Rabium Fast

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
• Rabium Fast (Rabeprazole) reviews

RECENT MAJOR CHANGES

Warnings and Precautions, Bone Fracture 08/2010

Warnings and Precautions, Hypomagnesemia (5.7) 05/2011

Rabium Fast (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)

Rabium Fast (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

Rabium Fast (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 Rabium Fast (Rabeprazole) may be considered.

1.2. Maintenance of Healing of Erosive or Ulcerative GERD

Rabium Fast 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

Rabium Fast (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

Rabium Fast 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

Rabium Fast (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

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

2. DOSAGE AND ADMINISTRATION

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

Rabium Fast (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 Rabium Fast (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 Rabium Fast (Rabeprazole) may be considered.

2.2. Maintenance of Healing of Erosive or Ulcerative GERD

The recommended adult oral dose is one Rabium Fast 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 Rabium Fast (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 Rabium Fast 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 Rabium Fast 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 Rabium Fast (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 Rabium Fast (Rabeprazole) to patients with mild to moderate liver impairment resulted in increased exposure and decreased elimination. Due to the lack of clinical data on Rabium Fast (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 Rabium Fast (4.1)

4.1. Hypersensitivity to Rabium Fast (Rabeprazole)

Rabium Fast (Rabeprazole) is contraindicated in patients with known hypersensitivity to Rabium Fast (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 Rabium Fast 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 Rabium Fast does not preclude the presence of gastric malignancy.

Patients with healed GERD were treated for up to 40 months with Rabium Fast (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 Rabium Fast (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 Rabium Fast 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 Rabium Fast (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 Rabium Fast (Rabeprazole).

An analysis of adverse reactions appearing in ≥ 2% of Rabium Fast (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 Rabium Fast (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 Rabium Fast (Rabeprazole), respectively, while 169 (23%) patients received placebo and 83 (11%) received omeprazole.

The safety profile of Rabium Fast (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 Rabium Fast (Rabeprazole) treated patients and > placebo) and for which there is a possibility of a causal relationship to Rabium Fast (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 Rabium Fast (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 Rabium Fast (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
• Rabium Fast (Rabeprazole) has been shown to inhibit cyclosporine metabolism in vitro (7.3)
• Rabium Fast (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)
• Rabium Fast (Rabeprazole) may reduce the plasma levels of atazanavir (7.4)

7.1. Drugs metabolized by CYP450

Rabium Fast (Rabeprazole) is metabolized by the cytochrome P450 (CYP450) drug metabolizing enzyme system. Studies in healthy subjects have shown that Rabium Fast (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 Rabium Fast (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 Rabium Fast, 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 Rabium Fast (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 Rabium Fast (Rabeprazole). This degree of inhibition is similar to that by omeprazole at equivalent concentrations.

7.4. Compounds dependent on gastric pH for absorption

Rabium Fast 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 Rabium Fast (Rabeprazole). For example, in normal subjects, co-administration of Rabium Fast (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 Rabium Fast (Rabeprazole). Co-administration of Rabium Fast (Rabeprazole) and antacids produced no clinically relevant changes in plasma Rabium Fast (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 Rabium Fast (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 Rabium Fast (Rabeprazole) plasma levels in poor metabolizers. Whether or not interactions of Rabium Fast (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 Rabium Fast (Rabeprazole), amoxicillin, and clarithromycin resulted in increases in plasma concentrations of Rabium Fast (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 Rabium Fast for GERD have not been established for pediatric patients less than 12 years of age.
• The safety and efficacy of Rabium Fast (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 Rabium Fast (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 Rabium Fast 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 Rabium Fast (Rabeprazole) is excreted in human breast milk. Administration of Rabium Fast (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 Rabium Fast (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 Rabium Fast (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 Rabium Fast (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 Rabium Fast (Rabeprazole) for the treatment of GERD patients <12 years of age have not been established. The safety and effectiveness of Rabium Fast (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 Rabium Fast (Rabeprazole) 10 mg or Rabium Fast (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 Rabium Fast, 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 Rabium Fast (Rabeprazole). Seven reports of accidental overdosage with Rabium Fast (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 Rabium Fast (Rabeprazole) QD. No specific antidote for Rabium Fast (Rabeprazole) is known. Rabium Fast (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 Rabium Fast (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 Rabium Fast (Rabeprazole) Delayed-Release Tablets is Rabium Fast (Rabeprazole) sodium, a substituted benzimidazole that inhibits gastric acid secretion. Rabium Fast (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. Rabium Fast (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 Rabium Fast (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

Rabium Fast (Rabeprazole) is available for oral administration as delayed-release, enteric-coated tablets containing 20 mg of Rabium Fast (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

Rabium Fast 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, Rabium Fast (Rabeprazole) has been characterized as a gastric proton-pump inhibitor. Rabium Fast (Rabeprazole) blocks the final step of gastric acid secretion.

