Ond-R

Ondansetron:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Drug abuse and dependence
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• References
• How supplied/storage and handling
• Patient counseling information
• Ond-R (Ondansetron) reviews

1 INDICATIONS AND USAGE

Ond-R is a 5-HT3 receptor antagonist indicated for:

• Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy. (1.1)
• Prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy. (1.2)
• Prevention of nausea and vomiting associated with radiotherapy in patients receiving total body irradiation, single high-dose fraction to abdomen, or daily fractions to the abdomen. (1.3)
• Prevention of postoperative nausea and/or vomiting. (1.4)

1.1 Prevention of Nausea and Vomiting Associated with Highly Emetogenic Cancer Chemotherapy

Ond-R (Ondansetron) (ondansetron) oral soluble film is indicated for the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥50 mg/m² .

1.2 Prevention of Nausea and Vomiting Associated with Moderately Emetogenic Cancer Chemotherapy

Ond-R is indicated for the prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy .

1.3 Prevention of Nausea and Vomiting Associated with Radiotherapy

Ond-R (Ondansetron) is indicated for the prevention of nausea and vomiting associated with radiotherapy in patients receiving either total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen .

1.4 Prevention of Postoperative Nausea and/or Vomiting

Ond-R (Ondansetron) is indicated for the prevention of postoperative nausea and/or vomiting. As with other antiemetics, routine prophylaxis is not recommended for patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and/or vomiting must be avoided postoperatively, Ond-R (Ondansetron) is recommended even where the incidence of postoperative nausea and/or vomiting is low .

2 DOSAGE AND ADMINISTRATION

• Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy: The adult oral dosage is 24 mg given successively as three 8 mg films administered 30 minutes before the start of chemotherapy.
• Prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy:
  • Adults and pediatric patients 12 years of age and older: One 8 mg film 30 minutes before chemotherapy followed by an 8 mg dose 8 hours later. Administer one 8 mg film twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy. (2.2)
  • Pediatric patients 4 through 11 years of age: One 4 mg film three times a day. Administer the first dose 30 minutes before chemotherapy, with subsequent doses 4 and 8 hours later. Administer one 4 mg film three times a day (every 8 hours) for 1 to 2 days after completion of chemotherapy. (2.2)
• Prevention of nausea and vomiting associated with radiotherapy: The adult dosage is one 8 mg film three times a day. (2.3)
• Postoperative nausea and vomiting: The adult dose is 16 mg given successively as two 8 mg films 1 hour before anesthesia. (2.4)
• See dosage adjustment for patients with impaired hepatic function. (2.5)

2.1 Prevention of Nausea and Vomiting Associated with Highly Emetogenic Cancer Chemotherapy

Adults

The recommended adult oral dosage of Ond-R (Ondansetron) (ondansetron) oral soluble film is 24 mg given successively as three 8 mg films administered 30 minutes before the start of single-day highly emetogenic chemotherapy, including cisplatin ≥50 mg/m². Each Ond-R (Ondansetron) oral soluble film should be allowed to dissolve completely before administering the next film [see Dosage and Administration (2.6 )]. Multiday, single-dose administration of a 24 mg dosage has not been studied.

Pediatrics

Safety and effectiveness of Ond-R (Ondansetron) in pediatric patients have not been established for this indication.

2.2 Prevention of Nausea and Vomiting Associated with Moderately Emetogenic Cancer Chemotherapy

Adults

The recommended adult oral dosage is one 8 mg Ond-R oral soluble film given twice a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. One 8 mg Ond-R (Ondansetron) oral soluble film should be administered twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy .

Pediatrics

For pediatric patients 12 years of age and older, the dosage is the same as for adults. For pediatric patients 4 through 11 years of age, the dosage is one 4 mg Ond-R (Ondansetron) oral soluble film given three times a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with subsequent doses 4 and 8 hours after the first dose. One 4 mg Ond-R (Ondansetron) oral soluble film should be administered three times a day (every 8 hours) for 1 to 2 days after completion of chemotherapy .

2.3 Prevention of Nausea and Vomiting Associated with Radiotherapy

Adults

The recommended adult oral dosage of Ond-R (Ondansetron) oral soluble film is one 8 mg film given three times a day .

For total body irradiation, one 8 mg Ond-R (Ondansetron) oral soluble film should be administered 1 to 2 hours before each fraction of radiotherapy administered each day.

For single high-dose fraction radiotherapy to the abdomen, one 8 mg Ond-R (Ondansetron) oral soluble film should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for 1 to 2 days after completion of radiotherapy.

For daily fractionated radiotherapy to the abdomen, one 8 mg Ond-R (Ondansetron) oral soluble film should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for each day radiotherapy is given.

Pediatrics

Safety and effectiveness of Ond-R (Ondansetron) in pediatric patients have not been established for this indication.

2.4 Prevention of Postoperative Nausea and/or Vomiting

Adults

The recommended adult oral dosage of Ond-R oral soluble film is 16 mg given successively as two 8 mg films 1 hour before induction of anesthesia. Each Ond-R (Ondansetron) oral soluble film should be allowed to dissolve completely before administering the next film .

Pediatrics

Safety and effectiveness of Ond-R (Ondansetron) in pediatric patients have not been established for this indication.

2.5 Dosage Adjustment for Patients with Impaired Hepatic Function

In patients with severe hepatic impairment (Child-Pugh score of 10 or greater)², clearance is reduced and apparent volume of distribution is increased with a resultant increase in plasma half-life . In such patients, a total daily dose of 8 mg should not be exceeded.

2.6 Important Administration Instructions

With dry hands, fold the pouch along the dotted line to expose the tear notch. While still folded, tear the pouch carefully along the edge and remove the Ond-R (Ondansetron) oral soluble film from the pouch. Immediately place the film on top of the tongue where it dissolves in 4 to 20 seconds. Once the Ond-R (Ondansetron) oral soluble film is dissolved, swallow with or without liquid . Wash hands after taking Ond-R (Ondansetron).

3 DOSAGE FORMS AND STRENGTHS

Ond-R (Ondansetron) (ondansetron) oral soluble film is available in 4 mg and 8 mg strengths. The thin white opaque films are rectangularly shaped strips with a printed identifier in black ink of “4 mg” for Ond-R (Ondansetron) 4 mg or “8 mg” for Ond-R (Ondansetron) 8 mg.

• 4 mg and 8 mg oral soluble film. (3)

4 CONTRAINDICATIONS

The concomitant use of apomorphine with Ond-R (Ondansetron) is contraindicated based on reports of profound hypotension and loss of consciousness when apomorphine was administered with Ond-R (Ondansetron).

Ond-R (Ondansetron) (ondansetron) oral soluble film is contraindicated for patients known to have hypersensitivity to the drug. Anaphylactic reactions have been reported in patients taking Ond-R (Ondansetron).

• Concomitant use of apomorphine. (4)
• Hypersensitivity to Ond-R (Ondansetron). (4)

5 WARNINGS AND PRECAUTIONS

• Hypersensitivity reactions, including anaphylaxis and bronchospasm, have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists.
• Ond-R (Ondansetron) in patients with congenital long QT syndrome. Monitor ECG in patients with electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, bradyarrhythmias or patients taking other medicinal products that lead to QT prolongation. (5.2)
• The use of Ond-R (Ondansetron) in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distension. (5.3)
• Serotonin syndrome has been reported with 5-HT3 receptor antagonists alone but particularly with concomitant use of serotonergic drugs. (5.3)

5.1 Hypersensitivity

Hypersensitivity reactions, including anaphylaxis and bronchospasm, have been reported in patients who have exhibited hypersensitivity to other selective 5-HT₃ receptor antagonists. Ond-R (Ondansetron) (ondansetron) oral soluble film should be discontinued immediately at the first sign of hypersensitivity.

5.2 Electrocardiographic Changes

ECG changes including QT interval prolongation have been seen in patients receiving Ond-R. In addition, post-marketing cases of Torsade de Pointes have been reported in patients using Ond-R (Ondansetron). Avoid Ond-R (Ondansetron) in patients with congenital long QT syndrome. ECG monitoring is recommended in patients with electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, bradyarrhythmias or patients taking other medicinal products that lead to QT prolongation.

5.3 Serotonin Syndrome

The development of serotonin syndrome has been reported with 5-HT3 receptor antagonists. Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue). Some of the reported cases were fatal. Serotonin syndrome occurring with overdose of Ond-R (Ondansetron) alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT3 receptor antagonist use occurred in a post anesthesia care unit or an infusion center.

Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of Ond-R (Ondansetron) and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue Ond-R (Ondansetron) and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if Ond-R (Ondansetron) is used concomitantly with other serotonergic drugs [see Drug Interactions (7.3), Overdosage (10.), Patient Counseling Information (17.)].

5.4 Masking of Progressive Ileus and/or Gastric Distension

The use of Ond-R in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distension.

5.5 Effect on Peristalsis

Ond-R (Ondansetron) is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction.

6 ADVERSE REACTIONS

• The most common adverse drug events in chemotherapy-induced nausea and vomiting and radiotherapy-induced nausea and vomiting were: headache, malaise/fatigue, constipation, and diarrhea. (6.1)
• The most common adverse event (≥5%) in postoperative nausea and vomiting was headache. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Galena Biopharma, Inc., Portland, OR, 97239, at 1 855 636 5710 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

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

The following adverse events have been reported in clinical trials of patients treated with Ond-R (Ondansetron), the active ingredient of Ond-R (Ondansetron). A causal relationship to therapy with Ond-R (Ondansetron) was unclear in many cases.

Chemotherapy-Induced Nausea and Vomiting

Central Nervous System: There have been rare reports consistent with, but not diagnostic of, extrapyramidal reactions in patients receiving Ond-R (Ondansetron).

Hepatic: In 723 patients receiving cyclophosphamide-based chemotherapy in US clinical trials, AST and/or ALT values have been reported to exceed twice the upper limit of normal in approximately 1% to 2% of patients receiving Ond-R (Ondansetron) HCl tablets. The increases were transient and did not appear to be related to dose or duration of therapy. On repeat exposure, similar transient elevations in transaminase values occurred in some courses, but symptomatic hepatic disease did not occur. The role of cancer chemotherapy in these biochemical changes cannot be clearly determined. There have been reports of liver failure and death in patients with cancer receiving concurrent medications including potentially hepatotoxic cytotoxic chemotherapy and antibiotics. The etiology of the liver failure is unclear.

Integumentary: Rash has occurred in approximately 1% of patients receiving Ond-R (Ondansetron).

Other: Rare cases of anaphylaxis, bronchospasm, tachycardia, angina (chest pain), hypokalemia, electrocardiographic alterations, vascular occlusive events, and grand mal seizures have been reported. Except for bronchospasm and anaphylaxis, the relationship to Ond-R (Ondansetron) was unclear.

Radiation-Induced Nausea and Vomiting

The adverse events reported in patients receiving Ond-R (Ondansetron) HCl tablets and concurrent radiotherapy were similar to those reported in patients receiving Ond-R (Ondansetron) HCl tablets and concurrent chemotherapy. The most frequently reported adverse events were headache, constipation, and diarrhea.

Postoperative Nausea and Vomiting

6.2 Postmarketing Experience

In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of oral formulations of Ond-R (Ondansetron). Because these events are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to Ond-R (Ondansetron).

Cardiovascular: Rarely and predominantly with intravenous Ond-R (Ondansetron), transient ECG changes including QT interval prolongation have been reported.

General: Flushing. Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylaxis reactions, angioedema, bronchospasm, shortness of breath, hypotension, laryngeal edema, stridor) have also been reported. Laryngospasm, shock, and cardiopulmonary arrest have occurred during allergic reactions in patients receiving injectable Ond-R (Ondansetron).

Hepatobiliary: Liver enzyme abnormalities

Lower Respiratory: Hiccups

Neurology: Oculogyric crisis, appearing alone, as well as with other dystonic reactions

Skin: Urticaria

Eye Disorders: Cases of transient blindness, predominantly during intravenous administration, have been reported. These cases of transient blindness were reported to resolve within a few minutes up to 48 hours.

