1.ACIPHEX HISTORY
(How was Aciphex discovered?)

Aciphex is a product of Eisai Inc.

Aciphex is a new proton pump inhibitor (Rabeprazole sodium) was approved for marketing in the US by the FDA on August 19,1999.

Aciphex was approved for the treatment of erosive or ulcerative gastroesophageal reflux disease (GERD), duodenal ulcer, and pathological hypersecretory conditions, including Zollinger-Ellison syndrome.

Note: World-drugs.net sells generic version of Aciphex

2.ACIPHEX FACTS

Eisai Inc. is supported by a strong parent company, Eisai Co., Ltd., which was founded in Japan in 1941 as Nihon Eisai Co., Ltd. To this day, Eisai Co., Ltd. is one of the few Japanese pharmaceutical companies to undertake aggressive global expansion through substantial infrastructure investments in its foreign affiliates.

Eisai Inc. is a U.S. pharmaceutical subsidiary of Tokyo-based Eisai Co., Ltd. Established in 1995, Eisai Inc. began marketing its first product in the United States in 1997 and has rapidly grown to become an integrated pharmaceutical business with sales of more than $1.7 billion in fiscal year 2003 (year ending March 31, 2004).

3.ABOUT ACIPHEX MEDICATION

What Is GERD?

GERD stands for Gastro Esophageal Reflux Disease. "Gastro" refers to the stomach. Esophageal refers to the esophagus, the tube that carries food from the mouth to the stomach. Reflux means to back-up or flow backwards. GERD is a condition in which acid; bile and partially digested food in the stomach back up into the esophagus.

 

• Partially digested food contains a strong acid. It also contains powerful enzymes that break down food. When acid and enzymes come into contact with the esophagus, they cause irritation, inflammation, pain, and other symptoms.

• The stomach lining has a special protective layer that protects the stomach from acid attack. However, this protective layer does not exist in the esophagus, making it vulnerable to damage from stomach acid and digestive enzymes

 

• Many people think that heartburn (or acid indigestion) is a separate disease. It actually is one symptom of GERD. Heartburn is an unpleasant burning sensation behind the breastbone that usually occurs after a meal.

• Most individuals with GERD also have hiatal hernias, which make it easier for stomach contents to reflux into the esophagus. A hiatal hernia occurs when part of the stomach bulges into the chest cavity through an opening in the diaphragm (hiatus). The diaphragm is a sheet of muscle that separates the stomach cavity from the chest cavity.

 

What are the symptoms of GERD?

Heartburn is the most common symptom of GERD. It feels like a burning chest pain right behind the breastbone. Pain may move upward toward the throat. It often is worse after meals. Bending over or lying down also may make heartburn worse. Standing up may bring relief. Heartburn often occurs after going to bed at night.

Other GERD symptoms include:

• Burping-up, or regurgitation, of sour-tasting, acidy material into the mouth.
• Difficult or painful swallowing.
• Sore throat, hoarseness, and/or cough.
• Wheezing in people with asthma.

GERD also occurs in young children who may have the same symptoms as adults but cannot describe them. The only noticeable symptoms in infants and children may be vomiting, coughing, wheezing or other respiratory problems, and failure to gain weight normally.

What Causes GERD?

GERD occurs when a muscle at the lower end of the esophagus does not work properly. The muscle is called the lower esophageal sphincter (LES). Sphincters are ring-like bands of muscle that contract, or squeeze together, to close off body passageways. The body has many sphincters. Perhaps the most familiar is the anal sphincter, which seals off the rectum between bowel movements.

The LES acts like a one-way valve that closes off the esophagus. It allows food to travel freely downward into the stomach. But it also seals off the stomach, preventing partially digested food from refluxing, or passing back up, through the esophagus.

Normally, the LES closes immediately after a person swallows food, keeping irritating stomach acid and digestive enzymes out of the esophagus.

In individuals with GERD, the LES may not close in a normal way or relaxes inappropriately between swallows. Stomach juices and partially digested food may flow back up and burn the lower esophagus. The result is heartburn and other symptoms of GERD.

Treating Acid Reflux Disease

There is a range of treatment options for acid reflux disease and associated symptoms. It's best to talk to your doctor about which treatment might work best for you.