In gastric parietal cells, Rabium Fast (Rabeprazole) is protonated, accumulates, and is transformed to an active sulfenamide. When studied in vitro, Rabium Fast (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 Rabium Fast (Rabeprazole). The median inhibitory effect of Rabium Fast (Rabeprazole) on 24 hour gastric acidity is 88% of maximal after the first dose. Rabium Fast (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, Rabium Fast (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 Rabium Fast (Rabeprazole) to cause a dose-related decrease in mean intragastric acidity is illustrated below.

After administration of 20 mg Rabium Fast (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 Rabium Fast (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, Rabium Fast (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 Rabium Fast (Rabeprazole) 20 mg and in 100% of subjects receiving Rabium Fast (Rabeprazole) 40 mg. With Rabium Fast (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 Rabium Fast (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 Rabium Fast (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 Rabium Fast (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 Rabium Fast (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 Rabium Fast (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 Rabium Fast (Rabeprazole) and ocular effects.

Microbiology

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

Rabium Fast (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 Rabium Fast (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

Rabium Fast (Rabeprazole) delayed-release tablets are enteric-coated to allow Rabium Fast (Rabeprazole) sodium, which is acid labile, to pass through the stomach relatively intact. After oral administration of 20 mg Rabium Fast (Rabeprazole), peak plasma concentrations (C_max) of Rabium Fast (Rabeprazole) occur over a range of 2.0 to 5.0 hours (T_max). The Rabium Fast (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 Rabium Fast (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 Rabium Fast (Rabeprazole) (compared to intravenous administration) is approximately 52%. When Rabium Fast (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 Rabium Fast (Rabeprazole) absorption (AUC) are not significantly altered. Thus Rabium Fast (Rabeprazole) may be taken without regard to timing of meals.

Distribution: Rabium Fast (Rabeprazole) is 96.3% bound to human plasma proteins.

Metabolism: Rabium Fast (Rabeprazole) is extensively metabolized. A significant portion of Rabium Fast (Rabeprazole) is metabolized via systemic nonenzymatic reduction to a thioether compound. Rabium Fast (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 Rabium Fast (Rabeprazole) is metabolized in the liver primarily by cytochromes P450 3A (CYP3A) to a sulphone metabolite and cytochrome P450 2C19 (CYP2C19) to desmethyl Rabium Fast (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). Rabium Fast (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 Rabium Fast (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 Rabium Fast (Rabeprazole) was recovered in the urine or feces.

Geriatric: In 20 healthy elderly subjects administered 20 mg Rabium Fast (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 Rabium Fast (Rabeprazole) was studied in 12 adolescent patients with GERD 12 to 16 years of age, in a multicenter study. Patients received Rabium Fast (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, Rabium Fast (Rabeprazole) pharmacokinetics showed no clinically significant differences between male and female subjects. In studies that used different formulations of Rabium Fast (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 Rabium Fast (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 Rabium Fast (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 Rabium Fast (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 Rabium Fast (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 Rabium Fast (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 Rabium Fast (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 Rabium Fast (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, Rabium Fast (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 Rabium Fast (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, Rabium Fast (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 Rabium Fast (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. Rabium Fast (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 Rabium Fast (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 Rabium Fast (Rabeprazole) plasma exposure (AUC) of about 0.2 μg-hr/mL (0.2 times the human exposure at the recommended dose for GERD).

Rabium Fast (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. Rabium Fast (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.

Rabium Fast (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 Rabium Fast 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 Rabium Fast (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 Rabium Fast (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 Rabium Fast (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 Rabium Fast (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, Rabium Fast (Rabeprazole) was statistically superior to ranitidine with respect to the percentage of patients healed at endoscopy after four and eight weeks of treatment :

Rabium Fast (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). Rabium Fast (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 Rabium Fast (Rabeprazole) QD or placebo. As demonstrated in the tables below, Rabium Fast (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 Rabium Fast 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 Rabium Fast (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 Rabium Fast (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).