7 DRUG INTERACTIONS

Ond-R does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver.

• Apomorphine – profound hypotension and loss of consciousness. Concomitant use with Ond-R (Ondansetron) is contraindicated. (7.1)

7.1 Apomorphine

Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with Ond-R (Ondansetron), the concomitant use of apomorphine with Ond-R (Ondansetron) is contraindicated [see Contraindications (4)].

7.2 Phenytoin, Carbamazepine, Rifampicin

In patients treated with potent inducers of CYP3A4, the clearance of Ond-R (Ondansetron) was significantly increased and Ond-R (Ondansetron) blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for Ond-R (Ondansetron) is recommended for patients on these drugs.^1,3

7.3 Serotonergic Drugs

Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT 3 receptor antagoinists and other serotonergic drugs, including selective serotonin reuptake inhibitor (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) .

7.4 Tramadol

Although there are no data on pharmacokinetic drug interactions between Ond-R and tramadol, data from two small studies indicate that concomitant use of Ond-R (Ondansetron) may result in reduced analgesic activity of tramadol. Patients in the studies self-administered tramadol more frequently, leading to an increased cumulative dose in patient controlled administration (PCA) of tramadol.^4,5

7.5 Chemotherapy

In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of Ond-R (Ondansetron).

In a crossover study in 76 pediatric patients, intravenous Ond-R (Ondansetron) did not increase blood levels of high-dose methotrexate.

7.6 Temazepam

The co-administration of Ond-R had no effect on the pharmacokinetics and pharmacodynamics of temazepam.

7.7 Antacids

Bioavailability of Ond-R (Ondansetron) is unaffected by antacids

7.8 Alfentanil and Atracurium

Ond-R (Ondansetron) does not alter the respiratory depressant effects produced by alfentanil or the degree of neuromuscular blockade produced by atracurium. Interactions with general or local anesthetics have not been studied.

8 USE IN SPECIFIC POPULATIONS

• Pediatrics: The safety and effectiveness in pediatric patients have only been established for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy in patients four years of age and older. For dosage recommendations see (2.2).
• Impaired Hepatic Function: In patients with severe hepatic impairment (Child-Pugh score of 10 or greater)², a total daily dose of 8 mg should not be exceeded. (8.7)

8.1 Pregnancy

Pregnancy Category B. Reproduction studies have been performed in pregnant rats and rabbits at daily oral doses up to 15 and 30 mg/kg/day, respectively (approximately 8 and 30 times the human dose of 16 mg/day, based on body surface area), and have revealed no evidence of impaired fertility or harm to the fetus due to Ond-R (Ondansetron). There are, however, no adequate and well- controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Ond-R (Ondansetron) (ondansetron) oral soluble film should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

Ond-R is excreted in the milk of rats. It is not known whether Ond-R (Ondansetron) is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Ond-R (Ondansetron) oral soluble film is administered to a nursing woman.

8.4 Pediatric Use

Little information is available about dosage in pediatric patients less than 4 years of age. For dosage recommendations in the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy for patients 4 years of age and older . The safety and effectiveness in pediatric patients have not been established for the following

Indications: prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, prevention of nausea and vomiting associated with radiotherapy, and prevention of postoperative nausea and/or vomiting.

8.5 Geriatric Use

Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting in US- and foreign- controlled clinical trials, for which there were subgroup analyses, 938 were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment is not needed in patients over the age of 65 [see Clinical Pharmacology ].

8.6 Renal Impairment

The dosage recommendation is the same as for the general population. There is no experience beyond first-day administration of Ond-R (Ondansetron).

8.7 Hepatic Impairment

In patients with severe hepatic impairment (Child-Pugh score of 10 or greater)², clearance is reduced and apparent volume of distribution is increased with a resultant increase in plasma half-life [see Clinical Pharmacology (12.3)]. In such patients, a total daily dose of 8 mg should not be exceeded.

9 DRUG ABUSE AND DEPENDENCE

Animal studies have shown that Ond-R (Ondansetron) is not discriminated as a benzodiazepine nor does it substitute for benzodiazepines in direct addiction studies.

10 OVERDOSAGE

There is no specific antidote for Ond-R (Ondansetron) overdose. Patients should be managed with appropriate supportive therapy. Individual intravenous doses as large as 150 mg and total daily intravenous doses as large as 252 mg have been inadvertently administered without significant adverse events. These doses are more than 10 times the recommended daily dose.

In addition to the adverse events listed above, the following events have been described in the setting of Ond-R (Ondansetron) overdose: “Sudden blindness” (amaurosis) of 2 to 3 minutes' duration plus severe constipation occurred in 1 patient that was administered 72 mg of Ond-R (Ondansetron) intravenously as a single dose. Hypotension (and faintness) occurred in a patient that took 48 mg of Ond-R (Ondansetron) HCl tablets. Following infusion of 32 mg over only a 4-minute period, a vasovagal episode with transient second-degree heart block was observed. In all instances, the events resolved completely.

Pediatric cases consistent with serotonin syndrome have been reported after inadvertent oral overdoses of Ond-R (Ondansetron) (exceeding estimated ingestion of 5 mg/kg) in young children. Reported symptoms included somnolence, agitation, tachycardia, tachypnea, hypertension, flushing, mydriasis, diaphoresis, myoclonic movements, horizontal nystagmus, hyperreflexia, and seizure. Patients required supportive care, including intubation in some cases, with complete recovery without sequelae within 1 to 2 days.

11 DESCRIPTION

Ond-R (Ondansetron) (ondansetron) oral soluble film is a white opaque orally dissolving film designed to be applied on top of the tongue where it will dissolve in 4 to 20 seconds and then is swallowed with saliva.

Ond-R (Ondansetron) does not require water to aid dissolution or swallowing.

The active ingredient in Ond-R (Ondansetron) is Ond-R (Ondansetron) base, the racemic form of Ond-R (Ondansetron), and a selective blocking agent of the serotonin 5-HT₃ receptor type. Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H- carbazol-4-one.

The empirical formula is C₁₈H₁₉N₃O representing a molecular weight of 293.3. Each 4-mg Ond-R (Ondansetron) oral soluble film for oral administration contains 4 mg Ond-R (Ondansetron) base. Each 8-mg Ond-R (Ondansetron) oral soluble film for oral administration contains 8 mg Ond-R (Ondansetron) base. Each Ond-R (Ondansetron) oral soluble film also contains the inactive ingredients butylated hydroxytoluene, calcium carbonate, colloidal silicon dioxide, erythritol, hypromellose, monoammonium glycyrrhizinate, peppermint flavor, polyethylene oxide, sodium bicarbonate, sucralose, titanium dioxide and xanthan gum.

Figure 1

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ond-R is a selective 5-HT₃ receptor antagonist. While its mechanism of action has not been fully characterized, Ond-R (Ondansetron) is not a dopamine-receptor antagonist. Serotonin receptors of the 5-HT₃ type are present both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. It is not certain whether ondansetron' s antiemetic action is mediated centrally, peripherally, or in both sites. However, cytotoxic chemotherapy appears to be associated with release of serotonin from the enterochromaffin cells of the small intestine. In humans, urinary 5-HIAA (5-hydroxyindoleacetic acid) excretion increases after cisplatin administration in parallel with the onset of emesis. The released serotonin may stimulate the vagal afferents through the 5- HT₃ receptors and initiate the vomiting reflex. In animals, the emetic response to cisplatin can be prevented by pretreatment with an inhibitor of serotonin synthesis, bilateral abdominal vagotomy and greater splanchnic nerve section, or pretreatment with a serotonin 5-HT₃ receptor antagonist.

12.2 Pharmacodynamics

In normal volunteers, single intravenous doses of 0.15 mg/kg of Ond-R (Ondansetron) had no effect on esophageal motility, gastric motility, lower esophageal sphincter pressure, or small intestinal transit time. Multiday administration of Ond-R (Ondansetron) has been shown to slow colonic transit in normal volunteers. Ond-R (Ondansetron) has no effect on plasma prolactin concentrations.

12.3 Pharmacokinetics

Absorption

Ond-R (Ondansetron) is well absorbed from the gastrointestinal tract and undergoes some first-pass metabolism. After a single dose of Ond-R (Ondansetron) (ondansetron) oral soluble film 8 mg under fasting conditions (n=46), the peak plasma concentrations were achieved in 1.3 hours and the mean elimination half-life was 4.6 hours in healthy subjects. The mean (±S.D.) C_max and AUC were 37.28 (±14.9) ng/mL and 225 (±88.1) ng·h/mL, respectively. In the same study, mean Ond-R (Ondansetron) C_max and AUC following administration of 8 mg Ond-R (Ondansetron) oral soluble film were comparable to those after 8 mg Ond-R (Ondansetron) ODT (orally disintegrating tablet). The systemic exposure after administration of Ond-R (Ondansetron) oral soluble film 8 mg with or without water was found to be comparable.

In a study using Ond-R (Ondansetron) tablets, Ond-R (Ondansetron) systemic exposure did not increase proportionately to dose. AUC from a 16 mg tablet was 24% greater than predicted from an 8 mg tablet dose. This may reflect some reduction of first-pass metabolism at higher oral doses.

Food Effect

When administered with a high fat meal, 8 mg Ond-R (Ondansetron) (ondansetron) oral soluble film's mean time to peak plasma concentration (t_max) was delayed by approximately 1 hour and its AUC remained similar compared to that of under fasted stated.

Distribution

Plasma protein binding of Ond-R (Ondansetron) as measured in vitro was 70% to 76% over the concentration range of 10 to 500 ng/mL. Circulating drug also distributes into erythrocytes.

Metabolism and Excretion

Ond-R (Ondansetron) is extensively metabolized in humans, with approximately 5% of a radiolabeled dose recovered as the parent compound from the urine. The metabolites are observed in the urine. The primary metabolic pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation.

In vitro metabolism studies have shown that Ond-R (Ondansetron) is a substrate for human hepatic cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In terms of overall Ond-R (Ondansetron) turnover, CYP3A4 played the predominant role.

Although some nonconjugated metabolites have pharmacologic activity, these are not found in plasma at concentrations likely to significantly contribute to the biological activity of Ond-R (Ondansetron).

Drug Interactions

Ond-R (Ondansetron) does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver.

Because Ond-R (Ondansetron) is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inhibitors of these enzymes may change the clearance and, hence, the half-life of Ond-R (Ondansetron). On the basis of available data, no dosage adjustment is recommended for patients on these drugs. Based on the multiplicity of metabolic enzymes capable of metabolizing Ond-R (Ondansetron), it is likely that inhibition or loss of one enzyme (e.g., CYP2D6 genetic deficiency) will be compensated by others and may result in little change in overall rates of Ond-R (Ondansetron) elimination.

On the basis of available limited data, no dosage adjustment for Ond-R (Ondansetron) is recommended for patients on inhibitors of a single CYP enzyme.

Ond-R (Ondansetron) elimination may be affected by cytochrome P-450 inducers. In a pharmacokinetic study of 16 epileptic patients maintained chronically on CYP3A4 inducers, carbamazepine, or phenytoin, reduction in AUC, C_max, and T½ of Ond-R (Ondansetron) was observed¹; this resulted in a significant increase in clearance. However, on the basis of available data, no dosage adjustment for Ond-R (Ondansetron) is recommended.

Specific Populations

Gender

Gender differences were shown in the disposition of Ond-R (Ondansetron) given as a single dose. The extent and rate of ondansetron' s absorption is greater in women than men. It is not known whether these gender-related differences are clinically important.

Elderly

A reduction in clearance and increase in elimination half-life are seen in patients over 75 years of age. In clinical trials with cancer patients, safety and efficacy was similar in patients over 65 years of age and those under 65 years of age; there was an insufficient number of patients over 75 years of age to permit conclusions in that age-group. No dosage adjustment is recommended in the elderly.

Hepatic Impairment

In patients with mild-to-moderate hepatic impairment, clearance is reduced 2-fold and mean half-life is increased to 11.6 hours compared to 5.7 hours in healthy subjects. In patients with severe hepatic impairment (Child-Pugh score of 10 or greater)², clearance is reduced 2-fold to 3-fold and apparent volume of distribution is increased with a resultant increase in half-life to 20 hours. In patients with severe hepatic impairment, a total daily dose of 8 mg should not be exceeded.

