Prevacid FDT/IV

Prevacid FDT/IV

lansoprazole

Manufacturer:

Takeda

Distributor:

DKSH
Full Prescribing Info
Contents
Lansoprazole.
Description
Each FDT contains lansoprazole which is in the form of enteric-coated microgranules.
Each vial contains lansoprazole which occurs as a white to brownish white crystalline powder with the molecular formula of C16H14F3N3O2S, molecular weight of 369.36 and a melting point of 166 °C (decomposed). It is freely soluble in N,N-dimethylforamide, soluble in methanol, sparingly soluble in ethanol (99.5), and practically insoluble in water.
It has a pH of 10.6-11.3 [when dissolved in 5 mL of isotonic sodium chloride solution (JP)] and an osmotic pressure ratio of approximately 1 [when dissolved in 5 mL of isotonic sodium chloride solution (JP)].
Lansoprazole is (±)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridine-2-yl] methyl}sulfinyl]-1H-benzimidazole.
Action
PREVACID FDT is a preparation of lansoprazole, a proton-pump inhibitor.
Pharmacology: Tablet: Lansoprazole inhibits the gastric acid secretion strongly and sustainedly by suppressing the activity of (H+,K+)-ATPase which locally exists in the parietal cells of the gastric mucosa and plays an important role as a proton pump.
Clinically, lansoprazole attains a rapid and high healing ratio against gastric and duodenal ulcers, and the usefulness of the drug has been proven. It has also been proved to be useful in the treatment of stomal ulcer, reflux esophagitis and Zollinger-Ellison syndrome.
Pharmacodynamics: Mechanism of Action: Tablet: Lansoprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the (H+,K+)-ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the parietal cell, lansoprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated gastric acid secretion irrespective of the stimulus. Lansoprazole does not exhibit anticholinergic or histamine type-2 antagonist activity.
IV: Lansoprazole is firstly transferred to the acid-producing region of the gastric mucosal parietal cells, and transformed into an activated form through conversion reaction by acid. This reaction product is considered to combine with the SH-groups of (H+, K+)-ATPase which is locally located in the acid-producing region and playing a role of the proton pump, suppressing the enzyme activity to inhibit the acid secretion.
It has been reported that blood coagulation and platelet aggregation capacities are severely impaired under acidic conditions, and that fibrin formed as a result of blood coagulation is dissolved by pepsin under acidic conditions. Lansoprazole is considered to increase gastric pH, thereby improving blood coagulation and platelet aggregation capacities and inhibiting peptic activity, resulting in suppression of bleeding.
Also, lansoprazole is considered to increase gastric pH by inhibiting acid secretion, thereby promoting repair of injured mucosa, which is inhibited under acidic conditions.
Inhibiting Activity on Gastric Bleeding: In rats (intravenous dose), lansoprazole shows an inhibiting activity on gastric bleeding due to hemorrhagic shock.
Inhibiting Activity on Formation of Gastric Mucosal Injury: In rats (intravenous dose), lansoprazole inhibits gastric mucosal injury due to aspirin or indomethacin.
Inhibiting Activity on Gastric Acid Secretion (24-hour Gastric pH monitoring): By intravenous administration of lansoprazole at a dose of 30 mg twice a day to healthy adults, continuous inhibition of gastric acid secretion is observed. The rates of 24-hour gastric pH 4 holding time (the time that the gastric pH is 4 or over) are similar between IV injection (approximately 3 minutes) and intravenous drip infusion (30 minutes).
In addition, the gastric acid secretion inhibiting effect (pH 4 holding time every 24 hours) after intravenous administration of lansoprazole 30 mg twice a day to healthy adults whose metabolizer types for lansoprazole were identified as EM or PM is as follows: The rates of pH 4 holding time are 56-69% in EMs and 90% in PMs on day 1 and 80-89% in EMs and 98% in PMs on day 5.
Clinical Studies: IV: In clinical trials of PREVACID I.V. in patients with peptic ulcer accompanied by bleeding etc., those in whom hemostasis was observed within 3 days (72 hours) accounted for 94.6% (192/203 patients) of 203 patients who had been evaluated for the hemostatic effect after intravenous administration of 30 mg of this drug twice a day. Of the 203 patients, 41 did not undergo endoscopic pretreatment, while 97.6% of these patients (40/41) had successful hemostasis within 3 days (72 hours).
In the previously mentioned the incidence of adverse events (excluding abnormal changes in laboratory data) was 14.9% (33/221) in the 221 patients intravenously given this drug twice a day.
The incidences of adverse events by background factors of patients were 21.8% (12/55 patients) in females, 33.9% (19/56) in the elderly, and 29.7% (11/37) in patients with body weight of less than 50.0 kg, indicating slightly higher incidences, respectively, compared with 12.7% (21/166) in males, 8.5% (14/165) in the non-elderly, and 14.9% (11/74) in patients with body weight of 50.0 kg or over but less than 60.0 kg, or 10.0% (10/100) in patients with body weight of 60.0 kg or over (excluding those with unknown body weight).
Pharmacokinetics: Tablet: PREVACID FDT contains an enteric-coated granule formulation of lansoprazole. Absorption of lansoprazole begins only after the granules leave the stomach. Absorption is rapid, with mean peak plasma levels of lansoprazole occurring after approximately 1.7 hours. Peak plasma concentrations of lansoprazole (Cmax) and the area under the plasma concentration curve (AUC) of lansoprazole are approximately proportional in doses from 15 mg to 60 mg after single-oral administration. Lansoprazole does not accumulate and its pharmacokinetics are unaltered by multiple dosing.
Absorption: The absorption of lansoprazole is rapid, with mean Cmax occurring approximately 1.7 hours after oral dosing, and relatively complete with absolute bioavailability over 80%. In healthy subjects, the mean (±SD) plasma half-life was 1.5 (±1.0) hours. Both Cmax and AUC are diminished by about 50% to 70 % if the drug is given 30 minutes after food as opposed to the fasting condition. There is no significant food effect if the drug is given before meals.
Distribution: Lansoprazole is 97% bound to plasma proteins. Plasma protein-binding is constant over the concentration range of 0.05 to 5 μg/mL.
Metabolism: Lansoprazole is extensively metabolized in the liver. Two metabolites have been identified in measurable quantities in plasma (the hydroxylated sulfinyl and sulfone derivatives of lansoprazole). These metabolites have very little or no antisecretory activity. Lansoprazole is thought to be transformed into two active species which inhibit acid secretion by (H+,K+)-ATPase within the parietal cell canaliculus, but are not present in the systemic circulation. The plasma elimination half-life of lansoprazole does not reflect its duration of suppression of gastric acid secretion. Thus, the plasma elimination half-life is less than two hours, while the acid inhibitory effect lasts more than 24 hours.