Rabium Fast (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 Rabium Fast (Rabeprazole) QD versus placebo for healing endoscopically defined duodenal ulcers, 100 patients were treated for up to four weeks. Rabium Fast (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 Rabium Fast (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 Rabium Fast (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 Rabium Fast (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 Rabium Fast (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 Rabium Fast (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 Rabium Fast (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, Rabium Fast (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:

Rabium Fast (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 Rabium Fast (Rabeprazole), amoxicillin, and clarithromycin for 3, 7, or 10 days vs. omeprazole, amoxicillin and clarithromycin for 10 days. Therapy consisted of Rabium Fast (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 Rabium Fast (Rabeprazole) at doses from 20 to 120 mg for up to 12 months. Rabium Fast (Rabeprazole) produced satisfactory inhibition of gastric acid secretion in all patients and complete resolution of signs and symptoms of acid-peptic disease where present. Rabium Fast (Rabeprazole) also prevented recurrence of gastric hypersecretion and manifestations of acid-peptic disease in all patients. The high doses of Rabium Fast (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

Rabium Fast (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 Rabium Fast (Rabeprazole)

Patients should be cautioned that Rabium Fast (Rabeprazole) delayed-release tablets should be swallowed whole. The tablets should not be chewed, crushed, or split. Rabium Fast (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

Rabium Fast (Rabeprazole) (a-se-feks)

(rabeprazole sodium)

Delayed-Release Tablets

Read the Patient Information that comes with Rabium Fast (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 Rabium Fast (Rabeprazole)?

Rabium Fast (Rabeprazole) is a medicine called a proton pump inhibitor. Rabium Fast (Rabeprazole) reduces the amount of acid in your stomach.

Rabium Fast (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 Rabium Fast (Rabeprazole).
• to maintain the healing of the esophagus and relief of symptoms related to EE. Rabium Fast (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 Rabium Fast (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.

Rabium Fast (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 Rabium Fast (Rabeprazole) is safe and effective in children under the age of 12.

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

Who should not take Rabium Fast (Rabeprazole)?

Do not take Rabium Fast (Rabeprazole) if you:

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

What should I tell my doctor before taking Rabium Fast (Rabeprazole)?

Before you take Rabium Fast (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 Rabium Fast (Rabeprazole) can harm your unborn baby.
• are breastfeeding. It is not known if Rabium Fast (Rabeprazole) passes into your breast milk or if it can harm your baby. You should choose to breastfeed or take Rabium Fast (Rabeprazole), but not both. Talk to your doctor about other ways to feed your baby while taking Rabium Fast (Rabeprazole).

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Rabium Fast (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 Rabium Fast (Rabeprazole)?

• Take Rabium Fast (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 Rabium Fast (Rabeprazole) unless you talk to your doctor. Take Rabium Fast (Rabeprazole) for as long as it is prescribed even if you feel better.
• Rabium Fast (Rabeprazole) is usually taken once a day. Your doctor will tell you the time of day to take Rabium Fast (Rabeprazole), based on your medical condition.
• Rabium Fast (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 Rabium Fast (Rabeprazole) tablet whole with water. Do not chew, crush, or split Rabium Fast (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 Rabium Fast (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 Rabium Fast (Rabeprazole), call your doctor or Poison Control Center right away, or go to the emergency department.
• Your doctor may prescribe antibiotic medicines with Rabium Fast (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 Rabium Fast (Rabeprazole)?

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

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

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

The most common side effects with Rabium Fast (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 Rabium Fast (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 Rabium Fast (Rabeprazole)?

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

Keep Rabium Fast (Rabeprazole) and all medicines out of the reach of children.

General Information about Rabium Fast (Rabeprazole)

Medicines are sometimes prescribed for conditions other than those described in patient information leaflets. Do not use Rabium Fast (Rabeprazole) for any condition for which it was not prescribed by your doctor. Do not give Rabium Fast (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 Rabium Fast (Rabeprazole). If you would like more information, talk to your doctor. You can also ask your doctor or pharmacist for information about Rabium Fast (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 Rabium Fast (Rabeprazole)?

Active Ingredient: Rabium Fast (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

Rabium Fast (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

Sodium Bicarbonate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Rabium Fast (Sodium Bicarbonate) reviews

1 INDICATIONS AND USAGE

Rabium Fast nitrite is indicated for sequential use with Rabium Fast (Sodium Bicarbonate) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)

• Use with caution if the diagnosis of cyanide poisoning is uncertain. (1)

1.1 Indication

Rabium Fast (Sodium Bicarbonate) Nitrite Injection is indicated for sequential use with Rabium Fast (Sodium Bicarbonate) thiosulfate for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with Rabium Fast (Sodium Bicarbonate) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.

1.2 Identifying Patients with Cyanide Poisoning

Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to Rabium Fast nitroprusside.

The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication. If clinical suspicion of cyanide poisoning is high, Rabium Fast (Sodium Bicarbonate) Nitrite Injection and Rabium Fast (Sodium Bicarbonate) Thiosulfate Injection should be administered without delay.