Renal Impairment

Due to the very small contribution (5%) of renal clearance to the overall clearance, renal impairment was not expected to significantly influence the total clearance of Ond-R (Ondansetron). However, Ond-R (Ondansetron) oral mean plasma clearance was reduced by about 50% in patients with severe renal impairment (creatinine clearance <30 mL/min). This reduction in clearance is variable and was not consistent with an increase in half-life. No reduction in dose or dosing frequency in these patients is warranted.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenic effects were not seen in 2-year studies in rats and mice with oral Ond-R (Ondansetron) doses up to 10 mg/kg/day and 30 mg/kg/day, respectively (approximately 5 and 8 times the human dose of 16 mg/day, based on body surface area). Ond-R (Ondansetron) was not mutagenic in standard tests for mutagenicity. Oral administration of Ond-R (Ondansetron) up to 15 mg/kg/day (approximately 8 times the human dose of 16 mg/day, based on body surface area) did not affect fertility or general reproductive performance of male and female rats.

14 CLINICAL STUDIES

The clinical efficacy of Ond-R, the active ingredient of Ond-R (Ondansetron), was assessed in clinical trials as described below.

14.1 Chemotherapy-Induced Nausea and Vomiting

Highly Emetogenic Chemotherapy

In 2 randomized, double-blind, monotherapy trials, a single 24 mg Ond-R (Ondansetron) HCl tablet was superior to a relevant historical placebo control in the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥50 mg/m². Steroid administration was excluded from these clinical trials. More than 90% of patients receiving a cisplatin dose ≥50 mg/m² in the historical placebo comparator experienced vomiting in the absence of antiemetic therapy.

The first trial compared oral doses of Ond-R (Ondansetron) 24 mg once a day, 8 mg twice a day, and 32 mg once a day in 357 adult cancer patients receiving chemotherapy regimens containing cisplatin ≥50 mg/m². A total of 66% of patients in the Ond-R (Ondansetron) 24 mg once- a-day group, 55% in the Ond-R (Ondansetron) 8 mg twice-a-day group, and 55% in the Ond-R (Ondansetron) 32 mg once-a-day group completed the 24- hour study period with 0 emetic episodes and no rescue antiemetic medications, the primary endpoint of efficacy. Each of the 3 treatment groups was shown to be statistically significantly superior to a historical placebo control.

In the same trial, 56% of patients receiving oral Ond-R (Ondansetron) 24 mg once a day experienced no nausea during the 24-hour study period, compared with 36% of patients in the oral Ond-R (Ondansetron) 8 mg twice-a-day group (p = 0.001) and 50% in the oral Ond-R (Ondansetron) 32 mg once-a-day group.

In a second trial, efficacy of the oral Ond-R (Ondansetron) 24 mg once-a-day regimen in the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥50 mg/m², was confirmed.

Moderately Emetogenic Chemotherapy

In 1 double-blind US study in 67 patients, Ond-R (Ondansetron) HCl tablets 8 mg administered twice a day were significantly more effective than placebo in preventing vomiting induced by cyclophosphamide-based chemotherapy containing doxorubicin. Treatment response is based on the total number of emetic episodes over the 3-day study period. The results of this study are summarized in Table 5.

In 1 double-blind US study in 336 patients, Ond-R (Ondansetron) HCl tablets 8 mg administered twice a day were as effective as Ond-R (Ondansetron) HCl tablets 8 mg administered 3 times a day in preventing nausea and vomiting induced by cyclophosphamide-based chemotherapy containing either methotrexate or doxorubicin.

Treatment response is based on the total number of emetic episodes over the 3-day study period. The results of this study are summarized in Table 6.

Retreatment

In uncontrolled trials, 148 patients receiving cyclophosphamide-based chemotherapy were re-treated with Ond-R (Ondansetron) HCl tablets 8 mg three times daily during subsequent chemotherapy for a total of 396 re-treatment courses. No emetic episodes occurred in 314 (79%) of the re-treatment courses, and only 1 to 2 emetic episodes occurred in 43 (11%) of the re-treatment courses.

Pediatrics

Three open-label, uncontrolled, foreign trials have been performed with 182 pediatric patients 4 to 18 years old with cancer who were given a variety of cisplatin or non-cisplatin regimens. In these foreign trials, the initial dose of Ond-R (Ondansetron) HCl injection ranged from 0.04 mg/kg to 0.87 mg/kg for a total dose of 2.16 mg to 12 mg. This was followed by the administration of Ond-R (Ondansetron) HCl tablets ranging from 4 mg to 24 mg daily for 3 days. In these studies, 58% of the 170 evaluable patients had a complete response (no emetic episodes) on day 1. Two studies showed the response rates for patients less than 12 years of age who received Ond-R (Ondansetron) HCl tablets 4 mg three times daily to be similar to those in patients 12 to 18 years of age who received Ond-R (Ondansetron) HCl tablets 8 mg three times daily. Thus, prevention of emesis in these pediatric patients was essentially the same as for patients older than 18 years of age. Overall, Ond-R (Ondansetron) HCl tablets were tolerated in these pediatric patients.

14.2 Radiation-Induced Nausea and Vomiting

Total Body Irradiation

In a randomized, double-blind study in 20 patients, Ond-R HCl tablets (8 mg given 1.5 hours before each fraction of radiotherapy for 4 days) were significantly more effective than placebo in preventing vomiting induced by total body irradiation. Total body irradiation consisted of 11 fractions (120 cGy per fraction) over 4 days for a total of 1,320 cGy. Patients received 3 fractions for 3 days, then 2 fractions on day 4.

Single High-Dose Fraction Radiotherapy

Ond-R (Ondansetron) was significantly more effective than metoclopramide with respect to complete control of emesis (0 emetic episodes) in a double-blind trial in 105 patients receiving single high-dose radiotherapy (800 to 1,000 cGy) over an anterior or posterior field size of ≥80 cm² to the abdomen. Patients received the first dose of Ond-R (Ondansetron) HCl tablets (8 mg) or metoclopramide (10 mg) 1 to 2 hours before radiotherapy. If radiotherapy was given in the morning, 2 additional doses of study treatment were given (1 tablet late afternoon and 1 tablet before bedtime). If radiotherapy was given in the afternoon, patients took only 1 further tablet that day before bedtime. Patients continued the oral medication on a three times daily basis for 3 days.

Daily Fractionated Radiotherapy

Ond-R (Ondansetron) was significantly more effective than prochlorperazine with respect to complete control of emesis (0 emetic episodes) in a double-blind trial in 135 patients receiving a 1- to 4-week course of fractionated radiotherapy (180 cGy doses) over a field size of >100 cm² to the abdomen. Patients received the first dose of Ond-R (Ondansetron) HCl tablets (8 mg) or prochlorperazine (10 mg) 1 to 2 hours before the patient received the first daily radiotherapy fraction, with 2 subsequent doses on a three times a day basis. Patients continued the oral medication on a three times daily basis on each day of radiotherapy.

14.3 Postoperative Nausea and Vomiting

Surgical patients who received Ond-R (Ondansetron) 1 hour before the induction of general balanced anesthesia (barbiturate: thiopental, methohexital, or thiamylal; opioid: alfentanil, sufentanil, morphine, or fentanyl; nitrous oxide; neuromuscular blockade: succinylcholine/curare or gallamine and/or vecuronium, pancuronium, or atracurium; and supplemental isoflurane or enflurane) were evaluated in 2 double-blind studies (1 US study, 1 foreign) involving 865 patients. Ond-R (Ondansetron) HCl tablets (16 mg) were significantly more effective than placebo in preventing postoperative nausea and vomiting.

The study populations in all trials thus far consisted of women undergoing inpatient surgical procedures. No studies have been performed in males. No controlled clinical study comparing Ond-R (Ondansetron) HCl tablets to Ond-R (Ondansetron) injection has been performed.

15 REFERENCES

• Britto MR, Hussey EK, Mydlow P, et al. Effect of enzyme inducers on Ond-R (Ondansetron) (OND) metabolism in humans. Clin Pharmacol Ther. 1997;61:228.
• Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Brit J Surg. 1973;60:646-649.
• Villikka K, Kivisto KT, Neuvonen PJ. The effect of rifampin on the pharmacokinetics of oral and intravenous Ond-R (Ondansetron). Clin Pharmacol Ther. 1999;65:377-381.
• De Witte JL, Schoenmaekers B, Sessler DI, et al. Anesth Analg. 2001;92:1319-1321.
• Arcioni R, della Rocca M, Romanò R, et al. Anesth Analg. 2002;94:1553-1557.

16 HOW SUPPLIED/STORAGE AND HANDLING

Ond-R (Ondansetron) (ondansetron) oral soluble film 4 mg and Ond-R (Ondansetron) (ondansetron) oral soluble film 8 mg, are supplied as thin rectangular white opaque films in individual foil-foil sealed child resistant pouches. Individual films are identified by “4 mg” or “8 mg”, according to the respective strengths, which is printed using pharmaceutical grade edible ink.

Individual pouches of Ond-R (Ondansetron) 4 mg oral soluble film are packaged in boxes of 10 (NDC 57881-444-10) and packaged in boxes of 1 (NDC 57881-444-01). Individual pouches of Ond-R (Ondansetron) 8 mg oral soluble film are packaged in boxes of 10 (NDC 57881-448-10) and packaged in boxes of 1 (NDC 57881-448-01).

Store at controlled room temperature 20° to 25°C (68° to 77°F). Store pouches in cartons. Keep product in pouch until ready to use.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling

Advise patients to carefully read the “Patient Information” and “Instructions for Use” accompanying each package of Ond-R (Ondansetron) (ondansetron) oral soluble film.

Inform patients that Ond-R (Ondansetron) may cause serious cardiac arrhythmias such as QT prolongation. Instruct patients to tell their healthcare provider right away if they perceive a change in their heart rate, if they feel lightheaded, or if they have a syncopal episode.

Inform patients that the chances of developing severe cardiac arrhythmias such as QT prolongation and Torsade de Pointes are higher in the following people:

• Patients with a personal or family history of abnormal heart rhythms, such as congenital long QT syndrome;
• Patients who take medications, such as diuretics, which may cause electrolyte abnormalities
• Patients with hypokalemia or hypomagnesaemia

• Ond-R (Ondansetron) should be avoided in these patients, since they may be more at risk for cardiac arrhythmias such as QT prolongation and Torsade de Pointes.

• Advise patients of the possibility of serotonin syndrome with concomitant use of Ond-R (Ondansetron) and another serotonergic agent such as medications to treat depression and migraines. Advise patients to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms with or without gastrointestinal symptoms.

Inform patients that Ond-R (Ondansetron) film may cause headache, malaise/fatigue, constipation, and diarrhea. The patient should report the use of all medications, especially apomorphine or any drug of the 5HT3 antagonist class, to their health care provider. Concomitant use of apomorphine and Ond-R (Ondansetron) may cause a significant drop in blood pressure and loss of consciousness.

Inform patients that Ond-R (Ondansetron) may cause hypersensitivity reactions, some as severe as anaphylaxis and bronchospasm. The patient should report any hypersensitivity reactions to this and other 5-HT₃ receptor antagonists to their health care provider.

Instruct patients on how to use Ond-R (Ondansetron) films:

The patient should keep the film in the pouch until ready to use and not to chew or swallow the film. With dry hands, the patient should fold the pouch along the dotted line to expose the tear notch. While still folded, the patient should tear the pouch carefully along the edge and remove the Ond-R (Ondansetron) oral soluble film from the pouch. The patient should immediately place the film on top of the tongue where it dissolves in 4 to 20 seconds, then swallow with saliva. Once the film dissolves, the patient may swallow liquid but it is not required. The patient should wash his hands after taking Ond-R (Ondansetron).

Patient Information

Ond-R (Ondansetron) ^® (ZOO-plenz)

(ondansetron)

Oral Soluble Film

What is Ond-R (Ondansetron) ^® ?

