with time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia has been found in these patients [see Clinical Pharmacology ( 12 )]. However, these studies are of insufficient duration and size to rule out the possible influence of long-term administration of Adprazole on the development of any premalignant or malignant conditions.

Other Effects

Systemic effects of Adprazole in the CNS, cardiovascular and respiratory systems have not been found to date. Adprazole, given in oral doses of 30 or 40 mg for 2 to 4 weeks, had no effect on thyroid function, carbohydrate metabolism, or circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin or secretin.

No effect on gastric emptying of the solid and liquid components of a test meal was demonstrated after a single dose of Adprazole 90 mg. In healthy subjects, a single I.V. dose of Adprazole (0.35 mg/kg) had no effect on intrinsic factor secretion. No systematic dose-dependent effect has been observed on basal or stimulated pepsin output in humans.

However, when intragastric pH is maintained at 4.0 or above, basal pepsin output is low, and pepsin activity is decreased.

As do other agents that elevate intragastric pH, Adprazole administered for 14 days in healthy subjects produced a significant increase in the intragastric concentrations of viable bacteria. The pattern of the bacterial species was unchanged from that commonly found in saliva. All changes resolved within three days of stopping treatment.

The course of Barrett's esophagus in 106 patients was evaluated in a U.S. double-blind controlled study of Adprazole Delayed-Release Capsules 40 mg twice daily for 12 months followed by 20 mg twice daily for 12 months or ranitidine 300 mg twice daily for 24 months. No clinically significant impact on Barrett's mucosa by antisecretory therapy was observed. Although neosquamous epithelium developed during antisecretory therapy, complete elimination of Barrett's mucosa was not achieved. No significant difference was observed between treatment groups in development of dysplasia in Barrett's mucosa and no patient developed esophageal carcinoma during treatment. No significant differences between treatment groups were observed in development of ECL cell hyperplasia, corpus atrophic gastritis, corpus intestinal metaplasia, or colon polyps exceeding 3 mm in diameter [see Clinical Pharmacology ( 12 )].

12.3 Pharmacokinetics

Absorption

Adprazole Delayed-Release Capsules contain an enteric-coated microtablet formulation of Adprazole, so that absorption of Adprazole begins only after the microtablets leave the stomach. Absorption is rapid, with peak plasma levels of Adprazole occurring within 0.5 to 3.5 hours. Peak plasma concentrations of Adprazole and AUC are approximately proportional to doses up to 40 mg, but because of a saturable first-pass effect, a greater than linear response in peak plasma concentration and AUC occurs with doses greater than 40 mg. Absolute bioavailability (compared with intravenous administration) is about 30-40% at doses of 20-40 mg, due in large part to presystemic metabolism. In healthy subjects the plasma half-life is 0.5 to 1 hour, and the total body clearance is 500-600 mL/min.

The bioavailability of Adprazole increases slightly upon repeated administration of Adprazole Delayed-Release Capsules.

Adprazole Delayed-Release Capsules 40 mg was bioequivalent when administered with and without applesauce. However, Adprazole Delayed-Release Capsules 20 mg was not bioequivalent when administered with and without applesauce. When administered with applesauce, a mean 25% reduction in Cmax was observed without a significant change in AUC for Adprazole Delayed-Release Capsules 20 mg. The clinical relevance of this finding is unknown.

Distribution

Protein binding is approximately 95%.

Metabolism

Adprazole is extensively metabolized by the cytochrome P450 (CYP) enzyme system.

Excretion

Following single dose oral administration of a buffered solution of Adprazole, little if any unchanged drug was excreted in urine. The majority of the dose (about 77%) was eliminated in urine as at least six metabolites. Two were identified as hydroxyomeprazole and the corresponding carboxylic acid. The remainder of the dose was recoverable in feces. This implies a significant biliary excretion of the metabolites of Adprazole. Three metabolites have been identified in plasma — the sulfide and sulfone derivatives of Adprazole, and hydroxyomeprazole. These metabolites have very little or no antisecretory activity.

Combination Therapy with Antimicrobials

Adprazole 40 mg daily was given in combination with clarithromycin 500 mg every 8 hours to healthy adult male subjects. The steady state plasma concentrations of Adprazole were increased (Cmax, AUC0-24, and T1/2 increases of 30%, 89% and 34% respectively) by the concomitant administration of clarithromycin. The observed increases in Adprazole plasma concentration were associated with the following pharmacological effects. The mean 24-hour gastric pH value was 5.2 when Adprazole was administered alone and 5.7 when co-administered with clarithromycin.

The plasma levels of clarithromycin and 14-hydroxy-clarithromycin were increased by the concomitant administration of Adprazole. For clarithromycin, the mean Cmax was 10% greater, the mean Cmin was 27% greater, and the mean AUC0-8 was 15% greater when clarithromycin was administered with Adprazole than when clarithromycin was administered alone. Similar results were seen for 14-hydroxy-clarithromycin, the mean Cmax was 45% greater, the mean Cmin was 57% greater, and the mean AUC0-8 was 45% greater. Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of Adprazole.

Tissue Clarithromycin Clarithromycin + Adprazole
Antrum 10.48 ± 2.01 (n = 5) 19.96 ± 4.71 (n=5)
Fundus 20.81 ± 7.64 (n = 5) 24.25 ± 6.37 (n= 5)
Mucus 4.15 ± 7.74 (n = 4) 39.29 ± 32.79 (n=4)
* Mean ± SD (mcg/g)

Special Populations

Geriatric Population

The elimination rate of Adprazole was somewhat decreased in the elderly, and bioavailability was increased. Adprazole was 76% bioavailable when a single 40 mg oral dose of Adprazole (buffered solution) was administered to healthy elderly volunteers, versus 58% in young volunteers given the same dose. Nearly 70% of the dose was recovered in urine as metabolites of Adprazole and no unchanged drug was detected. The plasma clearance of Adprazole was 250 mL/min (about half that of young volunteers) and its plasma half-life averaged one hour, about twice that of young healthy volunteers.