Elimination: Following single-dose oral administration of lansoprazole, virtually no unchanged lansoprazole was excreted in the urine. In one study, after a single oral dose of 14C-lansoprazole, approximately one-third of the administered radiation was excreted in the urine and two-thirds was recovered in the feces. This implies a significant biliary excretion of the metabolites of lansoprazole.
Special Populations: Geriatric: The clearance of lansoprazole is decreased in the elderly, with elimination half-life increased approximately 50% to 100%. Because the mean half-life in the elderly remains between 1.9 to 2.9 hours, repeated once daily dosing does not result in accumulation of lansoprazole. Peak plasma levels were not increased in the elderly.
Pediatric: One to 17 years of age: The pharmacokinetics of lansoprazole were studies in pediatric patients with GERD aged 1 to 11 years and 12 to 17 years in two separate clinical studies. In children aged 1 to 11 years, lansoprazole was dosed 15 mg q.d. for subjects weighing ≤ 30 kg and 30 mg q.d. for subjects weighing > 30 kg. Mean Cmax and AUC values observed on Day 5 of dosing were similar between the two dose groups and were not affected by weight or age within each weight-adjusted dose group used in the study. In adolescent subjects aged 12 to 17 years, subjects were randomized to receive lansoprazole at 15 mg or 30 mg q.d. Mean Cmax and AUC values of lansoprazole was not affected by bodyweight or age; and nearly dose-proportional increases in mean Cmax and AUC values were observed between the two dose groups in the study. Overall, lansoprazole pharmacokinetic patients aged 1 to 17 years were similar to those observed in healthy adult subjects.
Gender: In a study comparing 12 male and 6 female human subjects, no gender differences were found in pharmacokinetics and intragastric pH results.
Renal Insufficiency: In patients with severe renal impairment, plasma protein binding decreased by 1.0%-1.5% after administration of 60 mg of lansoprazole. Patients with renal impairment had a shortened elimination half-life and decreased total AUC (free and bound). AUC for free lansoprazole in plasma, however, was not related to the degree of renal impairment, and Cmax and Tmax (time to reach the maximum concentration) were not different than the Cmax and Tmax from subjects with normal renal function.
Therefore, the pharmacokinetics of lansoprazole were not clinically different in patients with mild, moderate or severe renal impairment compared to healthy subjects with normal renal function.
Hepatic Impairment: In patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment there was an approximate 3-fold increase in mean AUC compared to healthy subjects with normal hepatic function following multiple oral doses of 30 mg PREVACID for 7 days. The corresponding mean plasma half-life of lansoprazole was prolonged from 1.5 hours to 4 hours (Child-Pugh A) or 5 hours (Child-Pugh B).
In patients with compensated and decompensated cirrhosis, there was an approximate 6- and 5-fold increase in AUC, respectively, compared to healthy subjects with normal hepatic function following a single oral dose of 30 mg PREVACID (see Dosage & Administration).
Drug-Drug Interaction: Effect of Lansoprazole on Other Drugs: Cytochrome P450 Interactions: Lansoprazole is metabolized through the cytochrome P450 system, specifically through the CYP3A and CYP2C19 isozymes. Studies have shown that lansoprazole does not have clinically significant interactions with other drugs metabolized by the cytochrome P450 system such as warfarin, antipyrine, indomethacin, ibuprofen, phenytoin, propanolol, prednisolone, diazepam, clarithromycin, or terfenadine in healthy subjects. These compounds are metabolized through various cytochrome P450 isozymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A.
Theophylline: When lansoprazole was administered concomitantly with theophylline (CYP1A2, CYP3A), a minor increase (10%) in the clearance of theophylline was seen. Because of the small magnitude and the direction of the effect on theophylline clearance, this interaction has not been considered to be clinically concern.
Methotrexate and 7-hydromethotrexate: In an open-label, single-arm, eight-day, pharmacokinetic study of 28 adult rheumatoid arthritis patients (who required the chronic use of 7.5 to 15 mg of methotrexate given weekly), administration of 7 days of naproxen 500 mg twice daily and PREVACID 30 mg daily had no effect on the pharmacokinetics of methotrexate and 7-hydroxymethotrexate. While this study was not designed to assess the safety of this combination of drugs, no major adverse reactions were noted. However, this study was conducted with low doses of methotrexate. A drug interaction study with high doses of methotrexate has not been conducted.
Amoxicillin: Lansoprazole has also been shown to have no clinically significant interaction with amoxicillin.
Sucralfate: In a single-dose crossover study examining lansoprazole 30 mg administered alone and concomitantly with sucralfate 1 gram, absorption of lansoprazole was delayed and their bioavailability was reduced by 17% when administered concomitantly with sucralfate.
Antacids: In clinical trials, antacids were administered concomitantly with PREVACID and there was no evidence of a change in the efficacy of PREVACID.
Clopidogrel: Clopidogrel is metabolized to its active metabolite in part by CYP2C19. A study of healthy subjects who were CYP2C19 extensive metabolizers, receiving once daily administration of clopidogrel 75 mg alone or concomitantly with PREVACID 30 mg (n=40), for 9 days was conducted. The mean AUC of the active metabolite of clopidogrel was reduced by approximately 14% (mean AUC ratio was 86%, with 90% CI of 80 to 92%) when PREVACID was co-administered compared to administration of clopidogrel alone.
Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation (induced by 5 mcM ADP) was related to the change in the exposure to clopidogrel active metabolite. The effect on exposure to the active metabolite of clopidogrel and on clopidogrel-induced platelet inhibition is not considered clinically important.
Effect of Other Drugs on Lansoprazole: Because lansoprazole is metabolized by CYP2C19 and CYP3A4, inducers and inhibitors of these enzymes may potentially alter exposure of lansoprazole.
IV: Blood concentrations: The serum concentration of lansoprazole after intravenous administration of PREVACID I.V. varies among individuals.
The following figure shows the serum concentration of lansoprazole after intravenous drip of 30 mg of lansoprazole twice a day for 5 days to 12 healthy male adults classified into either extensive metabolizer (EM) group (8 subjects) in which lansoprazole is rapidly metabolized or poor metabolizer (PM) group (4 subjects) in which the drug is slowly metabolized according to CYP2C19 genotype (see Table 1 and Figure).