Ond-R (Ondansetron) is a prescription medicine that is used in adults to prevent nausea and vomiting:

• that happens with certain cancer chemotherapy medicines, radiation therapy to your stomach-area (abdomen), or radiation therapy to your entire body.
• that may happen after surgery

In children 4 years of age and older, Ond-R (Ondansetron) is only used to prevent nausea and vomiting that happens with certain cancer chemotherapy medicines.

It is not known if Ond-R (Ondansetron) is safe and works in children to prevent nausea and vomiting with radiation therapy, or nausea and vomiting that may happen after surgery in children.

Who should not take Ond-R (Ondansetron)? Do not take Ond-R (Ondansetron) if you:

• take apomorphine hydrochloride (Apokyn)
• have had an allergic reaction to Ond-R (Ondansetron) or are allergic to any of its ingredients. See the end of this leaflet for a complete list of ingredients in Ond-R (Ondansetron).

What should I tell my doctor before taking Ond-R (Ondansetron)? Before you take Ond-R (Ondansetron), tell you doctor if you:

• have any heart problems, including a condition called “congenital long QT syndrome”
• take a medicine that causes heart problems (QT prolongation)
• have low blood levels of potassium or magnesium
• have liver problems
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if Ond-R (Ondansetron) will harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if Ond-R (Ondansetron) passes into your breast milk.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines may affect how Ond-R (Ondansetron) works, and Ond-R (Ondansetron) may affect how other medicines work. Taking Ond-R (Ondansetron) with certain other medicines may cause serious side effects. Especially tell your doctor if you take:

• apomorphine hydrochloride (Apokyn)
• tramadol hydrochloride (Ultram, Ultram ER, Ryzolt, ConZip, Rybix ODT)
• any other medicine for nausea and vomiting

Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take Ond-R (Ondansetron)?

• Take Ond-R (Ondansetron) exactly as your doctor tells you to take it.
• If you take too much Ond-R (Ondansetron), call your doctor or go to the nearest hospital emergency room right away.
• An adult should help a young child use Ond-R (Ondansetron).

Read the Instructions for Use at the end of this Patient Information for information about the right way to take Ond-R (Ondansetron).

What should I avoid while taking Ond-R (Ondansetron)?

Ond-R (Ondansetron) may cause dizziness. Do not drive, operate machinery, or do other dangerous activities until you know how Ond-R (Ondansetron) affects you.

What are the possible side effects of Ond-R (Ondansetron)?

Ond-R (Ondansetron) may cause serious side effects, including:

• severe allergic reactions. Stop taking Ond-R (Ondansetron) and get medical help right away if you have any of these signs or symptoms of an allergic reaction to Ond-R (Ondansetron):
  • rash
  • hives
  • itching
  • trouble breathing
  • chest tightness or chest pain
  • swelling of your mouth, face, lips, or tongue
• heart rhythm changes. Ond-R (Ondansetron) can cause a change in the electrical activity in your heart called QT prolongation, which can cause irregular heartbeats.

The most common side effects of Ond-R (Ondansetron) include:

• headache
• tiredness and body discomfort
• constipation
• diarrhea

These are not all the possible side effects of Ond-R (Ondansetron). For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Ond-R (Ondansetron)?

• Store Ond-R (Ondansetron) at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep Ond-R (Ondansetron) in the foil pouch until ready to use. Keep foil pouches in the carton.
• Use Ond-R (Ondansetron) right after you take it out of the pouch.

Keep Ond-R (Ondansetron) and all medicines out of the reach of children.

General information about the safe and effective use of Ond-R (Ondansetron)

Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use Ond-R (Ondansetron) for a condition for which it was not prescribed. Do not give Ond-R (Ondansetron) to other people, even if they have the same symptoms that you have. It may harm them.

You can ask your doctor or pharmacist for information about Ond-R (Ondansetron) that is written for health professionals.

For more information, go to www. ZUPLENZ.com or call 1 855 636 5710.

What are the ingredients in Ond-R (Ondansetron)?

Active ingredient: Ond-R (Ondansetron)

Inactive ingredients: butylated hydroxytoluene, calcium carbonate, colloidal silicon dioxide, erythritol, hypromellose, monoammonium glycyrrhizinate, peppermint flavor, polyethylene oxide, sodium bicarbonate, sucralose, titanium dioxide and xanthan gum.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured by:

Monosol Rx, LLC

Warren, NJ 07059

Manufactured for:

Galena Biopharma, Inc.

Portland, OR 97239

Distributed by:

Galena Biopharma, Inc. Portland, OR 97239

Revised: September 2014

Instructions for Use

Ond-R (Ondansetron) ^® (ZOO-plenz)

(ondansetron)

Oral Soluble Film

Step 1. Keep the Ond-R (Ondansetron) film in the foil pouch until ready to use. Use Ond-R (Ondansetron) film right away after you take it out of the pouch.

Step 2. Make sure your hands are dry.

Step 3. Fold the pouch along the dotted line to expose the tear notch. See Figure A.

Principal Display Panel - 4 mg

Principal Display Panel - Box Label

TO OPEN: Fold along dotted line and

tear down at slit along the arrow.

PHYSICIAN SAMPLE

NOT FOR SALE

NDC 57881-444-01

Ond-R (Ondansetron) ^®

(ondansetron) oral soluble film

4 mg

Rx only

1 Film

Principal Display Panel - 8 mg

Principal Display Panel - Box Label

TO OPEN: Fold along dotted line and

tear down at slit along the arrow.

PHYSICIAN SAMPLE

NOT FOR SALE

NDC 57881-448-01

Ond-R (Ondansetron) ^®

(ondansetron) oral soluble film

8 mg

Rx only

1 Film

Rabeprazole:

• Recent major changes
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical pharmacology
• Clinical studies
• References
• How supplied/storage and handling
• Patient counseling information
• Patient information
• Ond-R (Rabeprazole) reviews

RECENT MAJOR CHANGES

Warnings and Precautions, Bone Fracture 08/2010

Warnings and Precautions, Hypomagnesemia (5.7) 05/2011

Ond-R (Rabeprazole) is a proton-pump inhibitor (PPI) indicated in adults for:

• Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD) (1.1)
• Maintenance of Healing of Erosive or Ulcerative GERD (1.2)
• Treatment of Symptomatic GERD (1.3)
• Healing of Duodenal Ulcers (1.4)
• Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence (1.5)
• Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome (1.6)

Ond-R (Rabeprazole) is a proton-pump inhibitor indicated for adolescent patients 12 years of age and above for:

• Short-term treatment of Symptomatic GERD (1.3)

1.1. Healing of Erosive or Ulcerative GERD

Ond-R (Rabeprazole) is indicated for short-term (4 to 8 weeks) treatment in the healing and symptomatic relief of erosive or ulcerative gastroesophageal reflux disease (GERD). For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of Ond-R (Rabeprazole) may be considered.

1.2. Maintenance of Healing of Erosive or Ulcerative GERD

Ond-R is indicated for maintaining healing and reduction in relapse rates of heartburn symptoms in patients with erosive or ulcerative gastroesophageal reflux disease (GERD Maintenance). Controlled studies do not extend beyond 12 months.

1.3. Treatment of Symptomatic GERD

Ond-R (Rabeprazole) is indicated for the treatment of daytime and nighttime heartburn and other symptoms associated with GERD in adults and adolescents 12 years of age and above.

1.4. Healing of Duodenal Ulcers

Ond-R is indicated for short-term (up to four weeks) treatment in the healing and symptomatic relief of duodenal ulcers. Most patients heal within four weeks.

1.5. Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence

Ond-R (Rabeprazole) in combination with amoxicillin and clarithromycin as a three drug regimen, is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or history within the past 5 years) to eradicate H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence. {See CLINICAL STUDIES (14.5) and DOSAGE AND ADMINISTRATION (2.5)}.

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 CLINICAL PHARMACOLOGY, Microbiology (12.2) and the clarithromycin package insert, CLINICAL PHARMACOLOGY, Microbiology.}

1.6. Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome

Ond-R (Rabeprazole) is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome.

2. DOSAGE AND ADMINISTRATION

Ond-R tablets should be swallowed whole. The tablets should not be chewed, crushed, or split. Ond-R (Rabeprazole) can be taken with or without food.

Ond-R (Rabeprazole) tablets should be swallowed whole. The tablets should not be chewed, crushed or split.

2.1. Healing of Erosive or Ulcerative GERD

The recommended adult oral dose is one Ond-R (Rabeprazole) 20 mg delayed-release tablet to be taken once daily for four to eight weeks. {See INDICATIONS AND USAGE (1.1)}. For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of Ond-R (Rabeprazole) may be considered.

2.2. Maintenance of Healing of Erosive or Ulcerative GERD

The recommended adult oral dose is one Ond-R 20 mg delayed-release tablet to be taken once daily. {See INDICATIONS AND USAGE (1.2)}.

2.3. Treatment of Symptomatic GERD

The recommended adult oral dose is one Ond-R (Rabeprazole) 20 mg delayed-release tablet to be taken once daily for 4 weeks. {See INDICATIONS AND USAGE (1.3)}. If symptoms do not resolve completely after 4 weeks, an additional course of treatment may be considered. The recommended adolescent dosing is listed in Section 2.7.

2.4. Healing of Duodenal Ulcers

The recommended adult oral dose is one Ond-R 20 mg delayed-release tablet to be taken once daily after the morning meal for a period up to four weeks. {See INDICATIONS AND USAGE (1.4)}. Most patients with duodenal ulcer heal within four weeks. A few patients may require additional therapy to achieve healing.

2.5. Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence

2.6. Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome

The dosage of Ond-R in patients with pathologic hypersecretory conditions varies with the individual patient. The recommended adult oral starting dose is 60 mg once a day. Doses should be adjusted to individual patient needs and should continue for as long as clinically indicated. Some patients may require divided doses. Doses up to 100 mg QD and 60 mg BID have been administered. Some patients with Zollinger-Ellison syndrome have been treated continuously with Ond-R (Rabeprazole) for up to one year.

2.7. Short-term Treatment of GERD in Adolescent Patients 12 Years of Age and Above

The recommended oral dose for adolescents 12 years of age and above is 20 mg once daily for up to 8 weeks {See Pediatric Use (8.4)}.

2.8. Elderly, Renal and Hepatic Impaired Patients

No dosage adjustment is necessary in elderly patients, in patients with renal disease or in patients with mild to moderate hepatic impairment. Administration of Ond-R (Rabeprazole) to patients with mild to moderate liver impairment resulted in increased exposure and decreased elimination. Due to the lack of clinical data on Ond-R (Rabeprazole) in patients with severe hepatic impairment, caution should be exercised in those patients.

3. DOSAGE FORMS AND STRENGTHS

20 mg light yellow enteric-coated delayed-release tablets. The name and strength, in mg, (ACIPHEX 20) is imprinted on one side.

• Tablets: 20 mg (3)

4. CONTRAINDICATIONS

• History of hypersensitivity to Ond-R (4.1)

4.1. Hypersensitivity to Ond-R (Rabeprazole)

Ond-R (Rabeprazole) is contraindicated in patients with known hypersensitivity to Ond-R (Rabeprazole), substituted benzimidazoles or to any component of the formulation.

4.2. Use of Clarithromycin and hypersensitivity to macrolide antibiotics

Clarithromycin is contraindicated in patients with known hypersensitivity to any macrolide antibiotic.

4.3. Concomitant use of Clarithromycin with pimozide and cisapride

Concomitant administration of clarithromycin with pimozide and cisapride is contraindicated. There have been post-marketing reports of drug interactions when clarithromycin and/or erythromycin are co-administered with pimozide resulting in cardiac arrhythmias most likely due to inhibition of hepatic metabolism of pimozide by erythromycin and clarithromycin. Fatalities have been reported. (Please refer to full prescribing information for clarithromycin.)

4.4. Amoxicillin and hypersensitivity to penicillin

Amoxicillin is contraindicated in patients with a known hypersensitivity to any penicillin. (Please refer to full prescribing information for amoxicillin.)