Pediatric Use

The pharmacokinetics of Adprazole have been investigated in pediatric patients 2 to 16 years of age

Single or Repeated Oral Dosing /Parameter Children* ≤ 20 kg 2-5 years Children* > 20 kg 6-16 years Adults(mean 76 kg) 23-29 years(n=12)
10 mg 20 mg
Single Dosing
Cmax (ng/mL) 288 (n=10) 495 (n=49) 668
AUC(ng h/mL) 511 (n=7) 1140 (n=32) 1220
Repeated Dosing
Cmax (ng/mL) 539 (n=4) 851 (n=32) 1458
AUC(ng h/mL) 1179 (n=2) 2276 (n=23) 3352

* Data from single and repeated dose studies

† Data from a single and repeated dose study

Doses of 10, 20 and 40 mg Adprazole as enteric-coated microtablets

Note: ‡ = plasma concentration adjusted to an oral dose of 1 mg/kg.


Following comparable mg/kg doses of Adprazole, younger children (2 to 5 years of age) have lower AUCs than children 6 to16 years of age or adults; AUCs of the latter two groups did not differ [see Dosage and Administration ( 2 )].

Hepatic Impairment

In patients with chronic hepatic disease, the bioavailability increased to approximately 100% compared with an I.V. dose, reflecting decreased first-pass effect, and the plasma half-life of the drug increased to nearly 3 hours compared with the half-life in normals of 0.5-1 hour. Plasma clearance averaged 70 mL/min, compared with a value of 500-600 mL/min in normal subjects. Dose reduction, particularly where maintenance of healing of erosive esophagitis is indicated, for the hepatically impaired should be considered.

Renal Impairment

In patients with chronic renal impairment, whose creatinine clearance ranged between 10 and 62 mL/min/1.73 m2, the disposition of Adprazole was very similar to that in healthy volunteers, although there was a slight increase in bioavailability. Because urinary excretion is a primary route of excretion of Adprazole metabolites, their elimination slowed in proportion to the decreased creatinine clearance. No dose reduction is necessary in patients with renal impairment.

Asian Population

In pharmacokinetic studies of single 20 mg Adprazole doses, an increase in AUC of approximately four-fold was noted in Asian subjects compared with Caucasians. Dose reduction, particularly where maintenance of healing of erosive esophagitis is indicated, for Asian subjects should be considered.

12.4 Microbiology

Adprazole and clarithromycin dual therapy and Adprazole, clarithromycin and amoxicillin triple therapy have been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections as described in the Indications and Usage section ( 1.1 ).

Helicobacter

Helicobacter pylori- Pretreatment Resistance

Clarithromycin pretreatment resistance rates were 3.5% (4/113) in the omeprazole/clarithromycin dual therapy studies (4 and 5) and 9.3% (41/439) in omeprazole/clarithromycin/amoxicillin triple therapy studies (1, 2, and 3).

Amoxicillin pretreatment susceptible isolates (≤ 0.25 mcg/mL) were found in 99.3% (436/439) of the patients in the omeprazole/clarithromycin/amoxicillin triple therapy studies (1, 2, and 3). Amoxicillin pretreatment minimum inhibitory concentrations (MICs) > 0.25 mcg/mL occurred in 0.7% (3/439) of the patients, all of whom were in the clarithromycin and amoxicillin study arm. One patient had an unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of > 256 mcg/mL by Etest®.

  • Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes*
    Clarithromycin Pretreatment Results Clarithromycin Post-treatment Results
    H. pylori negative – eradicated

    H. pylori positive – not eradicated

    Post-treatment susceptibility results

    S I R No MIC
    Dual Therapy – (omeprazole 40 mg once daily/clarithromycin 500 three times daily for 14 days followed by Adprazole 20 mg once daily for another 14 days) (Studies 4, 5)
    Susceptible 108 72 1 26 9
    Intermediate 1 1
    Resistant 4 4
    Triple Therapy – (omeprazole 20 mg twice daily/clarithromycin 500 mg twice daily/amoxicillin 1 g twice daily for 10 days – Studies 1, 2, 3; followed by Adprazole 20 mg once daily for another 18 days – Studies 1, 2)
    Susceptible 171 153 7 3 8
    Intermediate
    Resistant 14 4 1 6 3

    * Includes only patients with pretreatment clarithromycin susceptibility test results

    † Susceptible (S) MIC ≤ 0.25 mcg/mL, Intermediate (I) MIC 0.5 – 1 mcg/mL, Resistant (R) MIC ≥ 2 mcg/mL


Patients not eradicated of H. pylori following omeprazole/clarithromycin/amoxicillin triple therapy or omeprazole/clarithromycin dual therapy will likely have clarithromycin resistant H. pylori isolates. Therefore, clarithromycin susceptibility testing should be done, if possible. Patients with clarithromycin resistant H. pylori should not be treated with any of the following: omeprazole/clarithromycin dual therapy, omeprazole/clarithromycin/amoxicillin triple therapy, or other regimens which include clarithromycin as the sole antimicrobial agent.

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes

In the triple therapy clinical trials, 84.9% (157/185) of the patients in the omeprazole/clarithromycin/amoxicillin treatment group who had pretreatment amoxicillin susceptible MICs (≤ 0.25 mcg/mL) were eradicated of H. pylori and 15.1% (28/185) failed therapy. Of the 28 patients who failed triple therapy, 11 had no post-treatment susceptibility test results and 17 had post-treatment H. pylori isolates with amoxicillin susceptible MICs. Eleven of the patients who failed triple therapy also had post-treatment H. pylori isolates with clarithromycin resistant MICs.

