İHALE DÜNYASI
İHALE DÜNYASI
The active ingredient in ACIPHEX Delayed-Release Tablets is rabeprazole sodium, a substituted benzimidazole that inhibits gastric acid secretion. Rabeprazole sodium is known chemically as 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]sulfinyl]-1 H- benzimidazole sodium salt. It has an empirical formula of C 18 H 20 N 3 NaO 3 S and a molecular weight of 381.43. 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 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: ACIPHEX is available for oral administration as delayed-release, enteric-coated tablets containing 20 mg of 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. image of chemical structure
Enter section text here ACIPHEX is a proton-pump inhibitor indicated 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 ) ACIPHEX 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 ACIPHEX 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 ACIPHEX may be considered. 1.2 Maintenance of Healing of Erosive of Ulcerative GERD ACIPHEX 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 ACIPHEX 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 ACIPHEX 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 ACIPHEX 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 ACIPHEX is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome.
ACIPHEX tablets should be swallowed whole. The tablets should not be chewed, crushed, or split. ACIPHEX can be taken with or without food. ACIPHEX tablets should be swallowed whole. The tablets should not be chewed, crushed or split. Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD) ( 2.1 ) 20 mg once daily Maintenance of Healing of Erosive or Ulcerative GERD ( 2.2 ) 20 mg once daily Treatment of Symptomatic GERD ( 2.3 ) 20 mg once daily Healing of Duodenal Ulcers ( 2.4 ) 20 mg once daily after morning meal Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence ( 2.5 ) Three Drug Regimen All three medications should be taken twice daily with morning and evening meals for 7 days : ACIPHEX 20 mg Amoxicillin 1000 mg Clarithromycin 500 mg Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome ( 2.6 ) Starting dose 60 mg once daily then adjust to patient needs Short-term Treatment of GERD in Adolescent Patients 12 Years of Age and Above ( 2.7 ) 20 mg once daily for up to 8 weeks 2.1 Healing of Erosive or Ulcerative GERD The recommended adult oral dose is one ACIPHEX 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 ACIPHEX may be considered. 2.2 Maintenance of Healing of Erosive or Ulcerative GERD The recommended adult oral dose is one ACIPHEX 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 ACIPHEX 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 ACIPHEX 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 TABLE 1 THREE DRUG REGIMEN a : Aciphex 20 mg Twice Daily for 7 Days Amoxicillin 1000 mg Twice Daily for 7 Days Clarithromycin 500 mg Twice Daily for 7 Days All three medications should be taken twice daily with the morning and evening meals. a It is important that patients comply with the full 7-day regimen. {See CLINICAL STUDIES section.(14.5)}. 2.6 Treatment of Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome The dosage of ACIPHEX 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 ACIPHEX 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 rabeprazole to patients with mild to moderate liver impairment resulted in increased exposure and decreased elimination. Due to the lack of clinical data on rabeprazole in patients with severe hepatic impairment, caution should be exercised in those patients.
Enter section text here History of hypersensitivity to rabeprazole ( 4.1 ) 4.1 Hypersensitivity to rabeprazole Rabeprazole is contraindicated in patients with known hypersensitivity to rabeprazole, substituted benzimidazoles or to any component of the formulation. 4.2 Use of clarithromycin and hypersentivity 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 (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsade de pointes) 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 penicilllin Amoxicillin is contraindicated in patients with a known hypersensitivity to any penicillin. (Please refer to full prescribing information for amoxicillin.)
Worldwide, over 2900 patients have been treated with rabeprazole 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 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Studies Experience The data described below reflect exposure to ACIPHEX 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 ACIPHEX. An analysis of adverse reactions appearing in ? 2% of ACIPHEX 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 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 ACIPHEX, respectively, while 169 (23%) patients received placebo and 83 (11%) received omeprazole. The safety profile of rabeprazole in the maintenance studies was consistent with what was observed in the acute studies Other adverse events that were seen in controlled clinical trials which do not meet the above criteria (?2% of ACIPHEX treated patients and > placebo) and for which there is a possibility of a causal relationship to 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 ACIPHEX 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 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 ACIPHEX. 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 and 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; and TSH elevations. 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.
Enter section text here Symptomatic response to therapy with rabeprazole 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 ) 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 (anaphylactic) 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 rabeprazole does not preclude the presence of gastric malignancy. Patients with healed GERD were treated for up to 40 months with 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 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.
Enter section text here Increase INR and prothrombin times have been reported with concomitant use with warfarin. Patients need to be monitored ( 7.2 ) Rabeprazole has been shown to inhibit cyclosporine metabolism in vitro ( 7.3 ) ACIPHEX 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 ) ACIPHEX may reduce the plasma levels of atazanavir ( 7.4 ) 7.1 Drugs metabolized by CYP450 Rabeprazole is metabolized by the cytochrome P450 (CYP450) drug metabolizing enzyme system. Studies in healthy subjects have shown that 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 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 rabeprazole, 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 rabeprazole inhibited cyclosporine metabolism with an IC 50 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 rabeprazole. This degree of inhibition is similar to that by omeprazole at equivalent concentrations. 7.4 Compounds dependent on gastric pH for absorption Rabeprazole 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 rabeprazole. For example, in normal subjects, co-administration of 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 rabeprazole. Co-administration of rabeprazole and antacids produced no clinically relevant changes in plasma 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 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 rabeprazole plasma levels in poor metabolizers. Whether or not interactions of 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 rabeprazole, amoxicillin, and clarithromycin resulted in increases in plasma concentrations of rabeprazole and 14-hydroxyclarithromycin.{See CLINICAL PHARMACOLOGY, Combined Administration 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.)