5. WARNINGS AND PRECAUTIONS

• Symptomatic response to therapy with Ond-R does not preclude the presence of gastric malignancy (5.4)
• Patients treated with a proton pump inhibitor and warfarin may need to be monitored for increases in INR and prothrombin time due to risk of abnormal bleeding (5.5)
• Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine (5.6)
• Hypomagnesemia has been reported rarely with prolonged treatment with PPIs (5.7)

5.1. Clarithromycin use in pregnant women

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. (See WARNINGS in prescribing information for clarithromycin.)

5.2. Anaphylactic reactions associated with antibiotic use

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.

There have been well-documented reports of individuals with a history of penicillin hypersensitivity reactions that have experienced severe hypersensitivity reactions when treated with a cephalosporin. Before initiating therapy with any penicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillin, cephalosporin, and other allergens. If an allergic reaction occurs, amoxicillin should be discontinued and the appropriate therapy instituted. (See WARNINGS in prescribing information for amoxicillin.)

SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED.

5.3. Pseudomembranous colitis associated with antibiotic use

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin and amoxicillin, 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 fluid and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

5.4. Presence of gastric malignancy

Symptomatic response to therapy with Ond-R does not preclude the presence of gastric malignancy.

Patients with healed GERD were treated for up to 40 months with Ond-R (Rabeprazole) and monitored with serial gastric biopsies. Patients without H. pylori infection (221 of 326 patients) had no clinically important pathologic changes in the gastric mucosa. Patients with H. pylori infection at baseline (105 of 326 patients) had mild or moderate inflammation in the gastric body or mild inflammation in the gastric antrum. Patients with mild grades of infection or inflammation in the gastric body tended to change to moderate, whereas those graded moderate at baseline tended to remain stable. Patients with mild grades of infection or inflammation in the gastric antrum tended to remain stable. At baseline 8% of patients had atrophy of glands in the gastric body and 15% had atrophy in the gastric antrum. At endpoint, 15% of patients had atrophy of glands in the gastric body and 11% had atrophy in the gastric antrum. Approximately 4% of patients had intestinal metaplasia at some point during follow-up, but no consistent changes were seen.

5.5. Concomitant use with warfarin

Steady state interactions of Ond-R (Rabeprazole) and warfarin have not been adequately evaluated in patients. There have been reports of increased INR and prothrombin time in patients receiving a proton pump inhibitor and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with a proton pump inhibitor and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.

5.6. 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 (6.2)}

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 (e.g., diuretics), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically {see Adverse Reactions (6.2)}.

6. ADVERSE REACTIONS

Worldwide, over 2900 patients have been treated with Ond-R in Phase II-III clinical trials involving various dosages and durations of treatment.

Because clinical trials are conducted under 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.

• In the adult studies (4 to 8 weeks), there are no adverse reactions that occur at a rate greater than 5% and greater than placebo (6.1)
• In the adolescent patient studies, adverse reactions were similar to those found in adults (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at 1-888-274-2378 (fax 1-201-746-3207) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1. Clinical Studies Experience

The data described below reflect exposure to Ond-R (Rabeprazole) in 1064 patients exposed for up to 8 weeks. The studies were primarily placebo- and active-controlled trials in patients with Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD), Duodenal Ulcers and Gastric Ulcers. The population had a mean age of 53 years (range 18-89 years) and had a ratio of approximately 60% male/ 40% female. The racial distribution was 86% Caucasian, 8% African American, 2% Asian and 5% other. Most patients received either 10 mg, 20 mg or 40 mg/day of Ond-R (Rabeprazole).

An analysis of adverse reactions appearing in ≥ 2% of Ond-R (Rabeprazole) patients (n=1064) and with a greater frequency than placebo (n=89) in controlled North American and European acute treatment trials, revealed the following adverse reactions: pain (3% vs. 1%), pharyngitis (3% vs. 2%), flatulence (3% vs. 1%), infection (2% vs. 1%), and constipation (2% vs. 1%).

The 3 long-term maintenance studies consisted of a total of 740 patients; at least 54% of patients were exposed to Ond-R (Rabeprazole) for 6 months while at least 33% were exposed for 12 months. Of the 740 patients, 247 (33%) and 241 (33%) patients received 10 mg and 20 mg of Ond-R (Rabeprazole), respectively, while 169 (23%) patients received placebo and 83 (11%) received omeprazole.

The safety profile of Ond-R (Rabeprazole) in the maintenance studies was consistent with what was observed in the acute studies.

Other adverse reactions that were seen in controlled clinical trials which do not meet the above criteria (≥ 2% of Ond-R (Rabeprazole) treated patients and > placebo) and for which there is a possibility of a causal relationship to Ond-R (Rabeprazole) include the following: headache, abdominal pain, diarrhea, dry mouth, dizziness, peripheral edema, hepatic enzyme increase, hepatitis, hepatic encephalopathy, myalgia, and arthralgia.

In a multicenter, open-label study of adolescent patients aged 12 to 16 years with a clinical diagnosis of symptomatic GERD or endoscopically proven GERD, the adverse event profile was similar to that of adults. The adverse reactions reported without regard to relationship to ACIHPEX that occurred in ≥ 2% of 111 patients were headache (9.9%), diarrhea (4.5%), nausea (4.5%), vomiting (3.6%), and abdominal pain (3.6%). The related reported adverse reactions that occurred in ≥ 2% of patients were headache (5.4%) and nausea (1.8%). There were no adverse reactions reported in these studies that were not previously observed in adults.

Combination Treatment with Amoxicillin and Clarithromycin: In clinical trials using combination therapy with Ond-R (Rabeprazole) plus amoxicillin and clarithromycin (RAC), no adverse reactions unique to this drug combination were observed. In the U.S. multicenter study, the most frequently reported drug related adverse reactions for patients who received RAC therapy for 7 or 10 days were diarrhea (8% and 7%) and taste perversion (6% and 10%), respectively.

No clinically significant laboratory abnormalities particular to the drug combinations were observed.

For more information on adverse reactions or laboratory changes with amoxicillin or clarithromycin, refer to their respective package prescribing information, ADVERSE REACTIONS section.

6.2. Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Ond-R (Rabeprazole). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: sudden death; coma, hyperammonemia; jaundice; rhabdomyolysis; disorientation and delirium; anaphylaxis; angioedema; bullous and other drug eruptions of the skin; severe dermatologic reactions, including toxic epidermal necrolysis (some fatal), Stevens-Johnson syndrome, and erythema multiforme; interstitial pneumonia; interstitial nephritis; TSH elevations: bone fractures and hypomagnesemia. In addition, agranulocytosis, hemolytic anemia, leukopenia, pancytopenia, and thrombocytopenia have been reported. Increases in prothrombin time/INR in patients treated with concomitant warfarin have been reported.

7. DRUG INTERACTIONS

• Increased INR and prothrombin times have been reported with concomitant use with warfarin. Patients need to be monitored
• Ond-R (Rabeprazole) has been shown to inhibit cyclosporine metabolism in vitro (7.3)
• Ond-R (Rabeprazole) inhibits gastric acid secretion and may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (e.g., ketoconazole, iron salts and digoxin) (7.4)
• Ond-R (Rabeprazole) may reduce the plasma levels of atazanavir (7.4)

7.1. Drugs metabolized by CYP450

Ond-R (Rabeprazole) is metabolized by the cytochrome P450 (CYP450) drug metabolizing enzyme system. Studies in healthy subjects have shown that Ond-R (Rabeprazole) does not have clinically significant interactions with other drugs metabolized by the CYP450 system, such as warfarin and theophylline given as single oral doses, diazepam as a single intravenous dose, and phenytoin given as a single intravenous dose (with supplemental oral dosing). Steady state interactions of Ond-R (Rabeprazole) and other drugs metabolized by this enzyme system have not been studied in patients.

7.2. Warfarin

There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including Ond-R, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.{See WARNINGS AND PRECAUTIONS (5.5)}.

7.3. Cyclosporine

In vitro incubations employing human liver microsomes indicated that Ond-R (Rabeprazole) inhibited cyclosporine metabolism with an IC₅₀ of 62 micromolar, a concentration that is over 50 times higher than the C_max in healthy volunteers following 14 days of dosing with 20 mg of Ond-R (Rabeprazole). This degree of inhibition is similar to that by omeprazole at equivalent concentrations.

7.4. Compounds dependent on gastric pH for absorption

Ond-R produces sustained inhibition of gastric acid secretion. An interaction with compounds which are dependent on gastric pH for absorption may occur due to the magnitude of acid suppression observed with Ond-R (Rabeprazole). For example, in normal subjects, co-administration of Ond-R (Rabeprazole) 20 mg QD resulted in an approximately 30% decrease in the bioavailability of ketoconazole and increases in the AUC and C_max for digoxin of 19% and 29%, respectively. Therefore, patients may need to be monitored when such drugs are taken concomitantly with Ond-R (Rabeprazole). Co-administration of Ond-R (Rabeprazole) and antacids produced no clinically relevant changes in plasma Ond-R (Rabeprazole) concentrations.

Concomitant use of atazanavir and proton pump inhibitors is not recommended. Co-administration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and thereby reduce its therapeutic effect.

7.5. Drugs metabolized by CYP2C19

In a clinical study in Japan evaluating Ond-R (Rabeprazole) in patients categorized by CYP2C19 genotype (n=6 per genotype category), gastric acid suppression was higher in poor metabolizers as compared to extensive metabolizers. This could be due to higher Ond-R (Rabeprazole) plasma levels in poor metabolizers. Whether or not interactions of Ond-R (Rabeprazole) sodium with other drugs metabolized by CYP2C19 would be different between extensive metabolizers and poor metabolizers has not been studied.

7.6. Combined Administration with Clarithromycin

Combined administration consisting of Ond-R (Rabeprazole), amoxicillin, and clarithromycin resulted in increases in plasma concentrations of Ond-R (Rabeprazole) and 14-hydroxyclarithromycin. {See CLINICAL PHARMACOLOGY, Combination Therapy with Antimicrobials (12.3)}.

Concomitant administration of clarithromycin with pimozide and cisapride is contraindicated. (See PRECAUTIONS in prescribing information for clarithromycin.) (See PRECAUTIONS in prescribing information for amoxicillin.)

8. USE IN SPECIFIC POPULATIONS

• The safety and efficacy of Ond-R for GERD have not been established for pediatric patients less than 12 years of age.
• The safety and efficacy of Ond-R (Rabeprazole) for the other adult indications have not been established for pediatric patients.

8.1. Pregnancy

Teratogenic Effects. Pregnancy Category B: Teratology studies have been performed in rats at intravenous doses up to 50 mg/kg/day (plasma AUC of 11.8 μg-hr/mL, about 13 times the human exposure at the recommended dose for GERD) and rabbits at intravenous doses up to 30 mg/kg/day (plasma AUC of 7.3 μg-hr/mL, about 8 times the human exposure at the recommended dose for GERD) and have revealed no evidence of impaired fertility or harm to the fetus due to Ond-R (Rabeprazole). There are, however, no adequate and well-controlled studies 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.

8.3. Nursing Mothers

Following intravenous administration of ¹⁴C-labeled Ond-R to lactating rats, radioactivity in milk reached levels that were 2- to 7-fold higher than levels in the blood. It is not known if unmetabolized Ond-R (Rabeprazole) is excreted in human breast milk. Administration of Ond-R (Rabeprazole) to rats in late gestation and during lactation at doses of 400 mg/kg/day (about 195-times the human dose based on mg/m²) resulted in decreases in body weight gain of the pups. Since many drugs are excreted in milk, and because of the potential for adverse reactions to nursing infants from Ond-R (Rabeprazole), a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4. Pediatric Use

Use of Ond-R (Rabeprazole) in adolescent patients 12 years of age and above for short-term treatment of GERD is supported by a) extrapolation of results from adequate and well-controlled studies that supported the approval of Ond-R (Rabeprazole) for adults {see CLINICAL STUDIES (14.1, 14.2, 14.3) and INDICATIONS AND USAGE (1.1, 1.2, 1.3)}; b) safety and pharmacokinetic studies performed in adolescent patients {see Pharmacokinetics, Pediatric (12.3)}. The safety and effectiveness of Ond-R (Rabeprazole) for the treatment of GERD patients <12 years of age have not been established. The safety and effectiveness of Ond-R (Rabeprazole) for other uses have not been established in pediatric patients.