Susceptibility Test for Helicobacter pylori

The reference methodology for susceptibility testing of H. pylori is agar dilution MICs1. One to three microliters of an inoculum equivalent to a No. 2 McFarland standard (1 x 107 - 1 x 108 CFU/mL for H. pylori) are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5% aged defibrinated sheep blood (≥ 2 weeks old). The agar dilution plates are incubated at 35°C in a microaerobic environment produced by a gas generating system suitable for campylobacters. After 3 days of incubation, the MICs are recorded as the lowest concentration of antimicrobial agent required to inhibit growth of the organism. The clarithromycin and amoxicillin MIC values should be interpreted according to the following criteria:

Clarithromycin MIC (mcg/mL) * Interpretation
≤ 0.25 Susceptible (S)
0.5 Intermediate (I)
> 1 Resistant (R)
Amoxicillin MIC (mcg/mL) *, Interpretation
≤ 0.25 Susceptible (S)

* These are tentative breakpoints for the agar dilution methodology and they should not be used to interpret results obtained using alternative methods.

† There were not enough organisms with MICs > 0.25 mcg/mL to determine a resistance breakpoint.


Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard clarithromycin and amoxicillin powders should provide the following MIC values:

Microorganism Antimicrobial Agent MIC (mcg/mL) *
H. pylori ATCC 43504 Clarithromycin 0.016- 0.12 (mcg/mL)
H. pylori ATCC 43504 Amoxicillin 0.016- 0.12 (mcg/mL)
* These are quality control ranges for the agar dilution methodology and they should not be used to control test results obtained using alternative methods.

Effects on Gastrointestinal Microbial Ecology

Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and possibly Clostridium difficile in hospitalized patients.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In two 24-month carcinogenicity studies in rats, Adprazole at daily doses of 1.7, 3.4, 13.8, 44.0 and 140.8 mg/kg/day produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats; the incidence of this effect was markedly higher in female rats, which had higher blood levels of Adprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (about 6 times a human dose of 20 mg/day, based on body surface area) for one year, and then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of one year (94% treated vs 10% controls). By the second year the difference between treated and control rats was much smaller (46% vs 26%) but still showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor was seen in male or female rats treated for two years. For this strain of rat no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret. In a 52-week toxicity study in Sprague-Dawley rats, brain astrocytomas were found in a small number of males that received Adprazole at dose levels of 0.4, 2, and 16 mg/kg/day (about 0.2 to 6.5 times the human dose on a body surface area basis). No astrocytomas were observed in female rats in this study. In a 2-year carcinogenicity study in Sprague-Dawley rats, no astrocytomas were found in males or females at the high dose of 140.8 mg/kg/day (about 57 times the human dose on a body surface area basis). A 78-week mouse carcinogenicity study of Adprazole did not show increased tumor occurrence, but the study was not conclusive. A 26-week p53 (+/-) transgenic mouse carcinogenicity study was not positive.

Adprazole was positive for clastogenic effects in an in vitro human lymphocyte chromosomal aberration assay, in one of two in vivo mouse micronucleus tests, and in an in vivo bone marrow cell chromosomal aberration assay. Adprazole was negative in the in vitro Ames test, an in vitro mouse lymphoma cell forward mutation assay, and an in vivo rat liver DNA damage assay.

Adprazole at oral doses up to 138 mg/kg/day in rats (about 56 times the human dose on a body surface area basis) was found to have no effect on fertility and reproductive performance.

In 24-month carcinogenicity studies in rats, a dose-related significant increase in gastric carcinoid tumors and ECL cell hyperplasia was observed in both male and female animals [see Warnings and Precautions (5)]. Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of H2-receptor antagonists.

13.2 Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies

Reproductive studies conducted with Adprazole in rats at oral doses up to 138 mg/kg/day (about 56 times the human dose on a body surface area basis) and in rabbits at doses up to 69 mg/kg/day (about 56 times the human dose on a body surface area basis) did not disclose any evidence for a teratogenic potential of Adprazole. In rabbits, Adprazole in a dose range of 6.9 to 69.1 mg/kg/day (about 5.5 to 56 times the human dose on a body surface area basis) produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with Adprazole at 13.8 to 138.0 mg/kg/day (about 5.6 to 56 times the human doses on a body surface area basis).

14 CLINICAL STUDIES

14.1 Duodenal Ulcer Disease

Active Duodenal Ulcer—In a multicenter, double-blind, placebo-controlled study of 147 patients with endoscopically documented duodenal ulcer, the percentage of patients healed at 2 and 4 weeks was significantly higher with Adprazole 20 mg once daily than with placebo (p ≤ 0.01).

Adprazole Delayed-Release Capsules 20 mg a.m. Placebo a.m.
(n=99) (n=48)
Week 2 *41 13
Week 4 *75 27
*(p ≤ 0.01)

Complete daytime and nighttime pain relief occurred significantly faster (p ≤ 0.01) in patients treated with Adprazole Delayed-Release Capsules 20 mg than in patients treated with placebo. At the end of the study, significantly more patients who had received Adprazole Delayed-Release Capsules had complete relief of daytime pain (p ≤ 0.05) and nighttime pain (p ≤ 0.01).

In a multicenter, double-blind study of 293 patients with endoscopically documented duodenal ulcer, the percentage of patients healed (per protocol) at 4 weeks was significantly higher with Adprazole Delayed-Release Capsules 20 mg once daily than with ranitidine 150 mg b.i.d. (p < 0.01).

Adprazole Delayed-Release Capsules Ranitidine
20 mg a.m. 150 mg twice daily
(n = 145) (n = 148)
Week 2 42 34
Week 4 *82 63
*(p < 0.01)

Healing occurred significantly faster in patients treated with Adprazole Delayed-Release Capsules than in those treated with ranitidine 150 mg b.i.d. (p < 0.01).