Antacids are available without a prescription (over-the-counter, or "OTC") and are used primarily for heartburn. Typically, they can provide limited, short-term relief. If you are experiencing heartburn two or more days a week, even though you've tried some over-the-counter treatments and changed your diet, it may be a sign of something more serious, and you should talk to your doctor.

H2 blockers are available over-the-counter and by prescription. They get their name from the way they block one particular stimulus of acid production. H2 blockers reduce the amount of acid that is produced in the stomach, but not as much as proton pump inhibitors. If you continue to suffer from heartburn while you are taking an H2 blocker, you should see your doctor. Your doctor may develop a different treatment plan.

Proton pump inhibitors (PPIs) are available by prescription. PPIs block the final stage of acid production. They are very effective and can relieve symptoms in most people who have acid reflux disease.

Aciphex contains the active ingredient rabeprazole sodium, which is a type of medicine known as a proton pump inhibitor. Aciphex acts in the stomach to decrease the production of stomach acid.

Proton pumps are found on cells that line the stomach, and are used by these cells to produce stomach acid. Aciphex works by inhibiting the action of the proton pumps, and this reduces the production of stomach acid.

By reducing the amount of acid in the stomach and duodenum, Aciphex allows peptic ulcers to heal and stops excess acid flowing back into the food pipe and can be used to treat gastro-oesophageal reflux disease (GORD).

4.ACIPHEX EFFECTIVENESS
(When is Aciphex best taken?)

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

Absorption

Absolute bioavailability for a 20 mg oral tablet of Aciphex is approximately 52%. When Aciphex is administered with a high fat meal, its Tmax is variable and may delay its absorption up to 4 hours or longer, however, the Cmax and the extent of Aciphex absorption (AUC) are not significantly altered. Thus Aciphex may be taken without regard to timing of meals.

Distribution

Aciphex is 96.3% bound to human plasma proteins

Metabolism

Aciphex is extensively metabolized. 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 Aciphex is metabolized in the liver primarily by cytochromes P450 3A (CYP3A) to a sulphone metabolite and cytochrome P450 2C19 (CYP2C19) to desmethyl Aciphex. The thioether metabolite is formed non-enzymatically by reduction of Aciphex. 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). Aciphex 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 Aciphex, 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 of Aciphex was recovered in the feces. Total recovery of radioactivity was 99.8%. No unchanged Aciphex was recovered in the urine or feces. 

5.ACIPHEX EFFECTS ON SPECIAL POPULATION
(How do different people react to Aciphex?)

Geriatric
In 20 healthy elderly subjects administered 20 mg Aciphex once daily for seven days, AUC values approximately doubled and the Cmax increased by 60% compared to values in a parallel younger control group. There was no evidence of drug accumulation after once daily administration.

Pediatric
The pharmacokinetics of Aciphex in pediatric patients under the age of 18 years has not been studied.

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

6.ACIPHEX EFFECTS ON MEDICAL CONDITIONS
(How does Aciphex affect your existing condition/ailment?)

Renal Disease
In 10 patients with stable end-stage renal disease requiring maintenance hemodialysis, no clinically significant differences were observed in the pharmacokinetics after a single 20 mg oral dose of Aciphex when compared to 10 healthy volunteers.

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 Aciphex, AUC0-24 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 dose of Aciphex once daily for eight days, AUC0-8 and Cmax values increased approximately 20% compared to values in healthy age- and gender-matched subjects. These increases were not statistically significant.

No information exists on Aciphex disposition in patients with severe hepatic impairment.

7.OTHER/ALTERNATE USES OF ACIPHEX
(What else does Aciphex treat?)

Aciphex is also given together with antibiotics to help eradicate bacteria called Helicobacter pylori from the stomach. These bacteria can contribute to the formation of peptic ulcers.

Aciphex helps create an environment in the gut in which the antibiotics can be more effective at killing the bacteria.

8.ADVERSE/SIDE EFFECTS of ACIPHEX
(What are the side effects of Aciphex?)

Worldwide, over 2900 patients have been treated with Aciphex in Phase II-III clinical trials involving various dosages and durations of treatment. In general, Aciphex treatment has been well tolerated in both short-term and long-term trials. The adverse events rates were generally similar between the 10 and 20 mg doses.