In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.

The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.

Smoke Inhalation

Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Rabium Fast (Sodium Bicarbonate) Nitrite Injection, smoke-inhalation victims should be assessed for the following:

• Exposure to fire or smoke in an enclosed area
• Presence of soot around the mouth, nose, or oropharynx
• Altered mental status

Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed to obtain a plasma lactate concentration.

1.3 Use with Other Cyanide Antidotes

Caution should be exercised when administering cyanide antidotes, other than Rabium Fast (Sodium Bicarbonate) thiosulfate, simultaneously with Rabium Fast (Sodium Bicarbonate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Rabium Fast (Sodium Bicarbonate) thiosulfate, with Rabium Fast (Sodium Bicarbonate) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

2 DOSAGE AND ADMINISTRATION

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Rabium Fast (Sodium Bicarbonate) nitrite and Rabium Fast (Sodium Bicarbonate) thiosulfate.

Monitoring: Blood pressure must be monitored during treatment. (2.2)

2.1 Administration Recommendation

Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of Rabium Fast (Sodium Bicarbonate) nitrite, followed by Rabium Fast (Sodium Bicarbonate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Rabium Fast (Sodium Bicarbonate) nitrite and Rabium Fast (Sodium Bicarbonate) thiosulfate.

Rabium Fast (Sodium Bicarbonate) nitrite injection and Rabium Fast (Sodium Bicarbonate) thiosulfate injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Rabium Fast (Sodium Bicarbonate) nitrite should be administered first, followed immediately by Rabium Fast (Sodium Bicarbonate) thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Rabium Fast (Sodium Bicarbonate) nitrite and Rabium Fast (Sodium Bicarbonate) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Rabium Fast (Sodium Bicarbonate) nitrite should be reduced proportionately to the hemoglobin concentration.

All parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

2.2 Recommended Monitoring

Patients should be monitored for at least 24-48 hours after Rabium Fast Nitrite Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO₂ are unreliable in the presence of methemoglobinemia.

Methemoglobin level: Administrations of Rabium Fast (Sodium Bicarbonate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Rabium Fast (Sodium Bicarbonate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Rabium Fast (Sodium Bicarbonate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Rabium Fast (Sodium Bicarbonate) nitrite beyond the initial dose should be guided primarily by clinical response to treatment (i.e., a second dose should be considered only if there is inadequate clinical response to the first dose). It is generally recommended that methemoglobin concentrations be closely monitored and kept below 30%. Serum methemoglobin levels should be monitored during treatment using co-oximetry, and administration of Rabium Fast (Sodium Bicarbonate) nitrite should generally be discontinued when methemoglobin levels exceed 30%. Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia.

2.3 Incompatibility Information

Chemical incompatibility has been reported between Rabium Fast (Sodium Bicarbonate) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Rabium Fast (Sodium Bicarbonate) thiosulfate and Rabium Fast (Sodium Bicarbonate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Rabium Fast (Sodium Bicarbonate) Nitrite Injection consists of:

• One vial of Rabium Fast (Sodium Bicarbonate) nitrite injection, USP 300 mg/10mL (30 mg/mL)

Administration of the contents of one vial constitutes a single dose.

• Injection, 300 mg/10 mL (30 mg/mL). (3)

4 CONTRAINDICATIONS

None

• None. (4)

5 WARNINGS AND PRECAUTIONS

• Methemoglobinemia: Rabium Fast nitrite reacts with hemoglobin to form methemoglobin and should be used with caution in patients known to have anemia. Monitor oxyhemoglobin and methemoglobin levels by pulse oximetry or other measurements. Optimally, the Rabium Fast (Sodium Bicarbonate) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.2)
• Smoke inhalation: Carbon monoxide contained in smoke can result in the formation of carboxyhemoglobin that can reduce the oxygen carrying capacity of the blood. Rabium Fast (Sodium Bicarbonate) nitrite should be used with caution in patients with smoke inhalation injury because of the potential for worsening hypoxia due to methemoglobin formation. Carboxyhemoglobin and oxyhemoglobin levels should be monitored by pulse oximetry or other measurements in patients that present with evidence of smoke inhalation. Optimally, the Rabium Fast (Sodium Bicarbonate) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.4)