In a foreign multinational randomized, double-blind study of 105 patients with endoscopically documented duodenal ulcer, 20 mg and 40 mg of Adprazole Delayed-Release Capsules were compared with 150 mg b.i.d. of ranitidine at 2, 4 and 8 weeks. At 2 and 4 weeks both doses of Adprazole Delayed-Release Capsules were statistically superior (per protocol) to ranitidine, but 40 mg was not superior to 20 mg of Adprazole Delayed-Release Capsules, and at 8 weeks there was no significant difference between any of the active drugs.

Adprazole Delayed-Release Capsules Ranitidine
20 mg (n=34) 40 mg (n=36) 150 mg twice daily (n=35)
Week 2  *83  *83 53
Week 4  *97 *100 82
Week 8 100 100 94
*(p ≤ 0.01)

H. pylori Eradication in Patients with Duodenal Ulcer Disease

Triple Therapy (Omeprazole Delayed-Release Capsules/clarithromycin/amoxicillin)— Three U.S., randomized, double-blind clinical studies in patients with H. pylori infection and duodenal ulcer disease (n=558) compared Adprazole Delayed-Release Capsules plus clarithromycin plus amoxicillin with clarithromycin plus amoxicillin. Two studies (1 and 2) were conducted in patients with an active duodenal ulcer, and the other study (3) was conducted in patients with a history of a duodenal ulcer in the past 5 years but without an ulcer present at the time of enrollment. The dose regimen in the studies was Adprazole Delayed-Release Capsules 20 mg twice daily plus clarithromycin 500 mg twice daily plus amoxicillin 1 g twice daily for 10 days; or clarithromycin 500 mg twice daily, plus amoxicillin 1 g twice daily for 10 days. In studies 1 and 2, patients who took the Adprazole regimen also received an additional 18 days of Adprazole Delayed-Release Capsules 20 mg once daily. Endpoints studied were eradication of H. pylori and duodenal ulcer healing (studies 1 and 2 only). H. pylori status was determined by CLOtest®, histology and culture in all three studies. For a given patient, H. pylori was considered eradicated if at least two of these tests were negative, and none was positive.

The combination of Adprazole plus clarithromycin plus amoxicillin was effective in eradicating H. pylori.

Per-Protocol and Intent-to-Treat H. pylori Eradication Rates % of Patients Cured [95% Confidence Interval]
Adprazole Delayed-Release Capsules +clarithromycin +amoxicillin Clarithromycin +amoxicillin
Per-Protocol * Intent-to-Treat Per-Protocol * Intent-to-Treat
Study 1

77 [64, 86]

(n = 64)


69 [57, 79]

(n = 80)


43 [31, 56]

(n = 67)


37 [27, 48]

(n = 84)

Study 2

78 [67, 88]

(n = 65)


73 [61, 82]

(n = 77)


41 [29, 54]

(n = 68)


36 [26, 47]

(n = 83)

Study 3

90 [80, 96]

(n = 69)


83 [74, 91]

(n = 84)


33 [24, 44]

(n = 93)


32 [23, 42]

(n = 99)


* Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer, studies 1 and 2; history of ulcer within 5 years, study 3) and H. Pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest®, histology, and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as failures of therapy. The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer.

† Patients were included in the analysis if they had documented H. Pylori infection at baseline and had confirmed duodenal ulcer disease. All dropouts were included as failures of therapy.

‡ (p < 0.05) versus clarithromycin plus amoxicillin.


Dual Therapy (Omeprazole Delayed-Release Capsules/clarithromycin)

Four randomized, double-blind, multi-center studies (4, 5, 6, and 7) evaluated Adprazole Delayed-Release Capsules 40 mg once daily plus clarithromycin 500 mg three times daily for 14 days, followed by Adprazole Delayed-Release Capsules 20 mg once daily, (studies 4, 5, and 7) or by Adprazole Delayed-Release Capsules 40 mg once daily (Study 6) for an additional 14 days in patients with active duodenal ulcer associated with H. pylori. Studies 4 and 5 were conducted in the U.S. and Canada and enrolled 242 and 256 patients, respectively. H. pylori infection and duodenal ulcer were confirmed in 219 patients in Study 4 and 228 patients in Study 5. These studies compared the combination regimen to Adprazole Delayed-Release Capsules and clarithromycin monotherapies. Studies 6 and 7 were conducted in Europe and enrolled 154 and 215 patients, respectively. H. pylori infection and duodenal ulcer were confirmed in 148 patients in study 6 and 208 patients in Study 7. These studies compared the combination regimen with Adprazole monotherapy. The results for the efficacy analyses for these studies are described below. H. pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of treatment, and two negative tests were required to be considered eradicated of H. pylori. In the per-protocol analysis, the following patients were excluded: dropouts, patients with missing H. pylori tests post-treatment, and patients that were not assessed for H. pylori eradication because they were found to have an ulcer at the end of treatment.

The combination of Adprazole and clarithromycin was effective in eradicating H. pylori.

H. pylori Eradication Rates (Per-Protocol Analysis at 4 to 6 Weeks) % of Patients Cured [95% Confidence Interval]
Adprazole Delayed-Release Capsules +Clarithromycin Adprazole Delayed-Release Capsules Clarithromycin
U.S. Studies
Study 4

74 [60, 85]*†

(n=53)


0 [0, 7]

(n=54)


31 [18, 47]

(n=42)

Study 5

64 [51, 76] *†

(n=61)


0 [0, 6]

(n=59)


39 [24, 55]

(n=44)

Non U.S. Studies
Study 6

83 [71, 92]

(n=60)


1[0, 7]

(n=74)

N/A
Study 7

74 [64, 83]

(n=86)


1[0, 6]

(n=90)

N/A

* Statistically significantly higher than clarithromycin monotherapy (p < 0.05)

† Statistically significantly higher than Adprazole monotherapy (p < 0.05)


Ulcer healing was not significantly different when clarithromycin was added to Adprazole therapy compared with Adprazole therapy alone.