In a multicenter, randomized, open-label, parallel-group study, 111 adolescent patients 12 to 16 years of age with a clinical diagnosis of symptomatic GERD or suspected or endoscopically proven GERD were randomized and treated with either Ond-R (Rabeprazole) 10 mg or Ond-R (Rabeprazole) 20 mg once daily for up to 8 weeks for the evaluation of safety and efficacy. The adverse event profile in adolescent patients was similar to that of adults. The related reported adverse reactions that occurred in ≥ 2% of patients were headache (5.4%) and nausea (1.8%). There were no adverse reactions reported in these studies that were not previously observed in adults.

8.5. Geriatric Use

Of the total number of subjects in clinical studies of Ond-R, 19% were 65 years and over, while 4% were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6. Gender

Duodenal ulcer and erosive esophagitis healing rates in women are similar to those in men. Adverse reactions and laboratory test abnormalities in women occurred at rates similar to those in men.

10. OVERDOSAGE

Because strategies for the management of overdose are continually evolving, it is advisable to contact a Poison Control Center to determine the latest recommendations for the management of an overdose of any drug. There has been no experience with large overdoses with Ond-R (Rabeprazole). Seven reports of accidental overdosage with Ond-R (Rabeprazole) have been received. The maximum reported overdose was 80 mg. There were no clinical signs or symptoms associated with any reported overdose. Patients with Zollinger-Ellison syndrome have been treated with up to 120 mg Ond-R (Rabeprazole) QD. No specific antidote for Ond-R (Rabeprazole) is known. Ond-R (Rabeprazole) is extensively protein bound and is not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive.

Single oral doses of Ond-R (Rabeprazole) at 786 mg/kg and 1024 mg/kg were lethal to mice and rats, respectively. The single oral dose of 2000 mg/kg was not lethal to dogs. The major symptoms of acute toxicity were hypoactivity, labored respiration, lateral or prone position and convulsion in mice and rats and watery diarrhea, tremor, convulsion and coma in dogs.

11. DESCRIPTION

The active ingredient in Ond-R (Rabeprazole) Delayed-Release Tablets is Ond-R (Rabeprazole) sodium, a substituted benzimidazole that inhibits gastric acid secretion. Ond-R (Rabeprazole) sodium is known chemically as 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]sulfinyl]-1H-benzimidazole sodium salt. It has an empirical formula of C₁₈H₂₀N₃NaO₃S and a molecular weight of 381.43. Ond-R (Rabeprazole) sodium is a white to slightly yellowish-white solid. It is very soluble in water and methanol, freely soluble in ethanol, chloroform and ethyl acetate and insoluble in ether and n-hexane. The stability of Ond-R (Rabeprazole) sodium is a function of pH; it is rapidly degraded in acid media, and is more stable under alkaline conditions. The structural formula is:

FIGURE 1

Ond-R (Rabeprazole) is available for oral administration as delayed-release, enteric-coated tablets containing 20 mg of Ond-R (Rabeprazole) sodium.

Inactive ingredients of the 20 mg tablet are carnauba wax, crospovidone, diacetylated monoglycerides, ethylcellulose, hydroxypropyl cellulose, hypromellose phthalate, magnesium stearate, mannitol, propylene glycol, sodium hydroxide, sodium stearyl fumarate, talc, and titanium dioxide. Iron oxide yellow is the coloring agent for the tablet coating. Iron oxide red is the ink pigment.

12. CLINICAL PHARMACOLOGY

12.1. Mechanism of Action

Ond-R belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H₂-receptor antagonist properties, but suppress gastric acid secretion by inhibiting the gastric H⁺, K⁺ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, Ond-R (Rabeprazole) has been characterized as a gastric proton-pump inhibitor. Ond-R (Rabeprazole) blocks the final step of gastric acid secretion.

In gastric parietal cells, Ond-R (Rabeprazole) is protonated, accumulates, and is transformed to an active sulfenamide. When studied in vitro, Ond-R (Rabeprazole) is chemically activated at pH 1.2 with a half-life of 78 seconds. It inhibits acid transport in porcine gastric vesicles with a half-life of 90 seconds.

12.2. Pharmacodynamics

Antisecretory Activity

The antisecretory effect begins within one hour after oral administration of 20 mg Ond-R (Rabeprazole). The median inhibitory effect of Ond-R (Rabeprazole) on 24 hour gastric acidity is 88% of maximal after the first dose. Ond-R (Rabeprazole) 20 mg inhibits basal and peptone meal-stimulated acid secretion versus placebo by 86% and 95%, respectively, and increases the percent of a 24-hour period that the gastric pH>3 from 10% to 65%. This relatively prolonged pharmacodynamic action compared to the short pharmacokinetic half-life (1-2 hours) reflects the sustained inactivation of the H⁺, K⁺ATPase.

Compared to placebo, Ond-R (Rabeprazole), 10 mg, 20 mg, and 40 mg, administered once daily for 7 days significantly decreased intragastric acidity with all doses for each of four meal-related intervals and the 24-hour time period overall. In this study, there were no statistically significant differences between doses; however, there was a significant dose-related decrease in intragastric acidity. The ability of Ond-R (Rabeprazole) to cause a dose-related decrease in mean intragastric acidity is illustrated below.

After administration of 20 mg Ond-R (Rabeprazole) once daily for eight days, the mean percent of time that gastric pH>3 or gastric pH>4 after a single dose (Day 1) and multiple doses (Day 8) was significantly greater than placebo. The decrease in gastric acidity and the increase in gastric pH observed with 20 mg Ond-R (Rabeprazole) administered once daily for eight days were compared to the same parameters for placebo, as illustrated below:

Effects on Esophageal Acid Exposure

In patients with gastroesophageal reflux disease (GERD) and moderate to severe esophageal acid exposure, Ond-R (Rabeprazole) 20 mg and 40 mg per day decreased 24-hour esophageal acid exposure. After seven days of treatment, the percentage of time that esophageal pH<4 decreased from baselines of 24.7% for 20 mg and 23.7% for 40 mg, to 5.1% and 2.0%, respectively. Normalization of 24-hour intraesophageal acid exposure was correlated to gastric pH>4 for at least 35% of the 24-hour period; this level was achieved in 90% of subjects receiving Ond-R (Rabeprazole) 20 mg and in 100% of subjects receiving Ond-R (Rabeprazole) 40 mg. With Ond-R (Rabeprazole) 20 mg and 40 mg per day, significant effects on gastric and esophageal pH were noted after one day of treatment, and more pronounced after seven days of treatment.

Effects on Serum Gastrin

In patients given daily doses of Ond-R (Rabeprazole) for up to eight weeks to treat ulcerative or erosive esophagitis and in patients treated for up to 52 weeks to prevent recurrence of disease the median fasting gastrin level increased in a dose-related manner. The group median values stayed within the normal range.

In a group of subjects treated daily with Ond-R (Rabeprazole) 20 mg for 4 weeks a doubling of mean serum gastrin concentrations were observed. Approximately 35% of these treated subjects developed serum gastrin concentrations above the upper limit of normal. In a study of CYP2C19 genotyped subjects in Japan, poor metabolizers developed statistically significantly higher serum gastrin concentrations than extensive metabolizers.

Effects on Enterochromaffin-like (ECL) Cells

Increased serum gastrin secondary to antisecretory agents stimulates proliferation of gastric ECL cells which, over time, may result in ECL cell hyperplasia in rats and mice and gastric carcinoids in rats, especially in females {see Carcinogenesis, Mutagenesis, Impairment of Fertility (13.1)}.

In over 400 patients treated with Ond-R (Rabeprazole) (10 or 20 mg/day) for up to one year, the incidence of ECL cell hyperplasia increased with time and dose, which is consistent with the pharmacological action of the proton-pump inhibitor. No patient developed the adenomatoid, dysplastic or neoplastic changes of ECL cells in the gastric mucosa. No patient developed the carcinoid tumors observed in rats.

Endocrine Effects

Studies in humans for up to one year have not revealed clinically significant effects on the endocrine system. In healthy male volunteers treated with Ond-R (Rabeprazole) for 13 days, no clinically relevant changes have been detected in the following endocrine parameters examined: 17 β-estradiol, thyroid stimulating hormone, tri-iodothyronine, thyroxine, thyroxine-binding protein, parathyroid hormone, insulin, glucagon, renin, aldosterone, follicle-stimulating hormone, luteotrophic hormone, prolactin, somatotrophic hormone, dehydroepiandrosterone, cortisol-binding globulin, and urinary 6β-hydroxycortisol, serum testosterone and circadian cortisol profile.

Other Effects

In humans treated with Ond-R (Rabeprazole) for up to one year, no systemic effects have been observed on the central nervous, lymphoid, hematopoietic, renal, hepatic, cardiovascular, or respiratory systems. No data are available on long-term treatment with Ond-R (Rabeprazole) and ocular effects.

Microbiology

The following in vitro data are available but the clinical significance is unknown.

Ond-R (Rabeprazole) sodium, amoxicillin and clarithromycin as a three drug regimen has been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections as described in the CLINICAL STUDIES (14) and INDICATIONS AND USAGE (1) sections.

Helicobacter pylori

Susceptibility testing of H. pylori isolates was performed for amoxicillin and clarithromycin using agar dilution methodology¹, and minimum inhibitory concentrations (MICs) were determined. The clarithromycin and amoxicillin MIC values should be interpreted according to the following criteria:

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:

Incidence of Antibiotic-Resistant Organisms Among Clinical Isolates

Pretreatment Resistance: Clarithromycin pretreatment resistance rate (MIC ≥ 1 μg/mL) to H. pylori was 9% (51/560) at baseline in all treatment groups combined. A total of > 99% (558/560) of patients had H. pylori isolates which were considered to be susceptible (MIC ≤ 0.25 μg/mL) to amoxicillin at baseline. Two patients had baseline H. pylori isolates with an amoxicillin MIC of 0.5 μg/mL.

Clarithromycin Susceptibility Test Results and Clinical/Bacteriologic Outcomes: For the U.S. multicenter study, the baseline H. pylori clarithromycin susceptibility results and the H. pylori eradication results post-treatment are shown in the table below:

Patients with persistent H. pylori infection following Ond-R (Rabeprazole), amoxicillin, and clarithromycin therapy will likely have clarithromycin resistant clinical isolates. Therefore, clarithromycin susceptibility testing should be done when possible. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted.

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes: In the U.S. multicenter study, a total of >99% (558/560) of patients had H. pylori isolates which were considered to be susceptible (MIC ≤ 0.25 μg/mL) to amoxicillin at baseline. The other 2 patients had baseline H. pylori isolates with an amoxicillin MIC of 0.5 μg/mL, and both isolates were clarithromycin-resistant at baseline; in one case the H. pylori was eradicated. In the 7- and 10-day treatment groups 75% (107/145) and 79% (112/142), respectively, of the patients who had pretreatment amoxicillin susceptible MICs (≤ 0.25 μg/mL) were eradicated of H. pylori. No patients developed amoxicillin-resistant H. pylori during therapy.

12.3. Pharmacokinetics

Ond-R (Rabeprazole) delayed-release tablets are enteric-coated to allow Ond-R (Rabeprazole) sodium, which is acid labile, to pass through the stomach relatively intact. After oral administration of 20 mg Ond-R (Rabeprazole), peak plasma concentrations (C_max) of Ond-R (Rabeprazole) occur over a range of 2.0 to 5.0 hours (T_max). The Ond-R (Rabeprazole) C_max and AUC are linear over an oral dose range of 10 mg to 40 mg. There is no appreciable accumulation when doses of 10 mg to 40 mg are administered every 24 hours; the pharmacokinetics of Ond-R (Rabeprazole) is not altered by multiple dosing. The plasma half-life ranges from 1 to 2 hours.