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Protein-Binding Rate:
The human serum protein binding rate of lansoprazole at the concentration range of 0.05 to 5 μg/mL is approximately 98%.
Metabolism: Lansoprazole is mainly metabolized by CYP2C19 and CYP3A4. It has been reported that there is genetic polymorphism of CYP2C19, and the frequency of poor metabolizers among Asian-Mongolian populations including Japanese is appoximately 10-20%.
Urinary Excretion: After single intravenous administration lansoprazole 30 mg to healthy male adults (9 subjects), no unchanged compound was detected in the urine; all detected were metabolites. The accumulated urinary excretion rate up to 24 hours after administration was 12-17%.
Indications/Uses
Tablet: Gastric, duodenal and stomal ulcers and reflux esophagitis.
Relief of reflux-like symptoms (e.g., heartburn) and/or ulcer-like symptoms (e.g., upper epigastric pain) associated with acid-related dyspepsia.
Treatment and prophylaxis of NSAID-associated benign gastric ulcers, duodenal ulcers and relief of symptoms in patients requiring continued NSAID treatment.
Eradication of H. pylori from the upper gastrointestinal tract in patients with peptic ulcer (duodenal or benign gastric ulcer), when used in combination with appropriate antibiotics.
Maintenance treatment of healed duodenal ulcer.
Maintenance treatment of erosive esophagitis.
Gastroesophageal reflux disease (GERD).
Zollinger-Ellison syndrome (and other pathological hypersecretory condition).
Short-term treatment of symptomatic GERD and erosive esophagitis for children (1-17 years of age).
IV: Patients with the following diseases who are unable to take the oral formulation: Gastric ulcer, duodenal ulcer, acute stress ulcer, and acute gastric mucosal lesion accompanied by bleeding.
Dosage/Direction for Use
Tablet: See Table 2.