The combination of Adprazole and clarithromycin was effective in eradicating H. pylori and reduced duodenal ulcer recurrence.


Duodenal Ulcer Recurrence Rates by H. pylori Eradication Status

% of Patients with Ulcer Recurrence

H. pylori eradicated * H. pylori not eradicated *
U.S. Studies 6 months post-treatment
Study 4

35

(n=49)


60

(n=88)

Study 5

8

(n=53)


60

(n=106)

Non U.S. Studies § 6 months post-treatment
Study 6

5

(n=43)


46

(n=78)

Study 7 6 (n=53) 43 (n=107)
12 months post-treatment
Study 6

5

(n=39)


68

(n=71)


* H. pylori eradication status assessed at same time point as ulcer recurrence

† Combined results for Adprazole Delayed-Release Capsules + clarithromycin, Adprazole Delayed-Release Capsules, and clarithromycin treatment arms

‡ (p ≤ 0.01) versus proportion with duodenal ulcer recurrence who were not H. pylori eradicated

§ Combined results for Adprazole Delayed-Release Capsules + clarithromycin and Adprazole Delayed-Release Capsules treatment arms

14.2 Gastric Ulcer

In a U.S. multicenter, double-blind, study of Adprazole 40 mg once daily, 20 mg once daily, and placebo in 520 patients with endoscopically diagnosed gastric ulcer, the following results were obtained.


Adprazole Delayed-Release Capsules

20 mg once daily

(n=202)


Adprazole Delayed-Release Capsules

40 mg once daily

(n=214)


Placebo

(n=104)

Week 4 47.5 * 55.6 * 30.8
Week 8 74.8 * 82.7 *† 48.1

* (p < 0.01) Adprazole Delayed-Release Capsules 40 mg or 20 mg versus placebo

† (p < 0.05) Adprazole Delayed-Release Capsules 40 mg versus 20 mg


For the stratified groups of patients with ulcer size less than or equal to 1 cm, no difference in healing rates between 40 mg and 20 mg was detected at either 4 or 8 weeks. For patients with ulcer size greater than 1 cm, 40 mg was significantly more effective than 20 mg at 8 weeks.

In a foreign, multinational, double-blind study of 602 patients with endoscopically diagnosed gastric ulcer, Adprazole 40 mg once daily, 20 mg once daily, and ranitidine 150 mg twice a day were evaluated.


Adprazole Delayed-Release Capsules

20 mg once daily

(n=200)


Adprazole Delayed-Release Capsules

40 mg once daily

(n=187)


Ranitidine

150 mg twice daily.

(n=199)

Week 4 63.5 78.1 *,† 56.3
Week 8 81.5 91.4 *,† 78.4

* (p < 0.01) Adprazole Delayed-Release Capsules 40 mg versus ranitidine

† (p < 0.01) Adprazole Delayed-Release Capsules 40 mg versus 20 mg

14.3 Gastroesophageal Reflux Disease

Symptomatic GERD

A placebo-controlled study was conducted in Scandinavia to compare the efficacy of Adprazole 20 mg or 10 mg once daily for up to 4 weeks in the treatment of heartburn and other symptoms in GERD patients without erosive esophagitis.

Results are shown below.

Adprazole Delayed-Release Capsules 20 mg a.m. Adprazole Delayed-Release Capsules 10 mg a.m.

Placebo

a.m.


All patients


46 †,‡

(n=205)


31

(n=199)


13

(n=105)

Patients with confirmed GERD

56 †,‡

(n=115)


36

(n=109)


14

(n=59)


* Defined as complete resolution of heartburn

† (p < 0.005) versus 10 mg

‡ (p < 0.005) versus placebo

14.4 Erosive Esophagitis

In a U.S. multicenter double-blind placebo controlled study of 20 mg or 40 mg of Adprazole Delayed-Release Capsules in patients with symptoms of GERD and endoscopically diagnosed erosive esophagitis of grade 2 or above, the percentage healing rates were as follows:

Week

20 mg

Adprazole

Delayed-Release Capsules

(n=83)


40 mg

Adprazole

Delayed-Release Capsules

(n=87)


Placebo

(n=43)

4 39 * 45 * 7
8 74 * 75 * 14
* (p < 0.01) Adprazole Delayed-Release Capsules versus placebo.

In this study, the 40 mg dose was not superior to the 20 mg dose of Adprazole Delayed-Release Capsules in the percentage healing rate. Other controlled clinical trials have also shown that Adprazole Delayed-Release Capsules are effective in severe GERD. In comparisons with histamine H2-receptor antagonists in patients with erosive esophagitis, grade 2 or above, Adprazole Delayed-Release Capsules in a dose of 20 mg was significantly more effective than the active controls. Complete daytime and nighttime heartburn relief occurred significantly faster (p < 0.01) in patients treated with Adprazole Delayed-Release Capsules than in those taking placebo or histamine H2- receptor antagonists.

In this and five other controlled GERD studies, significantly more patients taking 20 mg Adprazole (84%) reported complete relief of GERD symptoms than patients receiving placebo (12%).

Long Term Maintenance Of Healing of Erosive Esophagitis

In a U.S. double-blind, randomized, multicenter, placebo controlled study, two dose regimens of Adprazole Delayed-Release Capsules were studied in patients with endoscopically confirmed healed esophagitis. Results to determine maintenance of healing of erosive esophagitis are shown below.


Adprazole Delayed-Release Capsules

20 mg once daily

(n=138)


Adprazole Delayed-Release Capsules

20 mg 3 days per week

(n=137)


Placebo

(n=131)

Percent in endoscopic remission at 6 months *70 34 11
* (p < 0.01) Adprazole Delayed-Release Capsules 20 mg once daily versus Adprazole Delayed-Release Capsules 20 mg 3 consecutive days per week or placebo.

