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Acute Interstitial Nephritis: Acute interstitial nephritis has been observed in patients taking PPIs including TAKEPRON. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue TAKEPRON if acute interstitial nephritis develops (see Contraindications).
Clostridium difficile Associated Diarrhea: Published observational studies suggest that proton pump inhibitor (PPI) therapy like TAKEPRON 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 (see Postmarketing Experience under Adverse Reactions).
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 TAKEPRON, refer to Warnings and Precautions sections of those prescribing information.
Bone Fracture: Several published observational studies suggest that 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 and Postmarketing Experience under Adverse Reactions).
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 TAKEPRON, 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.
Cyanocobalamin (Vitamin 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.
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), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically (see Postmarketing Experience under Adverse Reactions).
Concomitant Use of TAKEPRON with Methotrexate: Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) 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 Methotrexate under Interactions and Pharmacology: Pharmacokinetics under Actions).
Renal Impairment: No dosage adjustment of TAKEPRON is necessary in patients with renal impairment. The pharmacokinetics of lansoprazole in patients with various degrees of renal impairment were not substantially different compared to those in subjects with normal renal function (see Pharmacology: Pharmacokinetics under Actions).
Hepatic Impairment: In patients with various degrees of chronic hepatic impairment, an increase in the mean AUC of up to 500% was observed at steady state compared to healthy subjects. Consider dose reduction in patients with severe hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Gender: Over 4,000 women were treated with TAKEPRON. Ulcer healing rates in females were similar to those in males. The incidence rates of adverse reactions in females were similar to those seen in males (see Pharmacology: Pharmacokinetics under Actions).
Race: The pooled mean pharmacokinetic parameters of TAKEPRON from twelve U.S. Phase 1 studies (N=513) were compared to the mean pharmacokinetic parameters from two Asian studies (N=20). The mean AUCs of TAKEPRON in Asian subjects were approximately twice those seen in pooled U.S. data; however, the inter-individual variability was high. The Cmax values were comparable.
Use in Children: The safety and effectiveness of TAKEPRON 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 one month to less than one year of age in a multicenter, double-blind, placebo controlled study.
Neonate to less than one year of age: The pharmacokinetics of lansoprazole were studied in pediatric patients with GERD aged less than 28 days and one 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 mg/kg/day 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 four week multicenter, 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 seven 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 four 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.
One to 11 years of age: In an uncontrolled, open-label, U.S. multicenter study, 66 pediatric patients (one to 11 years of age) with GERD were assigned, based on body weight, to receive an initial dose of either TAKEPRON 15 mg daily if ≤30 kg or TAKEPRON 30 mg daily if greater than 30 kg administered for eight to 12 weeks. The TAKEPRON dose was increased (up to 30 mg twice daily) in 24 of 66 pediatric patients after two 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 eight to 12 weeks of TAKEPRON 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 eight weeks and 100% of patients were healed at 12 weeks by endoscopy (see Table 18.)
Click on icon to see table/diagram/imageIn a study of 66 pediatric patients in the age group one year to 11 years old after treatment with TAKEPRON given orally in doses of 15 mg daily to 30 mg twice daily, 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 to 75th percentile) of 71 to 130 pg/mL] at the final visit.
The pediatric safety of TAKEPRON Capsules has been assessed in 66 pediatric patients aged one to 11 years of age. Of the 66 patients with GERD 85% (56/66) took TAKEPRON for 8 weeks and 15% (10/66) took it for 12 weeks.
The most frequently reported (two or more patients) treatment-related adverse reactions in patients one to 11 years of age (N=66) were constipation (5%) and headache (3%).
Twelve to 17 years of age: In an uncontrolled, open-label, U.S. multicenter study, 87 adolescent patients (12 to 17 years of age) with symptomatic GERD were treated with TAKEPRON for 8 to 12 weeks. Baseline upper endoscopies classified these patients into two groups: 64 (74%) nonerosive GERD and 23 (26%) erosive esophagitis (EE). The nonerosive GERD patients received TAKEPRON 15 mg daily for eight weeks and the EE patients received TAKEPRON 30 mg daily for eight to 12 weeks. At baseline, 89% of these patients had mild to moderate overall GERD symptoms (assessed by investigator interviews). During 8 weeks of TAKEPRON 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 eight weeks of TAKEPRON treatment. One patient remained unhealed after 12 weeks of treatment (see Table 19).
Click on icon to see table/diagram/imageIn 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 to 75th percentile) of 44 to 88 pg/mL] at the final visit. (Normal serum gastrin levels are 25 to 111 pg/mL.)
The safety of TAKEPRON Capsules has been assessed in these 87 adolescent patients. Of the 87 adolescent patients with GERD, 6% (5/87) took TAKEPRON for less than six weeks, 93% (81/87) for 6 to 10 weeks, and 1% (1/87) for greater than 10 weeks.
The most frequently reported (at least 3%) treatment-related adverse reactions 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 less than 1% of adult patients, was reported in this study by three adolescent patients with nonerosive GERD, who had dizziness concurrently with other reactions (such as migraine, dyspnea, and vomiting).
Use in Elderly: No dosage adjustment of TAKEPRON is necessary in geriatric patients. The incidence rates of adverse reactions and laboratory test abnormalities are similar to those seen in younger patients (see Pharmacology: Pharmacokinetics under Actions).