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IV: Usually, for adults, one vial of PREVACID I.V. (Lansoprazole 30 mg) is mixed with isotonic sodium chloride solution (NSS) or 5% dextrose in water (D5W) and administered by intravenous injection or intravenous drip twice a day; with the following directions.
Intravenous injection: Use 5 - 10ml NSS or D5W to mix with PREVACID I.V., shake the vial gently until getting clear and colorless solution. Then draw all solution back and gently inject intravenously over 2 minutes.
Intravenous drip: Use 5 - 10ml NSS or D5W to mix with PREVACID I.V., shake the vial gently until getting clear and colorless solution.
Then draw all solution back and mix with NSS or D5W 100 ml and then administer by intravenous drip as follows: Mixing with NSS, drip the solution within 12 hours; Mixing with D5W, drip the solution within 5 hours.
Mode of Administration: Tablet: Take PREVACID FDT before meals. Do not crush or chew PREVACID FDT. Take PREVACID FDT at least 30 minutes prior to sucralfate (see Interactions).
Antacids may be used concomitantly with PREVACID FDT.
Missed doses: If a dose is missed, administer as soon as possible. However, if the next scheduled dose is due, do not take the missed dose, and take the next dose on time. Do not take two doses at one time to make up for a missed dose.
PREVACID FDT do not break or cut. Place the tablet on the tongue, allow it to disintegrate, with or without water, until the microgranules can be swallowed. Do not chew the microgranules. The tablet typically disintegrates in less than 1 minute.
Alternatively, for children or other patients who have difficulty swallowing tablets, PREVACID FDT can be administered with water via oral or NG tube as follows:
Administration with Water in an Oral Syringe: Place a 15 mg tablet in oral syringe and draw up approximately 4 ml of water, or place a 30 mg tablet in oral syringe and draw up approximately 10 ml of water.
Shake gently to allow for a quick dispersal.
After the tablet has dispersed, administer the contents within 15 minutes of mixing into the mouth. Do not save the water and microgranule mixture for later use.
Refill the syringe with approximately 2 ml (5 ml for the 30 mg tablet) of water, shake gently, and administer any remaining contents.
Administration with Water via a NG Tube (≥ 8 French): Place 15 mg tablet in a catheter-tip syringe and draw up 4 ml of water, or place a 30 mg tablet in a catheter-tip syringe and draw up 10 ml of water.
Shake gently to allow for a quick dispersal.
After the tablet has dispersed, shake the catheter-tip syringe gently in order to keep the microgranules from setting, and immediately inject the mixture through the NG tube into the stomach within 15 minutes of mixing. Do not save the water and microgranule mixture for later use.
Refill the catheter-tip syringe with approximately 5 ml of water, shake gently, and flush the tube.
Overdosage
Lansoprazole is not removed from the circulation by hemodialysis. In one reported case of overdose, the patient consumed 600 mg of lansoprazole with no adverse reaction.
Oral doses up to 5000 mg/kg in rats (approximately 1300 times the recommended human dose based on body surface area) and mice (about 675.7 times the recommended human dose based on body surface area) did not produce deaths or any clinical signs.
In the event of over-exposure, treatment should be symptomatic and supportive.
Contraindications
PREVACID is contraindicated in the Patients with known severe hypersensitivity to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute interstitial nephritis, and urticarial.
Tablet: Proton Pump Inhibitors (PPIs), including PREVACID FDT are contraindicated with rilpivirine-containing products (see Interactions).
IV: Patients who are receiving atazanavir sulfate or ripilvirine hydrochloride. (see Interactions).
Warnings
Tablet: Before using PREVACID FDT with antibiotics to eradicate H. pylori, prescribers should refer to the full prescribing information of the respective antibiotic for guidance.
Special Precautions
Careful Administration: Prevacid should be administered with caution to the following patients: Patients with a history of drug hypersensitivity; elderly patients (see Use in the elderly as follows); patients with impaired hepatic function (see Hepatic Impairment as follows).
Tablet: Presence of Gastric Malignancy: In adults, symptomatic response to therapy with PREVACID does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response on an early symptomatic relapse after completing treatment with a PPI. In older patients, also consider an endoscopy.
Acute Interstitial Nephritis: Acute interstitial nephritis has been observed in patients taking PPIs including PREVACID. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue PREVACID if acute interstitial nephritis develops.
Cyanocobalamin (vitamin B12) Deficiency: Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed in patients treated with PREVACID.
Clostridium difficile Associated Diarrhea: Published observational studies suggest that PPI therapy like PREVACID may be associated with an increased risk of Clostridium difficile-associated diarrhea (CDAD), especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve.
Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.
CDAD has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with PREVACID, refer to Warnings and Precautions section of their prescribing information.
Bone Fracture: Several published observational studies suggest that proton pump inhibitor (PPI) 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 & Administration).
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.
Interaction with Methotrexate: Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients (see Interactions).
Cutaneous and Systemic Lupus Erythematosus: Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including lansoprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE.
The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement.
Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported.
Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving PREVACID, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in four to 12 weeks.
Serological testing (e.g., ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.
Interactions with Investigations for Neuroendocrine Tumors: Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop lansoprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary (see Interactions).
Patients with Phenylketonuria: Phenylalanine can be harmful to patients with phenylketonuria (PKU). PREVACID FDT contains phenylalanine, a component of aspartame. Each 15 mg tablet contains 2.5 mg and each 30 mg tablet contains 5.1 mg of phenylalanine. Before prescribing PREVACID FDT to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including PREVACID FDT.
Hepatic Impairment: In patients with various degrees of chronic hepatic impairment the exposure to lansoprazole was increased compared to healthy subjects with normal hepatic function. No dosage adjustment for PREVACID is necessary for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. The recommended dosage is 15 mg orally daily in patients with severe hepatic impairment (Child-Pugh Class C).
IV: Important Precautions: As PREVACID I.V. was shown to have high hemostatic effect based on the data up to 3 days after starting treatment, once the patient is able to take medications orally, therapy should be switched to an oral formulation and this drug should not be administered aimlessly for a long period (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
There is no clinical experience of treatment over 7 days in Japanese clinical trials.
At the treatment, the course of the disease should be closely observed and the minimum therapeutic necessity should be used according to the disease condition. If PREVACID I.V. is ineffective, it should be switched to another treatment.
If the patient has projectile bleeding or oozing bleeding, or is considered at risk for rapid bleeding such as the case of presence of exposed blood vessels, the patient should undergo endoscopic hemostasis such as heater probe or clipping.
Other Precautions: In an animal study in which 50 mg/kg/day (about 100 times the clinical dose) of lansoprazole was given to rats by gavage administration for 52 weeks, benign testicularinterstitial cell tumors were observed in one animal. In another study in which 15 mg/kg/day or more was given to rats by gavage for 24 months, an increase in the frequency of benign testicular interstitial cell tumors was observed and, in which 5 mg/kg/day or more was given, carcinoid tumors in the stomach were observed. In addition, in the group of female rats given 15 mg/kg/day or more of lansoprazole and the group of male rats given 50 mg/kg/day or more, an increase in the frequency of retinal atrophy was observed. Testicular interstitial cell tumors and retinal atrophy were not observed in carcinogenicity studies in mice, as well as in toxicity studies in dogs or monkeys. Thus, these changes are considered to be specific to rats.
The administration of PREVACID I.V. may mask the symptoms of gastric cancer. It is, therefore, necessary to ascertain the ulcer is not of a malignant nature before initiating the administration of this drug.
In several observational studies in overseas, an increased risk for osteoporosis-related fractures of the hip, wrist or spine under the treatment with proton pump inhibitors has been reported. The risk of fracture was especially increased in the patients receiving high dose or long term (a year or longer) treatment.
In several overseas observational studies, mainly in hospitalized patients, increased risk of gastrointestinal infection caused by Clostridium difficile was reported in patients received proton pump inhibitors.
Cyanocobalamin (Vitmain B-12) Deficiency: Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than three years) may lead to malabsorption of cyanocobalamin (Vitamin B-12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed.
Use in Children: Tablet: The safety and effectiveness of PREVACID FDT have been established in pediatric patients one to 17 years of age for short-term treatment of symptomatic GERD and erosive esophagitis, however, lansoprazole was not effective in patients with symptomatic GERD 1 month to less than one year of age in a multi-center, double-blind, placebo controlled study.
Use of PREVACID FDT in this population is supported by evidence from adequate and well controlled studies of PREVACID FDT in adults with additional clinical, pharmacokinetic, and pharmacodynamic studies performed in pediatric patients. The adverse events profile in pediatric patients is similar to that of adults. There were no adverse events reported in U.S. clinical studies that were not previously observed in adults.
Neonate to less than 1 year of age: The pharmacokinetics of lansoprazole were studied in pediatric patients with GERD aged less than 28 days and 1 to 11 months. Compared to healthy adults receiving 30 mg, neonates had higher exposure (mean weight-based normalized AUC values 2.04- and 1.88-fold higher at doses of 0.5 and 1 mg/kg/day, respectively). Infants aged ≤10 weeks had clearance and exposure values that were similar to neonates. Infants aged greater than 10 weeks who received 1 mg/kg/day had mean AUC values that were similar to adults who received a 30 mg dose.
Lansoprazole was not found to be effective in a U.S. and Polish 4 week multi-center, double-blind, placebo-controlled, parallel-group study of 162 patients between one month and less than 12 months of age with symptomatic GERD based on a medical history of crying/fussing/irritability associated with feedings who had not responded to conservative GERD management (i.e., non-pharmacologic intervention) for 7 to 14 days. Patients received lansoprazole as a suspension daily (0.2 to 0.3 mg/kg/day in infants ≤10 weeks of age or 1.0 to 1.5 mg/kg/day in infants greater than 10 weeks or placebo) for up to 4 weeks of double-blind treatment.
The primary efficacy endpoint was assessed by greater than 50% reduction from baseline in either the percent of feedings with a crying/fussing/irritability episode or the duration (minutes) of a crying/fussing/irritability episode within one hour after feeding.
There was no difference in the percentage of responders between the lansoprazole pediatric suspension group and placebo group (54% in both groups).
There were no adverse events reported in pediatric clinical studies (one month to less than 12 months of age) that were not previously observed in adults.
Based on the results of the Phase 3 efficacy study, lansoprazole was not shown to be effective. Therefore, these results do not support the use of lansoprazole in treating symptomatic GERD in infants.
1 to 11 years of age: In an uncontrolled, open label, U.S. multi-center study, 66 pediatric patients (1 to 11 years of age) with GERD were assigned, based on body weight, to receive an initial dose of either PREVACID FDT 15 mg q.d. if ≤ 30 kg or PREVACID FDT 30 mg q.d. if > 30 kg administered for 8 to 12 weeks. The PREVACID FDT dose was increased (up to 30 mg b.i.d.) in 24 of 66 pediatric patients after 2 or more weeks of treatment if they remained symptomatic. At baseline 85% of patients had mild to moderate overall GERD symptoms (assessed by investigator interview), 58% had non-erosive GERD and 42% had erosive esophagitis (assessed by endoscopy).
After 8 to 12 weeks of PREVACID FDT treatment, the intent-to-treat analysis demonstrated an approximate 50% reduction in frequency and severity of GERD symptoms.
Twenty-one of 27 erosive esophagitis patients were healed at 8 weeks and 100% of patients were healed at 12 weeks by endoscopy. (See Table 3.)