In an international multicenter double-blind study, Adprazole Delayed-Release Capsules 20 mg daily and 10 mg daily were compared with ranitidine 150 mg twice daily in patients with endoscopically confirmed healed esophagitis. The table below provides the results of this study for maintenance of healing of erosive esophagitis.


Adprazole Delayed-Release Capsules

20 mg once daily

(n=131)


Adprazole Delayed-Release Capsules

10 mg once daily

(n=133)


Ranitidine

150 mg twice daily

(n=128)

Percent in endoscopic remission at 12 months *77 58 46

(p = 0.01) Adprazole Delayed-Release Capsules 20 mg once daily, versus Adprazole Delayed-Release Capsules 10 mg- once daily or Ranitidine

† (p= 0.03) Adprazole Delayed-Release Capsules 10 mg once daily, versus Ranitidine


In patients who initially had grades 3 or 4 erosive esophagitis, for maintenance after healing, 20 mg daily of Adprazole was effective, while 10 mg did not demonstrate effectiveness.

14.5 Pathological Hypersecretory Conditions

In open studies of 136 patients with pathological hypersecretory conditions, such as Zollinger-Ellison (ZE) syndrome with or without multiple endocrine adenomas, Adprazole Delayed-Release Capsules significantly inhibited gastric acid secretion and controlled associated symptoms of diarrhea, anorexia, and pain. Doses ranging from 20 mg every other day to 360 mg per day maintained basal acid secretion below 10 mEq/hr in patients without prior gastric surgery, and below 5 mEq/hr in patients with prior gastric surgery.

Initial doses were titrated to the individual patient need, and adjustments were necessary with time in some patients see Dosage and Administration ( 2 )]. Adprazole Delayed-Release Capsules were well tolerated at these high dose levels for prolonged periods (> 5 years in some patients). In most ZE patients, serum gastrin levels were not modified by Adprazole Delayed-Release Capsules. However, in some patients serum gastrin increased to levels greater than those present prior to initiation of Adprazole therapy. At least 11 patients with ZE syndrome on long-term treatment with Adprazole Delayed-Release Capsules developed gastric carcinoids. These findings are believed to be a manifestation of the underlying condition, which is known to be associated with such tumors, rather than the result of the administration of Adprazole Delayed-Release Capsules [see Adverse Reactions ( 6  )].

14.6 Pediatric GERD

Symptomatic GERD

The effectiveness of Adprazole Delayed-Release Capsules for the treatment of nonerosive GERD in pediatric patients 1 to 16 years of age is based in part on data obtained from pediatric patients in an uncontrolled Phase III study [see Use in Specific Populations ( 8.4 )].

The study enrolled 113 pediatric patients 2 to 16 years of age with a history of symptoms suggestive of nonerosive GERD. Patients were administered a single dose of Adprazole (10 mg or 20 mg, based on body weight) for 4 weeks either as an intact capsule or as an open capsule in applesauce. Successful response was defined as no moderate or severe episodes of either pain-related symptoms or vomiting/regurgitation during the last 4 days of treatment. Results showed success rates of 60% (9/15; 10 mg Adprazole) and 59% (58/98; 20 mg Adprazole), respectively.

Healing of Erosive Esophagitis

In an uncontrolled, open-label dose-titration study, healing of erosive esophagitis in pediatric patients 2 to 16 years of age required doses that ranged from 0.7 to 3.5 mg/kg/day (80 mg/day). Doses were initiated at 0.7 mg/kg/day. Doses were increased in increments of 0.7 mg/kg/day (if intraesophageal pH showed a pH of < 4 for less than 6% of a 24-hour study). After titration, patients remained on treatment for 3 months. Forty-four percent of the patients were healed on a dose of 0.7 mg/kg body weight; most of the remaining patients were healed with 1.4 mg/kg after an additional 3 months' treatment. Erosive esophagitis was healed in 51 of 57 (90%) children who completed the first course of treatment in the healing phase of the study. In addition, after 3 months of treatment, 33% of the children had no overall symptoms, 57% had mild reflux symptoms, and 40% had less frequent regurgitation/vomiting.

Maintenance of Healing of Erosive Esophagitis

In an uncontrolled, open-label study of maintenance of healing of erosive esophagitis in 46 pediatric patients, 54% of patients required half the healing dose. The remaining patients increased the healing dose (0.7 to a maximum of 2.8 mg/kg/day) either for the entire maintenance period, or returned to half the dose before completion. Of the 46 patients who entered the maintenance phase, 19 (41%) had no relapse. In addition, maintenance therapy in erosive esophagitis patients resulted in 63% of patients having no overall symptoms.

15 REFERENCES

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically—Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol, 20, No. 2, NCCLS, Wayne, PA, January 2000.

16 HOW SUPPLIED/STORAGE AND HANDLING

Adprazole Delayed-Release Capsules, 10 mg, are opaque white cap and opaque white body capsules imprinted with "KU" and "114" in black ink. They are supplied as follows:

Bottles of 30 NDC 62175-114-32

Bottles of 100 NDC 62175-114-37

Adprazole Delayed-Release Capsules, 20 mg, are opaque white cap and opaque gold body capsules imprinted with "KU" and "118" in black ink. They are supplied as follows:

Bottles of 30 NDC 62175-118-32

Bottles of 100 NDC 62175-118-37

Bottles of 1000 NDC 62175-118-43

Adprazole Delayed-Release Capsules, 40 mg, are opaque gold cap and opaque gold body capsules imprinted with "KU" and "136" in black ink. They are supplied as follows:

Bottles of 30 NDC 62175-136-32

Bottles of 100 NDC 62175-136-37

Bottles of 1000 NDC 62175-136-43

Storage

Store Adprazole Delayed-Release Capsules in a tight container protected from light and moisture. Store at 20°-25°C (68°-77°F).