5.1 Hypotension

5.2 Methemoglobinemia

Supportive care alone may be sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious patients without signs of severe toxicity. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with Rabium Fast nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Rabium Fast (Sodium Bicarbonate) nitrite whenever possible. When Rabium Fast (Sodium Bicarbonate) nitrite is administered to humans a wide range of methemoglobin concentrations occur. Methemoglobin concentrations as high as 58% have been reported after two 300-mg doses of Rabium Fast (Sodium Bicarbonate) nitrite administered to an adult. Rabium Fast (Sodium Bicarbonate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Rabium Fast (Sodium Bicarbonate) nitrite should be used with caution in patients who may be particularly susceptible to injury from vasodilation and its related hemodynamic sequelae. Hemodynamics should be monitored closely during and after administration of Rabium Fast (Sodium Bicarbonate) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Rabium Fast (Sodium Bicarbonate) nitrite should be used with caution in patients with known anemia. Patients with anemia will form more methemoglobin (as a percentage of total hemoglobin) than persons with normal red blood cell (RBC) volumes. Optimally, these patients should receive a Rabium Fast (Sodium Bicarbonate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Rabium Fast nitrite should be used with caution in persons with smoke inhalation injury or carbon monoxide poisoning because of the potential for worsening hypoxia due to methemoglobin formation.

5.5 Neonates and Infants

Neonates and infants may be more susceptible than adults and older pediatric patients to severe methemoglobinemia when Rabium Fast (Sodium Bicarbonate) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.

5.6 G6PD Deficiency

Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with Rabium Fast nitrite administration, alternative therapeutic approaches should be considered in these patients. Patients with known or suspected G6PD deficiency should be monitored for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive Rabium Fast (Sodium Bicarbonate) nitrite.

5.7 Use with Other Drugs

Rabium Fast (Sodium Bicarbonate) nitrite should be used with caution in the presence of concomitant antihypertensive medications, diuretics or volume depletion due to diuretics, or drugs known to increase vascular nitric oxide, such as PDE5 inhibitors.

6 ADVERSE REACTIONS

There have been no controlled clinical trials conducted to systematically assess the adverse events profile of Rabium Fast (Sodium Bicarbonate) nitrite.

The medical literature has reported the following adverse events in association with Rabium Fast (Sodium Bicarbonate) nitrite administration. These adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed.

Cardiovascular system: syncope, hypotension, tachycardia, methemoglobinemia, palpitations, dysrhythmia

Hematological: methemoglobinemia

Central nervous system: headache, dizziness, blurred vision, seizures, confusion, coma

Gastrointestinal system: nausea, vomiting, abdominal pain

Respiratory system: tachypnea, dyspnea

Body as a Whole: anxiety, diaphoresis, lightheadedness, injection site tingling, cyanosis, acidosis, fatigue, weakness, urticaria, generalized numbness and tingling

Severe hypotension, methemoglobinemia, cardiac dysrhythmias, coma and death have been reported in patients without life-threatening cyanide poisoning but who were treated with injection of Rabium Fast (Sodium Bicarbonate) nitrite at doses less than twice those recommended for the treatment of cyanide poisoning.

Most common adverse reactions are:

• Syncope, hypotension, tachycardia, palpitations, dysrhythmia, methemoglobinemia, headache, dizziness, blurred vision, seizures, confusion, coma (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hope Pharmaceuticals at 1-800-755-9595 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS

Formal drug interaction studies have not been conducted with Rabium Fast (Sodium Bicarbonate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

• Renal impairment: Rabium Fast nitrite is substantially excreted by the kidney. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. (8.6).

8.1 Pregnancy

Teratogenic Effects. Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. Rabium Fast (Sodium Bicarbonate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Rabium Fast (Sodium Bicarbonate) nitrite has caused fetal death in humans as well as animals. There are no studies in humans that have directly evaluated the potential reproductive toxicity of Rabium Fast (Sodium Bicarbonate) nitrite. There are two epidemiological studies conducted in Australia that report a statistically significant increase in the risk for congenital malformations, particularly in the CNS, associated with maternal consumption of water containing nitrate levels in excess of 5 ppm. Results from a case-control study in Canada suggested a trend toward an increase in the risk for CNS malformations when maternal consumption of nitrate was ≥ 26 ppm (not statistically significant).