Absorption: Absolute bioavailability for a 20 mg oral tablet of Ond-R (Rabeprazole) (compared to intravenous administration) is approximately 52%. When Ond-R (Rabeprazole) is administered with a high fat meal, its T_max is variable and may delay its absorption up to 4 hours or longer, however, the C_max and the extent of Ond-R (Rabeprazole) absorption (AUC) are not significantly altered. Thus Ond-R (Rabeprazole) may be taken without regard to timing of meals.

Distribution: Ond-R (Rabeprazole) is 96.3% bound to human plasma proteins.

Metabolism: Ond-R (Rabeprazole) is extensively metabolized. A significant portion of Ond-R (Rabeprazole) is metabolized via systemic nonenzymatic reduction to a thioether compound. Ond-R (Rabeprazole) is also metabolized to sulphone and desmethyl compounds via cytochrome P450 in the liver. The thioether and sulphone are the primary metabolites measured in human plasma. These metabolites were not observed to have significant antisecretory activity. In vitro studies have demonstrated that Ond-R (Rabeprazole) is metabolized in the liver primarily by cytochromes P450 3A (CYP3A) to a sulphone metabolite and cytochrome P450 2C19 (CYP2C19) to desmethyl Ond-R (Rabeprazole). CYP2C19 exhibits a known genetic polymorphism due to its deficiency in some sub-populations (e.g. 3 to 5% of Caucasians and 17 to 20% of Asians). Ond-R (Rabeprazole) metabolism is slow in these sub-populations, therefore, they are referred to as poor metabolizers of the drug.

Elimination: Following a single 20 mg oral dose of ¹⁴C-labeled Ond-R (Rabeprazole), approximately 90% of the drug was eliminated in the urine, primarily as thioether carboxylic acid; its glucuronide, and mercapturic acid metabolites. The remainder of the dose was recovered in the feces. Total recovery of radioactivity was 99.8%. No unchanged Ond-R (Rabeprazole) was recovered in the urine or feces.

Geriatric: In 20 healthy elderly subjects administered 20 mg Ond-R (Rabeprazole) once daily for seven days, AUC values approximately doubled and the C_max increased by 60% compared to values in a parallel younger control group. There was no evidence of drug accumulation after once daily administration. {see USE IN SPECIAL POPULATIONS Geriatric Use (8.5)}.

Pediatric: The pharmacokinetics of Ond-R (Rabeprazole) was studied in 12 adolescent patients with GERD 12 to 16 years of age, in a multicenter study. Patients received Ond-R (Rabeprazole) 20 mg once daily for five or seven days. An approximate 40% increase in exposure was noted following 5 to 7 days of dosing compared with the exposure after 1 day dosing. Pharmacokinetic parameters in adolescent patients with GERD 12 to 16 years of age were within the range observed in healthy adult volunteers.

Gender and Race: In analyses adjusted for body mass and height, Ond-R (Rabeprazole) pharmacokinetics showed no clinically significant differences between male and female subjects. In studies that used different formulations of Ond-R (Rabeprazole), AUC_0-∞ values for healthy Japanese men were approximately 50-60% greater than values derived from pooled data from healthy men in the United States.

Renal Disease: In 10 patients with stable end-stage renal disease requiring maintenance hemodialysis (creatinine clearance ≤5 mL/min/1.73 m²), no clinically significant differences were observed in the pharmacokinetics of Ond-R (Rabeprazole) after a single 20 mg oral dose when compared to 10 healthy volunteers. {see DOSAGE AND ADMINISTRATION (2.7)}.

Hepatic Disease: In a single dose study of 10 patients with chronic mild to moderate compensated cirrhosis of the liver who were administered a 20 mg dose of Ond-R (Rabeprazole), AUC_0-24 was approximately doubled, the elimination half-life was 2- to 3-fold higher, and total body clearance was decreased to less than half compared to values in healthy men.

In a multiple dose study of 12 patients with mild to moderate hepatic impairment administered 20 mg Ond-R (Rabeprazole) once daily for eight days, AUC_0-∞ and C_max values increased approximately 20% compared to values in healthy age- and gender-matched subjects. These increases were not statistically significant.

No information exists on Ond-R (Rabeprazole) disposition in patients with severe hepatic impairment. Please refer to the DOSAGE AND ADMINISTRATION section (2.7) for information on dosage adjustment in patients with hepatic impairment.

Combined Administration with Antimicrobials: Sixteen healthy volunteers genotyped as extensive metabolizers with respect to CYP2C19 were given 20 mg Ond-R (Rabeprazole) sodium, 1000 mg amoxicillin, 500 mg clarithromycin, or all 3 drugs in a four-way crossover study. Each of the four regimens was administered twice daily for 6 days. The AUC and C_max for clarithromycin and amoxicillin were not different following combined administration compared to values following single administration. However, the Ond-R (Rabeprazole) AUC and C_max increased by 11% and 34%, respectively, following combined administration. The AUC and C_max for 14-hydroxyclarithromycin (active metabolite of clarithromycin) also increased by 42% and 46%, respectively. This increase in exposure to Ond-R (Rabeprazole) and 14-hydroxyclarithromycin is not expected to produce safety concerns.

13. NONCLINICAL PHARMACOLOGY

13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 88/104-week carcinogenicity study in CD-1 mice, Ond-R (Rabeprazole) at oral doses up to 100 mg/kg/day did not produce any increased tumor occurrence. The highest tested dose produced a systemic exposure to Ond-R (Rabeprazole) (AUC) of 1.40 μg-hr/mL which is 1.6 times the human exposure (plasma AUC_0-∞ = 0.88 μg-hr/mL) at the recommended dose for GERD (20 mg/day). In a 28-week carcinogenicity study in p53^+/- transgenic mice, Ond-R (Rabeprazole) at oral doses of 20, 60, and 200 mg/kg/day did not cause an increase in the incidence rates of tumors but produced gastric mucosal hyperplasia at all doses. The systemic exposure to Ond-R (Rabeprazole) at 200 mg/kg/day is about 17-24 times the human exposure at the recommended dose for GERD. In a 104-week carcinogenicity study in Sprague-Dawley rats, males were treated with oral doses of 5, 15, 30 and 60 mg/kg/day and females with 5, 15, 30, 60 and 120 mg/kg/day. Ond-R (Rabeprazole) produced gastric enterochromaffin-like (ECL) cell hyperplasia in male and female rats and ECL cell carcinoid tumors in female rats at all doses including the lowest tested dose. The lowest dose (5 mg/kg/day) produced a systemic exposure to Ond-R (Rabeprazole) (AUC) of about 0.1 μg-hr/mL which is about 0.1 times the human exposure at the recommended dose for GERD. In male rats, no treatment related tumors were observed at doses up to 60 mg/kg/day producing a Ond-R (Rabeprazole) plasma exposure (AUC) of about 0.2 μg-hr/mL (0.2 times the human exposure at the recommended dose for GERD).

Ond-R (Rabeprazole) was positive in the Ames test, the Chinese hamster ovary cell (CHO/HGPRT) forward gene mutation test and the mouse lymphoma cell (L5178Y/TK+/-) forward gene mutation test. Its demethylated-metabolite was also positive in the Ames test. Ond-R (Rabeprazole) was negative in the in vitro Chinese hamster lung cell chromosome aberration test, the in vivo mouse micronucleus test, and the in vivo and ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) tests.

Ond-R (Rabeprazole) at intravenous doses up to 30 mg/kg/day (plasma AUC of 8.8 μg-hr/mL, about 10 times the human exposure at the recommended dose for GERD) was found to have no effect on fertility and reproductive performance of male and female rats.

14. CLINICAL STUDIES

14.1. Healing of Erosive or Ulcerative GERD

In a U.S., multicenter, randomized, double-blind, placebo-controlled study, 103 patients were treated for up to eight weeks with placebo, 10 mg, 20 mg or 40 mg Ond-R QD. For this and all studies of GERD healing, only patients with GERD symptoms and at least grade 2 esophagitis (modified Hetzel-Dent grading scale) were eligible for entry. Endoscopic healing was defined as grade 0 or 1. Each Ond-R (Rabeprazole) dose was significantly superior to placebo in producing endoscopic healing after four and eight weeks of treatment. The percentage of patients demonstrating endoscopic healing was as follows:

In addition, there was a statistically significant difference in favor of the Ond-R (Rabeprazole) 10 mg, 20 mg, and 40 mg doses compared to placebo at Weeks 4 and 8 regarding complete resolution of GERD heartburn frequency (p≤0.026). All Ond-R (Rabeprazole) groups reported significantly greater rates of complete resolution of GERD daytime heartburn severity compared to placebo at Weeks 4 and 8 (p≤0.036). Mean reductions from baseline in daily antacid dose were statistically significant for all Ond-R (Rabeprazole) groups when compared to placebo at both Weeks 4 and 8 (p≤0.007).

In a North American multicenter, randomized, double-blind, active-controlled study of 336 patients, Ond-R (Rabeprazole) was statistically superior to ranitidine with respect to the percentage of patients healed at endoscopy after four and eight weeks of treatment :

Ond-R (Rabeprazole) 20 mg once daily was significantly more effective than ranitidine 150 mg QID in the percentage of patients with complete resolution of heartburn at Weeks 4 and 8 (p<0.001). Ond-R (Rabeprazole) 20 mg once daily was also more effective in complete resolution of daytime heartburn (p≤0.025), and nighttime heartburn (p≤0.012) at both Weeks 4 and 8, with significant differences by the end of the first week of the study.

14.2. Long-term Maintenance of Healing of Erosive or Ulcerative GERD

The long-term maintenance of healing in patients with erosive or ulcerative GERD previously healed with gastric antisecretory therapy was assessed in two U.S., multicenter, randomized, double-blind, placebo-controlled studies of identical design of 52 weeks duration. The two studies randomized 209 and 285 patients, respectively, to receive either 10 mg or 20 mg of Ond-R (Rabeprazole) QD or placebo. As demonstrated in the tables below, Ond-R (Rabeprazole) was significantly superior to placebo in both studies with respect to the maintenance of healing of GERD and the proportions of patients remaining free of heartburn symptoms at 52 weeks:

14.3. Treatment of Symptomatic GERD

Two U.S., multicenter, double-blind, placebo controlled studies were conducted in 316 patients with daytime and nighttime heartburn. Patients reported 5 or more periods of moderate to very severe heartburn during the placebo treatment phase the week prior to randomization. Patients were confirmed by endoscopy to have no esophageal erosions.

The percentage of heartburn free daytime and/or nighttime periods was greater with Ond-R 20 mg compared to placebo over the 4 weeks of study in Study RAB-USA-2 (47% vs. 23%) and Study RAB-USA-3 (52% vs. 28%). The mean decreases from baseline in average daytime and nighttime heartburn scores were significantly greater for Ond-R (Rabeprazole) 20 mg as compared to placebo at week 4. Graphical displays depicting the daily mean daytime and nighttime scores are provided in Figures 2 to 5.

FIGURE 2: MEAN DAYTIME HEARTBURN SCORES RAB-USA-2

FIGURE 3: MEAN NIGHTTIME HEARTBURN SCORES RAB-USA-2

FIGURE 4: MEAN DAYTIME HEARTBURN SCORES RAB-USA-3

FIGURE 5: MEAN NIGHTTIME HEARTBURN SCORES RAB-USA-3

In addition, the combined analysis of these two studies showed Ond-R (Rabeprazole) 20 mg significantly improved other GERD-associated symptoms (regurgitation, belching and early satiety) by week 4 compared with placebo (all p values < 0.005).

Ond-R (Rabeprazole) 20 mg also significantly reduced daily antacid consumption versus placebo over 4 weeks (p<0.001).