Dispense in a tight and light-resistant container.

17 PATIENT COUNSELING INFORMATION

Adprazole Delayed-Release Capsule should be taken before eating. Patients should be informed that the Adprazole Delayed-Release Capsule should be swallowed whole.

For patients who have difficulty swallowing capsules, the contents of an Adprazole Delayed-Release Capsule can be added to applesauce. One tablespoon of applesauce should be added to an empty bowl and the capsule should be opened. All of the microtablets inside the capsule should be carefully emptied on the applesauce. The microtablets should be mixed with the applesauce and then swallowed immediately with a glass of cool water to ensure complete swallowing of the microtablets. The applesauce used should not be hot and should be soft enough to be swallowed without chewing. The microtablets should not be chewed or crushed. The microtablets/applesauce mixture should not be stored for future use.

Advise patients to immediately report and seek care for any cardiovascular or neurological symptoms including palpitations, dizziness, seizures, and tetany as these may be signs of hypomagnesemia [see Warnings and Precautions (5.7) ].

Distributed by:

Kremers Urban, Pharmaceuticals Inc.

Princeton, NJ 08540, USA

L3599Y

Revised: 9E 07/2011

FDA-Approved Patient Labeling

Adprazole Delayed-Release Capsules

Read the patient information that comes with Adprazole Delayed-Release Capsules before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment.

If you have any questions about Adprazole Delayed-Release Capsules, ask your doctor.

WHAT ARE Adprazole DELAYED-RELEASE CAPSULES?

Adprazole Delayed-Release Capsules are a prescription medicine called a proton pump inhibitor (PPI). Adprazole Delayed-Release Capsules reduce the amount of acid in your stomach. Adprazole Delayed-Release Capsules are used in adults:

  • for up to 4 weeks to treat heartburn and other symptoms that happen with gastroesophageal reflux disease (GERD).

    GERD is a chronic condition (lasts a long time) that occurs when acid from the stomach backs up into the esophagus (food pipe) causing symptoms, such as heartburn, or damage to the lining of the esophagus. Common symptoms include frequent heartburn that will not go away, a sour or bitter taste in the mouth, and difficulty swallowing.

  • for up to 8 weeks to heal acid-related damage to the lining of the esophagus (called erosive esophagitis or EE)
  • to maintain healing of the esophagus. Adprazole Delayed-Release Capsules have not been studied for treatment lasting longer than 12 months (1 year)
  • for up to 8 weeks for healing stomach ulcers
  • for up to 8 weeks for healing ulcers in the first part of the small bowel (duodenal ulcers)
  • to treat patients with a stomach infection (Helicobacter pylori), along with the antibiotics amoxicillin and clarithromycin.
  • for lowering the amount of stomach acid in people with certain conditions which cause them to make too much acid, including those with Zollinger-Ellison Syndrome.

For children and adolescents 2 to 17 years of age, Adprazole Delayed-Release Capsules are used:

  • for up to 4 weeks to treat the symptoms of gastroesophageal reflux disease (GERD).
  • for up to 8 weeks to heal acid-related damage to the lining of the esophagus (called erosive esophagitis or EE)
  • to maintain healing of the esophagus

Adprazole Delayed-Release Capsules are not recommended for children under the age of 2 years Adprazole Delayed-Release Capsules may help your acid-related symptoms, but you could still have serious stomach problems. Talk with your doctor.

WHO SHOULD NOT TAKE Adprazole DELAYED-RELEASE CAPSULES?

Do not take Adprazole Delayed-Release Capsules if you:

  • are allergic to any of the ingredients in Adprazole Delayed-Release Capsules. See the end of this leaflet for a complete list of ingredients in Adprazole Delayed-Release Capsules.
  • are allergic to any other Proton Pump Inhibitor (PPI) medicine.

WHAT SHOULD I TELL MY DOCTOR BEFORE TAKING Adprazole DELAYED-RELEASE CAPSULES?

Tell your doctor about all your medical conditions, including if you:

  • have been told that you have low magnesium levels in your blood
  • have liver problems
  • are pregnant or plan to become pregnant. It is not known if Adprazole Delayed-Release Capsules will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.
  • are breastfeeding or planning to breastfeed. You and your doctor should decide if you will take Adprazole Delayed-Release Capsules or breastfeed. You should not do both.

Tell your doctor about all of the medicines you take including prescription and non-prescription drugs, vitamins and herbal supplements. Adprazole Delayed-Release Capsules may affect how other medicines work, and other medicines may affect how Adprazole Delayed-Release Capsules works. Especially tell your doctor if you take:

  • atazanavir (Reyataz)
  • nelfinavir (Viracept)
  • saquinavir (Fortovase)
  • cilostazol (Pletal)
  • ketoconazole (Nizoral)
  • voriconazole (Vfend)
  • ampicillin (Unasyn)
  • products that contain iron
  • warfarin (Coumadin)
  • digoxin (Lanoxin, Lanoxincaps)
  • tacrolimus (Prograf)
  • diazepam (Valium)
  • phenytoin (Dilantin)
  • disulfiram (Antabuse)
  • clopidogrel (Plavix)
  • St. John's Wort (Hypericum perforatum)
  • rifampin

HOW SHOULD I TAKE Adprazole DELAYED-RELEASE CAPSULES?