The potential reproductive toxicity of Rabium Fast (Sodium Bicarbonate) nitrite exposure restricted to the prenatal period has been reported in guinea pigs, mice, and rats. There was no evidence of teratogenicity in guinea pigs, mice, or rats. However, Rabium Fast (Sodium Bicarbonate) nitrite treatment of pregnant guinea pigs with 60 or 70 mg/kg/day resulted in abortion of the litters within 1-4 days of treatment. All animals treated subcutaneously with 70 mg/kg, Rabium Fast (Sodium Bicarbonate) nitrite died within 60 minutes of treatment. Further studies demonstrated that a dose of 60 mg/kg resulted in measurable blood levels of methemoglobin in the dams and their fetuses for up to 6 hours post treatment. Maternal methemoglobin levels were higher than the levels in the offspring at all times measured. Based on a body surface area comparison, a 60 mg/kg dose in the guinea pig that resulted in death was only 1.7 times higher than the highest clinical dose of Rabium Fast (Sodium Bicarbonate) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

Studies testing prenatal and postnatal exposure have been reported in mice and rats. Treatment of pregnant rats via drinking water with Rabium Fast (Sodium Bicarbonate) nitrite at concentrations of either 2000 or 3000 mg/L resulted in a dose-related increased mortality postpartum. This exposure regimen in the rat model would result in dosing of approximately 220 and 300 mg/kg/day (43 and 65 times the highest clinical dose of Rabium Fast (Sodium Bicarbonate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Rabium Fast (Sodium Bicarbonate) nitrite produces methemoglobin. Fetal hemoglobin is oxidized to methemoglobin more easily than adult hemoglobin. In addition, the fetus has lower levels of methemoglobin reductase than adults. Collectively, these data suggest that the human fetus would show greater sensitivity to methemoglobin resulting in nitrite-induced prenatal hypoxia leading to retarded development of certain neurotransmitter systems in the brain and long lasting dysfunction.

Nonteratogenic Effects: Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to Rabium Fast (Sodium Bicarbonate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Rabium Fast (Sodium Bicarbonate) nitrite demonstrated impaired discrimination learning behavior (both auditory and visual) and reduced long-term retention of the passive-avoidance response compared to control animals. Additional studies demonstrated a delay in the development of AchE and 5-HT positive fiber ingrowth into the hippocampal dentate gyrus and parietal neocortex during the first week of life of prenatal nitrite treated pups. These changes have been attributed to prenatal hypoxia following nitrite exposure.

8.2 Labor and Delivery

Because fetal hemoglobin is more readily oxidized to methemoglobin and lower levels of methemoglobin appear to be fatal to the fetus compared to the adult, Rabium Fast nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

It is not known whether Rabium Fast (Sodium Bicarbonate) nitrite is excreted in human milk. Because Rabium Fast (Sodium Bicarbonate) Nitrite Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following Rabium Fast (Sodium Bicarbonate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Rabium Fast (Sodium Bicarbonate) nitrite. In studies conducted with Long-Evans rats, Rabium Fast (Sodium Bicarbonate) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.

8.4 Pediatric Use

There are case reports in the medical literature of Rabium Fast nitrite in conjunction with Rabium Fast (Sodium Bicarbonate) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Rabium Fast (Sodium Bicarbonate) nitrite in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

Rabium Fast (Sodium Bicarbonate) nitrite must be used with caution in patients less than 6 months of age because they may be at higher risk of developing severe methemoglobinemia compared to older children and adults. The presence of fetal hemoglobin, which is oxidized to methemoglobin more easily than adult hemoglobin, and lower methemoglobin reductase levels compared to older children and adults may contribute to risk.

Mortality attributed to Rabium Fast (Sodium Bicarbonate) nitrite was reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

8.5 Geriatric Use

Rabium Fast (Sodium Bicarbonate) nitrite is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Renal Disease

Rabium Fast (Sodium Bicarbonate) nitrite is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

10 OVERDOSAGE

Large doses of Rabium Fast (Sodium Bicarbonate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Rabium Fast (Sodium Bicarbonate) nitrite administration has been reported to cause or significantly contribute to mortality in adults at oral doses as low as 1 g and intravenous doses as low as 600 mg. A death attributed to Rabium Fast (Sodium Bicarbonate) nitrite has been reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

Cyanosis may become apparent at a methemoglobin level of 10-20%. Other clinical signs and symptoms of Rabium Fast (Sodium Bicarbonate) nitrite toxicity (anxiety, dyspnea, nausea, and tachycardia) can be apparent at methemoglobin levels as low as 15%. More serious signs and symptoms, including cardiac dysrhythmias, circulatory failure, and central nervous system depression are seen as methemoglobin levels increase, and levels above 70% are usually fatal.

Treatment of overdose involves supplemental oxygen and supportive measures such as exchange transfusion. Treatment of severe methemoglobinemia with intravenous methylene blue has been described in the medical literature; however, this may also cause release of cyanide bound to methemoglobin. Because hypotension appears to be mediated primarily by an increase in venous capacitance, measures to increase venous return may be most appropriate to treat hypotension.