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In a study of 66 pediatric patients in the age group 1 year to 11 years old after treatment with PREVACID FDT given orally in doses of 15 mg q.d. to 30 mg b.i.d., increases in serum gastrin levels were similar to those observed in adult studies. Median fasting serum gastrin levels increased 89% from 51 pg/ml at baseline to 97 pg/ml [interquartile range (25th-75th percentile) of 71-130 pg/ml] at the final visit.
The most frequently reported (2 or more patients) treatment-related adverse events in patients 1 to 11 years of age (N=66) were constipation (5%) and headache (3%).
12 to 17 years of age: In an uncontrolled, open-label, U.S. multi-center study, 87 adolescent patients (12-17 years of age) with symptomatic GERD were treated with PREVACID FDT for 8 to 12 weeks. Baseline upper endoscopies classified these patients into two groups: 64 (74%) non-erosive GERD and 23 (26%) erosive esophagitis (EE). The non-erosive GERD patients received PREVACID FDT 15 mg q.d. for 8 weeks and the EE patients received PREVACID FDT 30 mg q.d. for 8 to 12 weeks. At baseline, 89% of these patients had mild to moderate overall GERD symptoms (assessed by investigator interviews). During 8 weeks of PREVACID FDT treatment, adolescent patients experienced a 63% reduction in frequency and a 69% reduction in severity of GERD symptoms based on diary results.
Twenty-one of 22 (95.5%) adolescent erosive esophagitis patients were healed after 8 weeks of PREVACID FDT treatment. One patient remained unhealed after 12 weeks of treatment. (See Table 4.)