  • Take Adprazole Delayed-Release Capsules exactly as prescribed by your doctor.
  • Do not change your dose or stop Adprazole Delayed-Release Capsules without talking to your doctor.
  • Take Adprazole Delayed-Release Capsules at least 1 hour before a meal.
  • Swallow Adprazole Delayed-Release Capsules whole. Never chew or crush Adprazole Delayed-Release Capsules.
  • If you have difficulty swallowing Adprazole Delayed-Release Capsules, you may open the capsule and empty the contents into a tablespoon of applesauce. Be sure to swallow the applesauce right away. Do not store it for later use.
  • If you forget to take a dose of Adprazole Delayed-Release Capsules, take it as soon as you remember. If it is almost time for your next dose, do not take the missed dose. Take the next dose on time. Do not take a double dose to make up for a missed dose.
  • If you take too much Adprazole Delayed-Release Capsules, tell your doctor right away.

WHAT ARE THE POSSIBLE SIDE EFFECTS OF Adprazole DELAYED-RELEASE CAPSULES?

  • Serious allergic reactions. Tell your doctor if you get any of the following symptoms with Adprazole Delayed-Release Capsules.
  • rash
  • face swelling
  • throat tightness
  • difficulty breathing

Your doctor may stop Adprazole Delayed-Release Capsules if these symptoms happen.

  • Low magnesium levels in your body. This problem can be serious. Low magnesium can happen in some people who take a proton pump inhibitor medicine for at least 3 months. If low magnesium levels happen, it is usually after a year of treatment. You may or may not have symptoms of low magnesium.

Tell your doctor right away if you have any of these symptoms;

  • seizures
  • dizziness
  • abnormal or fast heart beat
  • jitteriness
  • jerking movements or shaking (tremors)
  • muscle weakness
  • spasms of the hands and feet
  • cramps or muscle aches
  • spasm of the voice box

Your doctor may check the level of magnesium in your body before you start taking Adprazole Delayed-Release Capsules or during treatment if you will be taking Adprazole Delayed-Release Capsules for a long period of time.

The most common side effects with Adprazole Delayed-Release Capsules in adults and children include:

  • Headache
  • Abdominal pain
  • Nausea
  • Diarrhea
  • Vomiting
  • Gas
  • Respiratory system events
  • Fever

People who are taking multiple daily doses of proton pump inhibitor medicines for a long period of time may have an increased risk of fractures of the hip, wrist or spine.

Tell your doctor about any side effects that bother you or that do not go away. These are not all the possible side effects with Adprazole Delayed-Release Capsules. Talk with your doctor or pharmacist if you have any questions about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

HOW SHOULD I STORE Adprazole DELAYED-RELEASE CAPSULES?

Store Adprazole Delayed-Release Capsules at 68°F to 77°F (20°C to 25°C).

Keep the container of Adprazole Delayed-Release Capsules closed tightly.

Keep Adprazole Delayed-Release Capsules and all medicines out of the reach of children.

GENERAL ADVICE

Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use Adprazole Delayed-Release Capsules for a condition for which it was not prescribed. Do not give Adprazole Delayed-Release Capsules to other people, even if they have the same symptoms you have. It may harm them.

This Patient Information leaflet provides a summary of the most important information about Adprazole Delayed-Release Capsules. For more information, ask your doctor. You can ask your doctor or pharmacist for information that is written for healthcare professionals. For more information, go to www. kremersurban.com or call toll free 1-866-822-0068.

PATIENT INSTRUCTIONS FOR USE

For instructions on taking Delayed-Release Capsules, please see "HOW SHOULD I TAKE Adprazole DELAYED-RELEASE CAPSULES?"

WHAT ARE THE INGREDIENTS IN Adprazole DELAYED-RELEASE CAPSULES?

Active ingredient in Adprazole DELAYED-RELEASE CAPSULES:

Adprazole

Inactive ingredients in Adprazole DELAYED-RELEASE CAPSULES:

(including the capsule shells): crospovidone, glyceryl behenate, hypromellose, lactose monohydrate, methacrylic acid copolymer dispersion, silicon dioxide, talc, titanium dioxide and triethyl citrate.  In addition, the capsule shells contain gelatin and may contain sodium lauryl sulfate.  In addition, the 20 mg and 40 mg capsule shells also contain yellow iron oxide.  The imprinting ink also contains ammonium hydroxide, butyl alcohol, black iron oxide, isopropyl alcohol, propylene glycol and shellac glaze.  The ink may also contain dehydrated alcohol.

Distributed by:

Kremers Urban Pharmaceuticals Inc.

Princeton, NJ 08540, USA

L3599Y

Revised: 9E 07/2011

Image of Label

Image of Label

Adprazole pharmaceutical active ingredients containing related brand and generic drugs:

infoActive ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Adprazole available forms, composition, doses:

infoForm of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Adprazole destination | category:

infoDestination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Adprazole Anatomical Therapeutic Chemical codes:

infoA medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Adprazole pharmaceutical companies:

infoPharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


advertisement

Frequently asked Questions

Can i drive or operate heavy machine after consuming Adprazole?

Depending on the reaction of the Adprazole after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Adprazole not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Adprazole addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

advertisement

Review

sDrugs.com conducted a study on Adprazole, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Adprazole consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

Visitor reported useful

No survey data has been collected yet


Visitor reported side effects

No survey data has been collected yet


Visitor reported price estimates

No survey data has been collected yet


Visitor reported frequency of use

No survey data has been collected yet


Visitor reported doses

No survey data has been collected yet


Visitor reported time for results

No survey data has been collected yet


One visitor reported administration

The drugs are administered in various routes, like oral or injection form. They are administered before food or after food. How are you taking Adprazole drug, before food or after food?
Click here to find out how other users of our website are taking it. For any doubts or queries on how and when the medicine is administered, contact your health care provider immediately.
Visitors%
With a meal1
100.0%


One visitor reported age

Visitors%
30-451
100.0%


Visitor reviews


There are no reviews yet. Be the first to write one!


Your name: 
Email: 
Spam protection:  < Type 25 here

The information was verified by Dr. Arunabha Ray, MD Pharmacology

© 2002 - 2018 "sDrugs.com". All Rights Reserved