Zolufen

The active ingredient in Zolufen is a substituted benzimidazole. (RS)-5-methoxy-2(4-methoxy-3,5-dimethyl-2-pyridylmethylsulphinyl) benzimidazole, a compound that inhibits gastric acid secretion. Its empirical formula is C₁₇H₁₉N₃O₃S, with a molecular weight of 345.42. Zolufen is a white to off-white crystalline powder which melts with decomposition at about 155°C. It is a weak base, freely soluble in ethanol and methanol, and slightly soluble in acetone and isopropanol and very slightly soluble in water. The stability of Zolufen is a function of pH; it is rapidly degraded in acid media, but has acceptable stability under alkaline conditions.

Zolufen is a proton pump inhibitor. It inhibits secretion of gastric acid by irreversibly blocking the enzyme system of hydrogen/potassium adenosine triphosphatase (H⁺/K⁺ ATPase), the "proton pump" of the gastric parietal cell. It is used in conditions where inhibition of gastric acid secretion may be beneficial, including aspiration syndromes, dyspepsia, gastro-esophageal reflux disease, peptic ulcer disease and the Zollinger-Ellison syndrome.

Duodenal Ulcer (adults)

Zolufen is indicated for short-term treatment of active duodenal ulcer in adults. Most patients heal within four weeks. Some patients may require an additional four weeks of therapy.

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

Zolufen in combination with clarithromycin is indicated for treatment of patients with H. pylori infection and duodenal ulcer disease to eradicate H. pylori in adults.

Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.

Among patients who fail therapy, Zolufen with clarithromycin is more likely to be associated with the development of clarithromycin resistance as compared with triple therapy. In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted, and the clarithromycin package insert, Microbiology section.

Gastric Ulcer (Adults)

Zolufen is indicated for short-term treatment (4-8 weeks) of active benign gastric ulcer in adults.

Treatment Of Gastroesophageal Reflux Disease (GERD) (Adults and Pediatric Patients)

Symptomatic GERD

Zolufen is indicated for the treatment of heartburn and other symptoms associated with GERD in pediatric patients and adults for up to 4 weeks.

Erosive Esophagitis

Zolufen is indicated for the short-term treatment (4-8 weeks) of erosive esophagitis that has been diagnosed by endoscopy in pediatric patients and adults.

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

Maintenance Of Healing Of Erosive Esophagitis (Adults and Pediatric Patients)

Zolufen is indicated to maintain healing of erosive esophagitis in pediatric patients and adults.

Controlled studies do not extend beyond 12 months.

Pathological Hypersecretory Conditions (Adults)

Zolufen is indicated for the long-term treatment of pathological hypersecretory conditions (eg, Zollinger-Ellison syndrome, multiple endocrine adenomas and systemic mastocytosis) in adults.

Zolufen + SyrSpend SF Alka is a proton pump inhibitor that decreases the amount of acid produced in the stomach.

Zolufen + SyrSpend SF Alka is used to treat symptoms of gastroesophageal reflux disease (GERD) and other conditions caused by excess stomach acid. Zolufen + SyrSpend SF Alka is also used to promote healing of erosive esophagitis (damage to your esophagus caused by stomach acid).

Zolufen + SyrSpend SF Alka may also be given together with antibiotics to treat gastric ulcer caused by infection with Helicobacter pylori (H. pylori).

Over-the-counter (OTC) Zolufen + SyrSpend SF Alka is used to help control heartburn that occurs 2 or more days per week. Zolufen + SyrSpend SF Alka + SyrSpend SF Alka not for immediate relief of heartburn symptoms. OTC Zolufen + SyrSpend SF Alka must be taken on a regular basis for 14 days in a row.

Zolufen + SyrSpend SF Alka may also be used for purposes not listed in this medication guide.

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

Patients should be informed that the Zolufen Delayed-Release Capsule should be swallowed whole.

For patients unable to swallow an intact capsule, alternative administration options are available.

Short-Term Treatment Of Active Duodenal Ulcer

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

H. pylori Eradication For The Reduction Of The Risk Of Duodenal Ulcer Recurrence

Triple Therapy (Zolufen/clarithromycin/amoxicillin)

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

Dual Therapy (Zolufen/clarithromycin)

The recommended adult oral regimen is Zolufen 40 mg once daily plus clarithromycin 500 mg three times daily for 14 days. In patients with an ulcer present at the time of initiation of therapy, an additional 14 days of Zolufen 20 mg once daily is recommended for ulcer healing and symptom relief.

Gastric Ulcer

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

Gastroesophageal Reflux Disease (GERD)

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

Maintenance Of Healing Of Erosive Esophagitis

The recommended adult oral dose is 20 mg daily. Controlled studies do not extend beyond 12 months.

Pathological Hypersecretory Conditions

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

Pediatric Patients

For the treatment of GERD and maintenance of healing of erosive esophagitis, the recommended daily dose for pediatric patients 1 to 16 years of age is as follows:

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

Alternative administrative options can be used for pediatric patients unable to swallow an intact capsule.

Alternative Administration Options

Zolufen is available as a delayed-release capsule or as a delayed-release oral suspension.

For patients who have difficulty swallowing capsules, the contents of a Zolufen Delayed-Release Capsule can be added to applesauce.

One tablespoon of applesauce should be added to an empty bowl and the capsule should be opened. All of the pellets inside the capsule should be carefully emptied on the applesauce. The pellets should be mixed with the applesauce and then swallowed immediately with a glass of cool water to ensure complete swallowing of the pellets. The applesauce used should not be hot and should be soft enough to be swallowed without chewing. The pellets should not be chewed or crushed. The pellets/applesauce mixture should not be stored for future use.

Zolufen For Delayed-Release

Oral Suspension should be administered as follows:

• Empty the contents of a 2.5 mg packet into a container containing 5 mL of water.
• Empty the contents of a 10 mg packet into a container containing 15 mL of water.
• Stir
• Leave 2 to 3 minutes to thicken.
• Stir and drink within 30 minutes.
• If any material remains after drinking, add more water, stir and drink immediately.

For patients with a nasogastric or gastric tube in place:

• Add 5 mL of water to a catheter tipped syringe and then add the contents of a 2.5 mg packet (or 15 mL of water for the 10 mg packet). It is important to only use a catheter tipped syringe when administering Zolufen through a nasogastric tube or gastric tube.
• Immediately shake the syringe and leave 2 to 3 minutes to thicken.
• Shake the syringe and inject through the nasogastric or gastric tube, French size 6 or larger, into the stomach within 30 minutes.
• Refill the syringe with an equal amount of water.
• Shake and flush any remaining contents from the nasogastric or gastric tube into the stomach.

How supplied

Dosage Forms And Strengths

Zolufen Delayed-Release Capsules, 10 mg, are opaque, hard gelatin, apricot and amethyst colored capsules, coded 606 on cap and Zolufen 10 on the body.

Zolufen Delayed-Release Capsules, 20 mg, are opaque, hard gelatin, amethyst colored capsules, coded 742 on cap and Zolufen 20 on the body.

Zolufen Delayed-Release Capsules, 40 mg, are opaque, hard gelatin, apricot and amethyst colored capsules, coded 743 on cap and Zolufen 40 on the body.

Zolufen For Delayed-Release

Oral Suspension, 2.5 mg or 10 mg, is supplied as a unit dose packet containing a fine yellow powder, consisting of white to brownish Zolufen granules and pale yellow inactive granules.

Storage And Handling

Zolufen Delayed-Release Capsules, 10 mg, are opaque, hard gelatin, apricot and amethyst colored capsules, coded 606 on cap and Zolufen 10 on the body. They are supplied as follows:

NDC 0186-0606-31 unit of use bottles of 30

Zolufen Delayed-Release Capsules, 20 mg, are opaque, hard gelatin, amethyst colored capsules, coded 742 on cap and Zolufen 20 on body. They are supplied as follows:

NDC 0186-0742-31 unit of use bottles of 30

NDC 0186-0742-82 bottles of 1000

Zolufen Delayed-Release Capsules, 40 mg, are opaque, hard gelatin, apricot and amethyst colored capsules, coded 743 on cap and Zolufen 40 on the body. They are supplied as follows:

NDC 0186-0743-31 unit of use bottles of 30

NDC 0186-0743-68 bottles of 100

Zolufen For Delayed-Release

Oral Suspension, 2.5 mg or 10 mg

NDC 0186-0625-01 unit dose packages of 30: 2.5 mg packets

NDC 0186-0610-01 unit dose packages of 30: 10 mg packets

Storage

Store Zolufen Delayed-Release Capsules in a tight container protected from light and moisture. Store between 15°C and 30°C (59°F and 86°F).

Store Zolufen For Delayed-Release

Oral Suspension at 25°C (77°F); excursions permitted to 15 – 30°C (59 – 86°F).

AstraZeneca Pharmaceuticals LP Wilmington, DE 19850. Revised December 2014

See also:
What is the most important information I should know about Zolufen?

You should not take this medication if you are allergic to Zolufen or to any other benzimidazole medication such as albendazole or mebendazole. Zolufen is not for immediate relief of heartburn symptoms.

Ask a doctor or pharmacist if it is safe for you to take Zolufen if you have liver disease or heart disease, or low levels of magnesium in your blood.

Some conditions are treated with a combination of Zolufen and antibiotics. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice.

Take this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared.

Zolufen OTC (over-the-counter) should be taken for no longer than 14 days in a row. Allow at least 4 months to pass before you start another 14-day treatment.

Heartburn is often confused with the first symptoms of a heart attack. Seek emergency medical attention if you have chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, and a general ill feeling.

Use Zolufen delayed-release oral suspension as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Zolufen delayed-release oral suspension comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Zolufen delayed-release oral suspension refilled.
• Take Zolufen delayed-release oral suspension by mouth before a meal or as directed by your doctor.
• Mix Zolufen delayed-release oral suspension in a small amount of water before taking your dose. Use an oral syringe to measure the amount of water needed to mix your dose. Ask your pharmacist for an oral syringe. The recommended amount of water for mixing each dose is as follows:
  • If your dose of Zolufen delayed-release oral suspension is 2.5 mg, add 1 teaspoon (5 mL) of water to a container.
  • If your dose of Zolufen delayed-release oral suspension is 10 mg, add 1 tablespoon (15 mL) of water to a container.
• Tear open the medicine packet and add the contents of the packet to the container. Stir well. Allow the mixture to thicken for 2 to 3 minutes. Stir again. Drink the mixture within 30 minutes. If it is not used within 30 minutes, throw it away and mix a new dose. If any medicine remains in the glass after drinking, add more water. Stir, then drink right away.
• If your doctor has instructed you to use more than 1 packet for your dose, follow the mixing instructions provided by your doctor or pharmacist.
• If the patient is taking Zolufen delayed-release oral suspension through a nasogastric (NG) tube or gastric tube, follow the instructions for use in the extra patient leaflet.
• You may take antacids while you are using Zolufen delayed-release oral suspension if you are directed to do so by your doctor.
• Continue to take Zolufen delayed-release oral suspension even if you feel well. Do not miss any doses.
• If you miss a dose of Zolufen delayed-release oral suspension, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Zolufen delayed-release oral suspension.

Use: Labeled Indications

Gastroesophageal reflux disease, erosive or nonerosive (Rx only):

Treatment of erosive esophagitis: Short-term treatment of erosive esophagitis (EE) due to acid-mediated gastroesophageal reflux disease (GERD) diagnosed by endoscopy in patients ≥1 year of age; short-term treatment (up to 6 weeks) of EE due to acid-mediated GERD in pediatric patients 1 month to <1 year of age.

Maintenance healing of erosive esophagitis: Maintenance healing of EE due to acid-mediated GERD in patients ≥1 year of age.

Symptomatic gastroesophageal reflux disease: Treatment of heartburn and other symptoms associated with GERD for up to 4 weeks in patients ≥1 year of age.

Heartburn (OTC only): Treatment of frequent, uncomplicated heartburn (occurring ≥2 or more days per week) in adults.

Helicobacter pylori eradication (Rx only): Treatment of H. pylori infection and duodenal ulcer disease in adults as part of an appropriate combination regimen with antibiotics.

Peptic ulcer disease, treatment of duodenal or gastric ulcers (Rx only): Short-term treatment of active duodenal or gastric ulcers in adults.

Zollinger-Ellison syndrome (Rx only): Long-term treatment of pathological hypersecretory conditions, such as Zollinger-Ellison syndrome, in adults.

Off Label Uses

Aspiration prophylaxis in patients undergoing anesthesia

Data from several studies of varying methodologies (including randomized, double-blind, double-dummy, parallel-group trials) and a meta-analysis support the use of Zolufen for the prevention of aspiration in patients undergoing anesthesia. Studies were conducted in the elective surgery setting, including scheduled cesarean deliveries.

Based on the Surviving Sepsis Campaign international guidelines for the management of severe sepsis and septic shock, stress ulcer prophylaxis using a PPI is an effective and recommended option in select critically ill patients with GI bleeding risk factors.

See also:
What other drugs will affect Zolufen?

Effects of Zolufen on the Pharmacokinetics of Other Drugs: The following combination with Zolufen should be avoided: Ketoconazole and itraconazole.

Zolufen might influence the absorption of other drugs due to its effect on the gastric pH. The dissolution of ketoconazole tablets in the stomach is adversely affected if the pH of the gastric juice increases as a result of drug treatment (antacids, secretion-inhibiting agents, sucralfate). This leads to ineffective plasma concentrations of ketoconazole. During concomitant administration of Zolufen and itraconazole, the plasma concentration and area under the curve (AUC) of itraconazole are reduced by approximately 65%, probably as a result of poorer absorption, which is dependent on pH.

Zolufen inhibits the enzyme CYP2C19 and therefore, increased plasma levels of other drugs (diazepam, warfarin, phenytoin) metabolized via this enzyme might be expected. Monitoring is recommended during initiation or withdrawal of Zolufen in patients being treated with phenytoin, warfarin or other vitamin K antagonist.

During concomitant administration of clarithromycin or erythromycin and Zolufen, the plasma concentrations of Zolufen were increased. The plasma concentrations of Zolufen are not influenced during concomitant administration with amoxicillin or metronidazole.

Concomitant administration of Zolufen (40 mg once daily) and atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a marked reduction in total atazanavir exposure (approximately 75% reduction of AUC, C_max and C_min). An increase in the atazanavir dose to 400 mg did not compensate for the effect that Zolufen had on atazanavir exposure. Proton pump inhibitors including Zolufen should therefore not be administered concomitantly with atazanavir.

Concomitant administration of Zolufen and tacrolimus may increase the serum levels of tacrolimus. Monitoring of the plasma tacrolimus concentration is recommended when treatment with Zolufen is being initiated or discontinued. Zolufen (40 mg daily) increased the C_max and AUC of voriconazole (CYP2C19 substrate) by 15% and 41%, respectively.

Effects of Other Drugs on the Pharmacokinetics of Zolufen: Drugs inhibiting the enzymes CYP2C19 or CYP3A (HIV protease inhibitors, ketoconazole, itraconazole) might increase the plasma concentrations of Zolufen. Voriconazole increases the AUC of Zolufen by 280%. In cases of concomitant treatment, an adjustment of the Zolufen dose should be considered for patients with considerable impaired hepatic function and in cases of long-term treatment.

Case reports, published population pharmacokinetic studies and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high doses) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted.

No interactions between Zolufen and antacids, theophylline, caffeine, quinidine, lidocaine, propranolol, metoprolol or ethanol have been detected.

See also:
What are the possible side effects of Zolufen?

Clinical Trials Experience With Zolufen Monotherapy

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

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

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

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

The clinical trial safety profile in pediatric patients who received Zolufen Delayed-Release Capsules was similar to that in adult patients. Unique to the pediatric population, however, adverse reactions of the respiratory system were most frequently reported in both the 1 to < 2 and 2 to 16 year age groups (75.0% and 18.5%, respectively). Similarly, fever was frequently reported in the 1 to 2 year age group (33.0%), and accidental injuries were reported frequently in the 2 to 16 year age group (3.8%).

Clinical Trials Experience With Zolufen In Combination Therapy For H. pylori Eradication

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

Dual Therapy (Zolufen/clarithromycin)

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

Triple Therapy (Zolufen/clarithromycin/amoxicillin)

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

Post-marketing Experience

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

Body As a Whole: Hypersensitivity reactions including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, urticaria,; fever; pain; fatigue; malaise;

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

Endocrine: Gynecomastia

Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, stomatitis, abdominal swelling, dry mouth, microscopic colitis. During treatment with Zolufen, gastric fundic gland polyps have been noted rarely. These polyps are benign and appear to be reversible when treatment is discontinued.

Gastroduodenal carcinoids have been reported in patients with ZE syndrome on long-term treatment with Zolufen. This finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors.

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

Infections and Infestations: Clostridium difficile associated diarrhea

Metabolism and Nutritional disorders: Hypoglycemia, hypomagnesemia, with or without hypocalcemia and/or hypokalemia, hyponatremia, weight gain

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

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

Respiratory: Epistaxis, pharyngeal pain

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

Special Senses: Tinnitus, taste perversion

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

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

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