Incidence in Controlled North American and European Clinical Trials

In an analysis of adverse events assessed as possibly or probably related to treatment appearing in greater than 1% of Aciphex patients and appearing with greater frequency than placebo in controlled North American and European trials, the incidence of headache was 2.4% (n=1552) for Aciphex versus 1.6% (n=258) for placebo. In short and long-term studies, the following adverse events, regardless of causality, were reported in Aciphex treated patients. Rare events are those reported in <1/1000 patients.

Body as a Whole: asthenia, fever, allergic reaction, chills, malaise, chest pain substernal, neck rigidity, photosensitivity reaction. Rare: abdomen enlarged, face edema, hangover effect.

Cardiovascular System: hypertension, myocardial infarct, electrocardiogram abnormal, migraine, syncope, angina pectoris, bundle branch block, palpitation, sinus bradycardia, tachycardia. Rare: bradycardia, pulmonary embolus, supraventricular tachycardia, thrombophlebitis, vasodilation, QTC prolongation and ventricular tachycardia.

Digestive System: diarrhea, nausea, abdominal pain, vomiting, dyspepsia, flatulence, constipation, dry mouth, eructation, gastroenteritis, rectal hemorrhage, melena, anorexia, cholelithiasis, mouth ulceration, stomatitis, dysphagia, gingivitis, cholecystitis, increased appetite, abnormal stools, colitis, esophagitis, glossitis, pancreatitis, proctitis. Rare: bloody diarrhea, cholangitis, duodenitis, gastrointestinal hemorrhage, hepatic encephalopathy, hepatitis, hepatoma, liver fatty deposit, salivary gland enlargement, thirst.

Endocrine System: hyperthyroidism, hypothyroidism.

Hemic & Lymphatic System: anemia, ecchymosis, lymphadenopathy, hypochromic anemia. Metabolic & Nutritional Disorders: peripheral edema, edema, weight gain, gout, dehydration, weight loss.

Musculo-Skeletal System: myalgia, arthritis, leg cramps, bone pain, arthrosis, bursitis. Rare: twitching.

Nervous System: insomnia, anxiety, dizziness, depression, nervousness, somnolence, hypertonia, neuralgia, vertigo, convulsion, abnormal dreams, libido decreased, neuropathy, paresthesia, tremor. Rare: agitation, amnesia, confusion, extrapyramidal syndrome, hyperkinesia.

Respiratory System: dyspnea, asthma, epistaxis, laryngitis, hiccup, hyperventilation. Rare: apnea, hypoventilation.

Skin and Appendages: rash, pruritus, sweating, urticaria, alopecia. Rare: dry skin, herpes zoster, psoriasis, skin discoloration.

Special Senses: cataract, amblyopia, glaucoma, dry eyes, abnormal vision, tinnitus, otitis media. Rare: corneal opacity, blurry vision, diplopia, deafness, eye pain, retinal degeneration, strabismus.

Urogenital System: cystitis, urinary frequency, dysmenorrhea, dysuria, kidney calculus, metrorrhagia, polyuria. Rare: breast enlargement, hematuria, impotence, leukorrhea, menorrhagia, orchitis, urinary incontinence.

Laboratory Values: The following changes in laboratory parameters were reported as adverse events: abnormal platelets, albuminuria, creatine phosphokinase increased, erythrocytes abnormal, hypercholesteremia, hyperglycemia, hyperlipemia, hypokalemia, hyponatremia, leukocytosis, leukorrhea, liver function tests abnormal, prostatic specific antigen increase, SGPT increased, urine abnormality, WBC abnormal.

In controlled clinical studies, 3/1456 (0.2%) patients treated with rabeprazole and 2/237 (0.8%) patients treated with placebo developed treatment-emergent abnormalities (which were either new on study or present at study entry with an increase of 1.25 x baseline value) in SGOT (AST), SGPT (ALT), or both. None of the three Aciphex patients experienced chills, fever, right upper quadrant pain, nausea or jaundice.

Combination Treatment with Amoxicillin and Clarithromycin: In clinical trials using combination therapy with Aciphex plus amoxicillin and clarithromycin (RAC), no adverse events unique to this drug combination were observed. In the U.S. multicenter study, the most frequently reported drug related adverse events 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.

Post-Marketing Adverse Events:

Additional adverse events reported from worldwide marketing experience with Aciphex sodium are: 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 most instances, the relationship to rabeprazole sodium was unclear. 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.