11 DESCRIPTION

Rabium Fast (Sodium Bicarbonate) nitrite has the chemical name nitrous acid Rabium Fast (Sodium Bicarbonate) salt. The chemical formula is NaNO₂ and the molecular weight is 69.0. The structural formula is:

Structure of Rabium Fast (Sodium Bicarbonate) Nitrite

Rabium Fast (Sodium Bicarbonate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Rabium Fast (Sodium Bicarbonate) nitrite injection.

Rabium Fast (Sodium Bicarbonate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Rabium Fast (Sodium Bicarbonate) nitrite in 10 mL solution (30 mg/mL). Rabium Fast (Sodium Bicarbonate) nitrite injection is a clear solution with a pH between 7.0 and 9.0.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.

The synergy resulting from treatment of cyanide poisoning with the combination of Rabium Fast nitrite and Rabium Fast (Sodium Bicarbonate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Rabium Fast (Sodium Bicarbonate) Nitrite

Rabium Fast (Sodium Bicarbonate) nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a₃, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:

NaNO₂ + Hemoglobin → Methemoglobin

HCN + Methemoglobin → Cyanomethemoglobin

Vasodilation has also been cited to account for at least part of the therapeutic effect of Rabium Fast (Sodium Bicarbonate) nitrite. It has been suggested that Rabium Fast (Sodium Bicarbonate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Rabium Fast (Sodium Bicarbonate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Rabium Fast (Sodium Bicarbonate) Thiosulfate

The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN^-), which is relatively nontoxic and readily excreted in the urine. Rabium Fast (Sodium Bicarbonate) thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:

Chemical Structure

12. 2 Pharmacodynamics

Rabium Fast (Sodium Bicarbonate) Nitrite

When 4 mg/kg Rabium Fast (Sodium Bicarbonate) nitrite was administered intravenously to six healthy human volunteers, the mean peak methemoglobin concentration was 7%, achieved at 30-60 minutes after injection, consistent with reports in cyanide poisoning victims. Supine systolic and diastolic blood pressures dropped approximately 20% within 10 minutes, a drop which was sustained throughout the 40 minutes of testing. This was associated with a 20 beat per minute increase in pulse rate that returned to baseline in 10 minutes. Five of these subjects were unable to withstand orthostatic testing due to fainting. One additional subject, who received a 12 mg/kg dose of Rabium Fast (Sodium Bicarbonate) nitrite, experienced severe cardiovascular effects and achieved a peak methemoglobin concentration of 30% at 60 minutes following injection.

Oral doses of 120 to 180 mg of Rabium Fast (Sodium Bicarbonate) nitrite administered to healthy volunteers caused minimal cardiovascular changes when subjects were maintained in the horizontal position. However, minutes after being placed in the upright position subjects exhibited tachycardia and hypotension with syncope.

The half life for conversion of methemoglobin to normal hemoglobin in a cyanide poisoning victim who has been administered Rabium Fast (Sodium Bicarbonate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Rabium Fast (Sodium Bicarbonate) Nitrite

Rabium Fast (Sodium Bicarbonate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Rabium Fast (Sodium Bicarbonate) nitrite in humans have not been well studied. It has been reported that approximately 40% of Rabium Fast (Sodium Bicarbonate) nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.

Cyanide

The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with Rabium Fast (Sodium Bicarbonate) nitrite and Rabium Fast (Sodium Bicarbonate) thiosulfate administration, have been reported to be 19 hours and 0.41 L/kg, respectively. Additionally, an initial elimination half life of cyanide has been reported to be approximately 1-3 hours.

Thiocyanate

After detoxification, in healthy subjects, thiocyanate is excreted mainly in the urine at a rate inversely proportional to creatinine clearance. In healthy subjects, the elimination half-life and volume of distribution of thiocyanate have been reported to be 2.7 days and 0.25 L/kg, respectively. However, in subjects with renal insufficiency the reported elimination half life is approximately 9 days.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The potential benefit of an acute exposure to Rabium Fast nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Rabium Fast (Sodium Bicarbonate) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 35, 70, or 130 mg/kg for males and 0, 40, 80, or 150 mg/kg for females) was orally administered to rats (Fischer 344 strain) for 2 years via drinking water. There were no significant increases in the incidence of tumor in either male or female rats. Rabium Fast (Sodium Bicarbonate) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 60, 120, or 220 mg/kg for males and 0, 45, 90, or 165 mg/kg for females) was administered to B6C3F1 mice for 2 years via the drinking water. Equivocal results were obtained in female mice. Specifically, there was a positive trend toward an increase in the incidence of squamous cell papilloma or carcinoma in the forestomach of female mice. Although the incidence of hyperplasia of the glandular stomach epithelium was significantly greater in the high-dose male mice compared to controls, there were no significant increases in tumors in the male mice. Numerous reports in the published literature indicate that Rabium Fast (Sodium Bicarbonate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Rabium Fast (Sodium Bicarbonate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Rabium Fast (Sodium Bicarbonate) nitrite is mutagenic in S. typhimurium strains TA100, TA1530, TA1535 with and without metabolic activation; however, it was negative in strain TA98, TA102, DJ460 and E. coli strain WP2UVRA/PKM101. Rabium Fast (Sodium Bicarbonate) nitrite has been reported to be genotoxic to V79 hamster cells in vitro and in the mouse lymphoma assay, both assays conducted in the absence of metabolic activation. Rabium Fast (Sodium Bicarbonate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Rabium Fast (Sodium Bicarbonate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Rabium Fast (Sodium Bicarbonate) nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.