14.4. Healing of Duodenal Ulcers

In a U.S., randomized, double-blind, multicenter study assessing the effectiveness of 20 mg and 40 mg of Ond-R (Rabeprazole) QD versus placebo for healing endoscopically defined duodenal ulcers, 100 patients were treated for up to four weeks. Ond-R (Rabeprazole) was significantly superior to placebo in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing are presented below:

At Weeks 2 and 4, significantly more patients in the Ond-R (Rabeprazole) 20 and 40 mg groups reported complete resolution of ulcer pain frequency (p≤0.018), daytime pain severity (p≤0.023), and nighttime pain severity (p≤0.035) compared with placebo patients. The only exception was the Ond-R (Rabeprazole) 40 mg group versus placebo at Week 2 for duodenal ulcer pain frequency (p=0.094). Significant differences in resolution of daytime and nighttime pain were noted in both Ond-R (Rabeprazole) groups relative to placebo by the end of the first week of the study. Significant reductions in daily antacid use were also noted in both Ond-R (Rabeprazole) groups compared to placebo at Weeks 2 and 4 (p<0.001).

An international randomized, double-blind, active-controlled trial was conducted in 205 patients comparing 20 mg Ond-R (Rabeprazole) QD with 20 mg omeprazole QD. The study was designed to provide at least 80% power to exclude a difference of at least 10% between Ond-R (Rabeprazole) and omeprazole, assuming four-week healing response rates of 93% for both groups. In patients with endoscopically defined duodenal ulcers treated for up to four weeks, Ond-R (Rabeprazole) was comparable to omeprazole in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing at two and four weeks are presented below:

Ond-R (Rabeprazole) and omeprazole were comparable in providing complete resolution of symptoms.

14.5. Helicobacter pylori Eradication in Patients with Peptic Ulcer Disease or Symptomatic Non-Ulcer Disease

The U.S. multicenter study was a double-blind, parallel-group comparison of Ond-R (Rabeprazole), amoxicillin, and clarithromycin for 3, 7, or 10 days vs. omeprazole, amoxicillin and clarithromycin for 10 days. Therapy consisted of Ond-R (Rabeprazole) 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily (RAC) or omeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily (OAC). Patients with H. pylori infection were stratified in a 1:1 ratio for those with peptic ulcer disease (active or a history of ulcer in the past five years) [PUD] and those who were symptomatic but without peptic ulcer disease [NPUD], as determined by upper gastrointestinal endoscopy. The overall H. pylori eradication rates, defined as negative ¹³C-UBT for H. pylori ≥ 6 weeks from the end of the treatment are shown in the following table. The eradication rates in the 7-day and 10-day RAC regimens were found to be similar to 10-day OAC regimen using either the Intent-to-Treat (ITT) or Per-Protocol (PP) populations. Eradication rates in the RAC 3-day regimen were inferior to the other regimens.

14.6. Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome

Twelve patients with idiopathic gastric hypersecretion or Zollinger-Ellison syndrome have been treated successfully with Ond-R (Rabeprazole) at doses from 20 to 120 mg for up to 12 months. Ond-R (Rabeprazole) produced satisfactory inhibition of gastric acid secretion in all patients and complete resolution of signs and symptoms of acid-peptic disease where present. Ond-R (Rabeprazole) also prevented recurrence of gastric hypersecretion and manifestations of acid-peptic disease in all patients. The high doses of Ond-R (Rabeprazole) used to treat this small cohort of patients with gastric hypersecretion were well tolerated.

15. REFERENCES

• 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

Ond-R (Rabeprazole) 20 mg is supplied as delayed-release light yellow enteric-coated tablets. The name and strength, in mg, (ACIPHEX 20) is imprinted on one side.

Bottles of 30 (NDC#62856-243-30)

Bottles of 90 (NDC#62856-243-90)

Unit Dose Blisters Package of 100 (10 x 10) (NDC#62856-243-41)

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Protect from moisture.

17. PATIENT COUNSELING INFORMATION

How to Take Ond-R (Rabeprazole)

Patients should be cautioned that Ond-R (Rabeprazole) delayed-release tablets should be swallowed whole. The tablets should not be chewed, crushed, or split. Ond-R (Rabeprazole) can be taken with or without food.

Advise patients to immediately report and seek care for any cardiovascular or neurological symptoms including palpitations, dizziness, and tetany as these may be signs of hypomagnesemia {see WARNINGS AND PRECAUTIONS (5.7)}.

FDA-Approved Patient Labeling

PATIENT INFORMATION

Ond-R (Rabeprazole) (a-se-feks)

(rabeprazole sodium)

Delayed-Release Tablets

Read the Patient Information that comes with Ond-R (Rabeprazole) 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 to your healthcare provider about your medical condition or treatment.

What is Ond-R (Rabeprazole)?

Ond-R (Rabeprazole) is a medicine called a proton pump inhibitor. Ond-R (Rabeprazole) reduces the amount of acid in your stomach.

Ond-R (Rabeprazole) is used in adults:

• for up to 8 weeks to heal acid-related damage to the lining of the esophagus (called erosive esophagitis or EE) and to relieve symptoms, such as heartburn pain. If needed, your doctor may prescribe an additional 8 weeks of Ond-R (Rabeprazole).
• to maintain the healing of the esophagus and relief of symptoms related to EE. Ond-R (Rabeprazole) has not been studied for treatment lasting longer than 12 months (1 year).
• for 4 weeks for the treatment of daytime and nighttime heartburn and other symptoms that happen with Gastroesophageal Reflux Disease (GERD). If needed your doctor may prescribe an additional 4 weeks of Ond-R (Rabeprazole).
  

  GERD happens when acid in your stomach backs up into the tube (esophagus) that connects your mouth to your stomach. This may cause a burning feeling in your chest or throat, sour taste, or burping.

• for up to 4 weeks for the healing and relief of duodenal ulcers. The duodenal area is the area where food passes when it leaves the stomach.
• with certain antibiotic medicines for the treatment of an infection caused by bacteria called H. pylori. Sometimes H. pylori bacteria can cause duodenal ulcers. The infection needs to be treated to prevent the ulcers from coming back.
• for the long-term treatment of conditions where your stomach makes too much acid. This includes a rare condition called Zollinger-Ellison syndrome.

Ond-R (Rabeprazole) is used in adolescents 12 years of age and above:

• for up to 8 weeks for the treatment of GERD.

It is not known if Ond-R (Rabeprazole) is safe and effective in children under the age of 12.

Ond-R (Rabeprazole) may help your acid-related symptoms, but you could still have serious stomach problems. Talk with your doctor.

Who should not take Ond-R (Rabeprazole)?

Do not take Ond-R (Rabeprazole) if you:

• are allergic to any of the ingredients in Ond-R (Rabeprazole). See the end of this leaflet for a complete list of ingredients in Ond-R (Rabeprazole).
• are allergic to any other Proton Pump Inhibitor (PPI) medicine.

What should I tell my doctor before taking Ond-R (Rabeprazole)?

Before you take Ond-R (Rabeprazole) tell your doctor about all of your medical conditions, including if you:

• have been told that you have low magnesium levels in your blood.
• have any liver problems.
• have any allergies.
• are pregnant or planning to become pregnant. It is not known if Ond-R (Rabeprazole) can harm your unborn baby.
• are breastfeeding. It is not known if Ond-R (Rabeprazole) passes into your breast milk or if it can harm your baby. You should choose to breastfeed or take Ond-R (Rabeprazole), but not both. Talk to your doctor about other ways to feed your baby while taking Ond-R (Rabeprazole).

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Ond-R (Rabeprazole) and certain medicines can affect each other. This can cause serious side effects. Know the medicines that you take. Keep a list of them with you and show it to your doctor when you get a new medicine. Be sure to tell your doctor if you are taking:

• atazanavir (Reyataz)
• cyclosporine (Sandimmune, Neoral)
• digoxin (Lanoxin)
• ketoconazole (Nizoral)
• warfarin (Coumadin)
• theophylline (THEO-24 Thelair)
• diazepam (Valium)
• phenytoin (Dilantin)
• antibiotics

Ask your doctor or pharmacist if you are not sure if your medicine is listed above.

How should I take Ond-R (Rabeprazole)?

• Take Ond-R (Rabeprazole) exactly as prescribed. Your doctor will prescribe the dose that is right for you and your medical condition. Do not change your dose or stop taking Ond-R (Rabeprazole) unless you talk to your doctor. Take Ond-R (Rabeprazole) for as long as it is prescribed even if you feel better.
• Ond-R (Rabeprazole) is usually taken once a day. Your doctor will tell you the time of day to take Ond-R (Rabeprazole), based on your medical condition.
• Ond-R (Rabeprazole) can be taken with or without food. Your healthcare provider will tell you whether to take this medicine with or without food based on your medical condition.
• Swallow each Ond-R (Rabeprazole) tablet whole with water. Do not chew, crush, or split Ond-R (Rabeprazole) tablets because this will damage the tablet and the medicine will not work. Tell your doctor if you cannot swallow tablets whole. You may need a different medicine.
• If you miss a dose of Ond-R (Rabeprazole), take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your normal schedule. Do not take 2 doses at the same time.
• If you take too much Ond-R (Rabeprazole), call your doctor or Poison Control Center right away, or go to the emergency department.
• Your doctor may prescribe antibiotic medicines with Ond-R (Rabeprazole) to help treat a stomach infection and heal stomach-area (duodenal) ulcers that are caused by bacteria called H. pylori. Make sure you read the patient information that comes with an antibiotic before you start taking it.

What are the possible side effects of Ond-R (Rabeprazole)?

Ond-R (Rabeprazole), like other proton pump inhibitors, may cause serious allergic reactions. See the end of this leaflet for a complete list of ingredients in Ond-R (Rabeprazole).

• Serious allergic reactions. Tell your doctor if you have any of the following symptoms with Ond-R (Rabeprazole).
• rash
• face swelling
• throat tightness
• difficulty breathing

Your doctor may stop Ond-R (Rabeprazole) 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 Ond-R (Rabeprazole), during treatment, or if you will be taking Ond-R (Rabeprazole) for a long period of time.

The most common side effects with Ond-R (Rabeprazole) may include:

• headache
• pain
• sore throat
• gas
• infection
• constipation

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 if you have any side effect that bothers you or that does not go away. These are not all the side effects of Ond-R (Rabeprazole). For more information, ask your doctor or pharmacist.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Ond-R (Rabeprazole)?

• Store Ond-R (Rabeprazole) in a dry place at room temperature, 59°F to 86°F (15°C to 30°C).

Keep Ond-R (Rabeprazole) and all medicines out of the reach of children.

General Information about Ond-R (Rabeprazole)

Medicines are sometimes prescribed for conditions other than those described in patient information leaflets. Do not use Ond-R (Rabeprazole) for any condition for which it was not prescribed by your doctor. Do not give Ond-R (Rabeprazole) to other people, even if they have the same symptoms as you. It may harm them.

This leaflet summarizes the most important information about Ond-R (Rabeprazole). If you would like more information, talk to your doctor. You can also ask your doctor or pharmacist for information about Ond-R (Rabeprazole) that is written for healthcare professionals. For full product information, visit the website at http://www.aciphex.com/ or call the toll-free numbers 1-888-4-ACIPHEX or 1-800 JANSSEN.

What are the ingredients in Ond-R (Rabeprazole)?

Active Ingredient: Ond-R (Rabeprazole) sodium

Inactive ingredients of the 20 mg tablet are carnauba wax, crospovidone, diacetylated monoglycerides, ethylcellulose, hydroxypropyl cellulose, hypromellose phthalate, magnesium stearate, mannitol, propylene glycol, sodium hydroxide, sodium stearyl fumarate, talc, and titanium dioxide. Iron oxide yellow is the coloring agent for the tablet coating. Iron oxide red is the ink pigment.

The following are registered trademarks of their respective manufacturers:

Reyataz (Bristol-Myers Squibb Company), Sandimmune and Neoral (Novartis Pharmaceuticals Corporation), Lanoxin (GlaxoSmithKline), Nizoral (Janssen Pharmaceutica Products, LP), and Coumadin (Bristol-Myers Squibb Company).

For prescription only

Revised May 2011

Ond-R (Rabeprazole) is a registered trademark of Eisai Co., Ltd., Tokyo, Japan.

Manufactured and Marketed by Eisai Inc., Woodcliff Lake, NJ 07677

Marketed by PRICARA, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., Raritan, NJ 08869