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In these 87 adolescent patients, increases in serum gastrin levels were similar to those-observed in adult studies, median fasting serum gastrin levels increased 42% from 45 pg/ml at baseline to 64 pg/ml [interquartile range (25th - 75th percentile) of 44 - 88 pg/ml] at the final visit. (Normal serum gastrin levels are 25 to 111 pg/ml).
The most frequently reported (at least 3%) treatment-related adverse events in these patients were headache (7%), abdominal pain (5%), nausea (3%) and dizziness (3%). Treatment-related dizziness, reported in this prescribing information as occurring in <1% of adult patients, was reported in this study by 3 adolescent patients with non-erosive GERD, who had dizziness concurrently with other events (such as migraine, dyspnea, and vomiting).
IV: The safety of PREVACID I.V. in children has not been established (no clinical experience).
Use in the Elderly: Tablet: Of the total number of patients (n=21,486) in clinical studies of PREVACID, 16% of patients were aged 65 years and over, while 4% were 75 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients and other reported clinical experience has not identified significant differences in responses between geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
IV: Since physiological function is generally decreased in elderly patients, PREVACID I.V. should be carefully administered.
Use In Pregnancy & Lactation
Use in Pregnancy: Tablet: Teratogenic Effects: Pregnancy Category B: Reproduction studies have been performed in pregnant rats at oral doses up to 40 times the recommended human dose and in pregnant rabbits at oral doses up to 16 times the recommended human dose and have revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole.
There are, however, no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Prevacid should be used during pregnancy only if clearly needed.
IV: PREVACID I.V. should be used in pregnant women or women having possibilities of being pregnant only if the expected therapeutic benefit is thought to outweigh any possible risk. (In animal studies [rats, oral dose], higher plasma concentration of lansoprazole in the fetus than in the mother animal was observed. In pregnant rabbits [oral doses of 30 mg/kg/day], an increased fetus death rate was observed.)
Use in lactation: Tablet: Lansoprazole or its metabolites are excreted in the milk of rats. It is not known whether lansoprazole is excreted in human milk. Because many drugs are excreted in human milk, because of the potential for serious adverse reactions in nursing infants from lansoprazole and because of the potential for tumorigenicity shown for lansoprazole in rat carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
IV: It is advisable to avoid the administration of PREVACID I.V. to nursing mothers. However, when the administration is indispensable, nursing should be discontinued. (It has been reported in animal studies [rats, oral dose] that lansoprazole is transferred to mother's milk).
Adverse Reactions
Tablet: The following serious adverse reactions are described below and elsewhere in labeling: Acute Interstitial Nephritis; Clostridium difficile-Associated Diarrhea; Bone Fracture; Cutaneous and Systemic Lupus Erythematosus; Cyanocobalamin (Vitamin B-12) Deficiency; Hypomagnesemia.
Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Worldwide, over 10,000 patients have been treated with PREVACID in Phase 2 or Phase 3 clinical trials involving various dosages and durations of treatment. In general, PREVACID treatment has been well-tolerated in both short-term and long-term trials.
The following adverse reactions were reported by the treating physician to have a possible or probable relationship to drug in 1% or more of PREVACID-treated patients and occurred at a greater rate in PREVACID-treated patients than placebo-treated patients in Table 5 (see Table 5).

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Headache was also seen at greater than 1% incidence but was more common on placebo. The incidence of diarrhea was similar between patients who received placebo and patients who received 15 and 30 mg of PREVACID, but higher in the patients who received 60 mg of PREVACID (2.9, 1.4, 4.2, and 7.4%, respectively).
The most commonly reported possibly or probably treatment-related adverse event during maintenance therapy was diarrhea.
In the risk reduction study of PREVACID for NSAID-associated gastric ulcers, the incidence of diarrhea for patients treated with PREVACID, misoprostol, and placebo was 5, 22, and 3%, respectively.
Another study for the same indication, where patients took either a COX-2 inhibitor or lansoprazole and naproxen, demonstrated that the safety profile was similar to the prior study. Additional reactions from this study not previously observed in other clinical trials with PREVACID included contusion, duodenitis, epigastric discomfort, esophageal disorder, fatigue, hunger, hiatal hernia, hoarseness, impaired gastric emptying, metaplasia, and renal impairment.
Combination Therapy with Amoxicillin and Clarithromycin: In clinical trials using combination therapy with PREVACID plus amoxicillin and clarithromycin, and PREVACID plus amoxicillin, no adverse reactions peculiar to these drug combinations were observed. Adverse reactions that have occurred have been limited to those that had been previously reported with PREVACID, amoxicillin, or clarithromycin.
Triple Therapy: PREVACID/amoxicillin/clarithromycin: The most frequently reported adverse reactions for patients who received triple therapy for 14 days were diarrhea (7%), headache (6%), and taste perversion (5%). There were no statistically significant differences in the frequency of reported adverse reactions between the 10- and 14-day triple therapy regimens. No treatment-emergent adverse reactions were observed at significantly higher rates with triple therapy than with any dual therapy regimen.
For information about adverse reactions with antibacterial agents (amoxicillin and clarithromycin) indicated in combination with PREVACID, refer to the Undesirable Effects section of their prescribing information.
Laboratory Values: The following changes in laboratory parameters in patients who received PREVACID were reported as adverse reactions: Abnormal liver function tests, increased SGOT (AST), increased SGPT (ALT), increased creatinine, increased alkaline phosphatase, increased globulins, increased GGTP, increased/decreased/abnormal WBC, abnormal AG ratio, abnormal RBC, bilirubinemia, blood potassium increased, blood urea increased, crystal urine present, eosinophilia, hemoglobin decreased, hyperlipemia, increased/decreased electrolytes, increased/decreased cholesterol, increased glucocorticoids, increased LDH, increased/decreased/abnormal platelets, increased gastrin levels and positive fecal occult blood. Urine abnormalities such as albuminuria, glycosuria, and hematuria were also reported. Additional isolated laboratory abnormalities were reported.
In the placebo controlled studies, when SGOT (AST) and SGPT (ALT) were evaluated, 0.4% (4/978) and 0.4% (11/2677) patients, who received placebo and PREVACID, respectively, had enzyme elevations greater than three times the upper limit of normal range at the final treatment visit. None of these patients who received PREVACID reported jaundice at any time during the study.
In clinical trials using combination therapy with PREVACID plus amoxicillin and clarithromycin, and PREVACID plus amoxicillin, no increased laboratory abnormalities particular to these drug combinations were observed.
For information about laboratory value changes with antibacterial agents (amoxicillin and clarithromycin) indicated in combination with PREVACID, refer to the Undesirable Effects section of their prescribing information.
IV: Adverse reactions, including abnormalities in laboratory data, were observed in 31 (14.0%) of 221 patients given lansoprazole at a dose of 30 mg twice a day in clinical trials before approval. Main adverse reactions included abnormal changes in laboratory data such as increased ALT (GPT) (6.2%), AST (GOT) (5.7%), LDH (2.0%), and γ-GTP (1.5%). (At the time of approval).
Adverse reactions, including abnormalities in laboratory data, were observed in 35 (3.1%) of 1,142 patients in the postmarketing investigations. The major adverse reactions were diarrhea, hepatic dysfunction, hepatic disorder, fever and leukocyte count decreased (0.3% each). (As of the end of the reexamination).
Clinically significant adverse reactions (All frequencies unknown): Anaphylactic reactions (generalized rash, facial edema, dyspnea, etc.) may occur, and shock has consequently occurred in certain cases. Therefore, close observation should be made, and if any abnormality is observed, PREVACID I.V. should be discontinued and appropriate measures taken.
Pancytopenia, agranulocytosis or hemolytic anemia may occur. Granulocytopenia, thrombocytopenia or anemia may occur. Therefore, close observation should be made, and if any abnormality is observed, such appropriate measures as discontinuation of PREVACID I.V. should be taken.
Severe hepatic dysfunction with jaundice, increased AST(GOT), ALT(GPT), etc., may occur. Therefore, close observation should be made. If any abnormality is observed, PREVACID I.V. should be discontinued and appropriate measures taken.
Toxic epidermal necrolysis: TEN and oculomucocutaneous syndrome (Stevens-Johnson syndrome) may occur. Therefore, close observation should be made. If any abnormality is observed, PREVACID I.V. should be discontinued and appropriate measures taken.
Interstitial pneumonia may occur. Therefore, if fever, coughing, dyspnea, abnormal lung sound (crepitation), etc., are observed, such examinations as chest X-ray should immediately be performed, and PREVACID I.V. should be discontinued. Appropriate measures, such as treatment with a corticosteroid preparation, should be taken.
Interstitial nephritis may occur, resulting in acute renal failure in some cases. Therefore, pay attention to renal function test values (increases in BUN, creatinine, etc), and if any abnormality is observed, PREVACID I.V. should be discontinued and appropriate measures taken.
Clinically significant adverse reactions (similar drug): The following adverse reactions are reported in a similar drug (Omeprazole).
Visual disturbance may occur. Therefore, if any abnormality is observed, PREVACID I.V. should be discontinued and appropriate measures taken.
Other adverse reactions: See Table 6.

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Postmarketing Experience: Tablet: Additional adverse experiences have been reported since PREVACID has been marketed. The majority of these cases are foreign-sourced and a relationship to PREVACID has not been established. Because these reactions were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events are listed as follows by COSTART body system.
Body as a Whole: anaphylactic/anaphylactoid reactions, systemic lupus erythematosus.
Digestive System: hepatotoxicity, pancreatitis, vomiting.
Hemic and Lymphatic System: agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, thrombocytopenia, and thrombotic thrombocytopenic purpura.
Infections and Infestations: Clostridium difficile associated diarrhea.
Metabolism and Nutritional Disorders: hypomagnesemia.
Musculoskeletal System: bone fracture, myositis.
Skin and Appendages: severe dermatologic reactions including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal), cutaneous lupus erythematosus.
Special Senses: speech disorder.
Urogenital System: interstitial nephritis, urinary retention.
Drug Interactions
Tablet: Tables 7 and 8 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with PREVACID and instructions for preventing or managing them. (See Tables 7 and 8.)
Consult the labeling of concomitantly used drug to obtain further information about interactions with PPIs.

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IV: PREVACID I.V. is metabolized mainly by hepatic drug-metabolizing enzyme CYP2C19 and CYP3A4.
Gastric antisecretory effect of PREVACID I.V. may promote or inhibit absorption of concomitant drugs.
Contraindications for coadministration: (PREVACID I.V. should not be coadministered with the following drug.): See Table 9.

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Precautions for coadministration (PREVACID I.V. should be administered with care when coadministered with the following drugs.): See Table 10.

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Caution For Usage
Tablet: Prevacid is orally dispersed, but the ingredients are not absorbed through oral mucous membrane. Therefore, the tablet should be swallowed with saliva or water after placing the tablet on the tongue.
This product is more fragile compared with the tablets heretofore in use.
Use the tablet as soon as possible after unsealing, even before the expiration date.
IV: Route of administration: PREVACID I.V. should be used only by intravenous route.
After dissolution: PREVACID I.V. should be used immediately after dissolution and the dissolved solution should not be stored.
Mixing with NSS, drip the solution within 12 hours.
Mixing with D5W, drip the solution within 5 hours.
Incompatibilities: IV: Combined injection of PREVACID I.V. with solutions other than isotonic sodium chloride solution or 5% glucose (dextrose) injection, infusion fluid, replacement fluid, and other drugs should be avoided.
Storage
Store below 30°C.
ATC Classification
A02BC03 - lansoprazole ; Belongs to the class of proton pump inhibitors. Used in the treatment of peptic ulcer and gastro-oesophageal reflux disease (GERD).
FDT: D; Vial: S
Presentation/Packing
FDT 15 mg (fast-disintegrating, white to yellowish white, uncoated, with orange to dark brown speckles) x 28's. 30 mg x 28's.
Powd for inj (vial) 30 mg (white to yellowish-white mass or powder) x 1's.
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