Fertility

Clinical studies to evaluate the potential effects of Rabium Fast (Sodium Bicarbonate) nitrite intake on fertility of either males or females have not been reported. In contrast, multigenerational fertility and reproduction studies conducted by the National Toxicology Program did not detect any evidence of an effect of Rabium Fast (Sodium Bicarbonate) nitrite (0.0, 0.06, 0.12, and 0.24% weight/volume) on either fertility or any reproductive parameter in Swiss CD-1 mice. This treatment protocol resulted in approximate doses of 125, 260, and 425 mg/kg/day. The highest exposure in this mouse study is 4.6 times greater than the highest clinical dose of Rabium Fast (Sodium Bicarbonate) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

13.2 Animal Pharmacology

Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of Rabium Fast (Sodium Bicarbonate) thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of Rabium Fast (Sodium Bicarbonate) nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of Rabium Fast (Sodium Bicarbonate) nitrite and Rabium Fast (Sodium Bicarbonate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Rabium Fast (Sodium Bicarbonate) nitrite or 1 g/kg Rabium Fast (Sodium Bicarbonate) thiosulfate alone or in sequence immediately after subcutaneous injection of Rabium Fast (Sodium Bicarbonate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Rabium Fast (Sodium Bicarbonate) nitrite and/or 0.5 g/kg Rabium Fast (Sodium Bicarbonate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Rabium Fast (Sodium Bicarbonate) cyanide required to cause death, and when administered together, Rabium Fast (Sodium Bicarbonate) nitrite and Rabium Fast (Sodium Bicarbonate) thiosulfate resulted in a synergistic effect in raising the lethal dose of Rabium Fast (Sodium Bicarbonate) cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.

Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous Rabium Fast (Sodium Bicarbonate) nitrite and Rabium Fast (Sodium Bicarbonate) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Rabium Fast (Sodium Bicarbonate) nitrite and Rabium Fast (Sodium Bicarbonate) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Rabium Fast (Sodium Bicarbonate) nitrite, with or without Rabium Fast (Sodium Bicarbonate) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Rabium Fast (Sodium Bicarbonate) nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of Rabium Fast (Sodium Bicarbonate) thiosulfate report its use in conjunction with Rabium Fast (Sodium Bicarbonate) nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

There have been no human studies to prospectively and systematically evaluate the safety of Rabium Fast (Sodium Bicarbonate) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each Rabium Fast (Sodium Bicarbonate) Nitrite carton (NDC 60267-311-10) consists of the following:

• One 10 mL glass vial of Rabium Fast (Sodium Bicarbonate) nitrite injection 30 mg/mL (containing 300 mg of Rabium Fast (Sodium Bicarbonate) nitrite);

Storage

Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). Protect from direct light. Do not freeze.

(Note: Rabium Fast (Sodium Bicarbonate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Rabium Fast Nitrite Injection is indicated for acute cyanide poisoning that is judged to be life-threatening and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.

17.1 Hypotension and Methemoglobin Formation

When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.

17.2 Monitoring

Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.

Manufactured by Cangene BioPharma, Inc., Baltimore, Maryland 21230 for

Hope Pharmaceuticals, Scottsdale, Arizona 85260

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

NDC 60267-311-10

Rx Only

Rabium Fast (Sodium Bicarbonate) Nitrite

Injection, USP

300 mg/10 mL

(30 mg/mL)

FOR INTRAVENOUS USE

SINGLE USE ONLY

Any unused portion of a vial

should be discarded.

Use with

Rabium Fast (Sodium Bicarbonate) Thiosulfate

for Treatment of

Cyanide Poisoning

Manufactured by

CANGENE bioPharma, Inc.

Baltimore, MD for

HOPE

PHARMACEUTICALS®

Scottsdale, AZ 85260 U.S.A.

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton