Lialda 1.2 GM Delayed Release Oral Tablet
DRUG INTERACTIONS
7 No investigations of interaction between LIALDA and other drugs except for certain antibiotics have been performed [see Pharmacokinetics (12.3)] .
However, the following drug-drug interactions have been reported for products containing mesalamine: Nephrotoxic agents including NSAIDs: renal reactions have been reported.
( 7.1 ) Azathioprine or 6-mercaptopurine: blood disorders have been reported.
( 7.2 ) 7.1 Nephrotoxic Agents, Including Non-Steroidal Anti-Inflammatory Drugs The concurrent use of mesalamine with known nephrotoxic agents, including non-steroidal anti-inflammatory drugs (NSAIDs) may increase the risk of renal reactions.
7.2 Azathioprine or 6-mercaptopurine The concurrent use of mesalamine with azathioprine or 6-mercaptopurine may increase the risk for blood disorders.
OVERDOSAGE
10 LIALDA is an aminosalicylate, and symptoms of salicylate toxicity may include tinnitus, vertigo, headache, confusion, drowsiness, sweating, seizures, hyperventilation, dyspnea, vomiting, and diarrhea.
Severe intoxication may lead to disruption of electrolyte balance and blood-pH, hyperthermia, dehydration, and end organ damage.
There is no specific known antidote for mesalamine overdose; however, conventional therapy for salicylate toxicity may be beneficial in the event of acute overdosage.
Fluid and electrolyte imbalance should be corrected by the administration of appropriate intravenous therapy.
Adequate renal function should be maintained.
DESCRIPTION
11 Each LIALDA delayed-release tablet for oral administration contains 1.2 g 5-aminosalicylic acid (5-ASA; mesalamine), an anti-inflammatory agent.
Mesalamine also has the chemical name 5-amino-2-hydroxybenzoic acid and its structural formula is: Molecular formula: C 7 H 7 NO 3 Molecular weight: 153.14 The tablet is coated with a pH dependent polymer film, which breaks down at or above pH 6.8, normally in the terminal ileum where mesalamine then begins to be released from the tablet core.
The tablet core contains mesalamine with hydrophilic and lipophilic excipients and provides for extended release of mesalamine.
The inactive ingredients of LIALDA are sodium carboxymethylcellulose, carnauba wax, stearic acid, silica (colloidal hydrated), sodium starch glycolate (type A), talc, magnesium stearate, methacrylic acid copolymer types A and B, triethylcitrate, titanium dioxide, red ferric oxide and polyethylene glycol 6000.
lialda-1
CLINICAL STUDIES
14 14.1 Active, Mild to Moderate Ulcerative Colitis Two similarly designed, randomized, double blind, placebo-controlled trials were conducted in 517 adult patients with active, mild to moderate ulcerative colitis.
The study population was primarily Caucasian (80%), had a mean age of 42 years (6% age 65 years or older), and was approximately 50% male.
Both studies used LIALDA doses of 2.4 g/day and 4.8 g/day administered once daily for 8 weeks except for the 2.4 g/day group in Study 1, which was given in two divided doses (1.2 g twice daily).
The primary efficacy end-point in both trials was to compare the percentage of patients in remission after 8 weeks of treatment for the LIALDA treatment groups versus placebo.
Remission was defined as an Ulcerative Colitis Disease Activity Index (UC-DAI) of ≤ 1, with scores of zero for rectal bleeding and for stool frequency, and a sigmoidoscopy score reduction of 1 point or more from baseline.
In both studies, the LIALDA doses of 2.4 g/day and 4.8 g/day demonstrated superiority over placebo in the primary efficacy endpoint (Table 5).
Both LIALDA doses also provided consistent benefit in secondary efficacy parameters, including clinical improvement, treatment failure, clinical remission, and sigmoidoscopic improvement.
LIALDA 2.4 g/day and 4.8 g/day had similar efficacy profiles.
Table 5: Patients in Remission at Week 8 Dose Study 1 (n=262) n/N (%) Study 2 (n=255) n/N (%) LIALDA 2.4 g/day 30/88 (34.1) 34/84 (40.5) LIALDA 4.8 g/day 26/89 (29.2) 35/85 (41.2) Placebo 11/85 (12.9) 19/86 (22.1) 14.2 Maintenance of Remission in Patients with Ulcerative Colitis A multicenter, randomized, double-blind, active comparator study was conducted in a total of 826 adult patients in remission from ulcerative colitis.
The study population had a mean age of 45 years (8% age 65 years or older), were 52% male, and were primarily Caucasian (64%).
Maintenance of remission was assessed using a modified Ulcerative Colitis Disease Activity Index (UC-DAI).
For this trial, maintenance of remission was based on maintaining endoscopic remission defined as a modified UC-DAI endoscopy subscore of ≤1.
An endoscopy subscore of 0 represented normal mucosal appearance with intact vascular pattern and no friability or granulation.
For this trial the endoscopy score definition of 1 (mild disease) was modified such that it could include erythema, decreased vascular pattern, and minimal granularity; however, it could not include friability.
Subjects were randomized in a 1:1 ratio to receive either LIALDA 2.4 g/day administered once daily or mesalamine delayed release 1.6 g/day administered as 0.8 g twice daily.
The proportion of patients who maintained remission at Month 6 in this study using LIALDA 2.4 g once daily (83.7%) was similar to that seen using the comparator (mesalamine delayed release) 1.6 g/day (81.5%).
HOW SUPPLIED
16 /STORAGE AND HANDLING LIALDA is available as red-brown ellipsoidal film coated delayed-release tablets containing 1.2 g mesalamine, and debossed on one side imprinted with S476.
NDC 0179-0142-70 Box of 30 Delayed-Release Unit Dose Tablets.
Store at room temperature 15 ° C to 25 ° C (59 ° F to 77 ° F); excursions permitted to 30 ° C (86 ° F).
See USP Controlled Room Temperature.
REPACKAGED BY: KAISER FOUNDATION HOSPITALS LIVERMORE, CA 94551
RECENT MAJOR CHANGES
Warnings and Precautions, Interference with Laboratory Tests (5.6), 08/2013
GERIATRIC USE
8.5 Geriatric Use Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias, i.e., neutropenia and pancytopenia in patients who were 65 years or older who were taking mesalamine-containing products such as LIALDA.
Caution should be taken to closely monitor blood cell counts during mesalamine therapy.
Clinical trials of LIALDA did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.
Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
Systemic exposures are increased in elderly subjects.
[see Clinical Pharmacology (12.3) ] .
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concurrent disease or other drug therapy in elderly patients.
DOSAGE FORMS AND STRENGTHS
3 The red-brown ellipsoidal delayed-release tablet containing 1.2 g mesalamine is debossed on one side and imprinted with S476.
Delayed-Release Tablets: 1.2 g ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action The mechanism of action of mesalamine is not fully understood, but appears to have a topical anti-inflammatory effect on the colonic epithelial cells.
Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase and lipoxygenase pathways, is increased in patients with chronic inflammatory bowel disease, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon.
Mesalamine has the potential to inhibit the activation of nuclear factor kappa B (NFκB) and consequently the production of key pro-inflammatory cytokines.
It has been proposed that reduced expression of PPARγ nuclear receptors (γ-form of peroxisome proliferator-activated receptors) may be implicated in ulcerative colitis.
There is evidence that mesalamine produces pharmacodynamic effects through direct activation of PPARγ receptors in the colonic/rectal epithelium.
INDICATIONS AND USAGE
1 LIALDA is indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis and for the maintenance of remission of ulcerative colitis.
LIALDA is a locally acting 5-aminosalicylic acid (5-ASA) indicated for the induction of remission in adults with active, mild to moderate ulcerative colitis and for the maintenance of remission of ulcerative colitis.
( 1 )
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness of LIALDA in pediatric patients have not been established.
PREGNANCY
8.1 Pregnancy Pregnancy Category B.
Reproduction studies with mesalamine have been performed in rats at doses up to 1000 mg/kg/day (1.8 times the maximum recommended human dose based on a body surface area comparison) and rabbits at doses up to 800 mg/kg/day (2.9 times the maximum recommended human dose based on a body surface area comparison) and have revealed no evidence of impaired fertility or harm to the fetus due to mesalamine.
There are, however, no adequate and well-controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Mesalamine is known to cross the placental barrier.
NUSRING MOTHERS
8.3 Nursing Mothers Low concentrations of mesalamine and higher concentrations of its N-acetyl metabolite have been detected in human breast milk.
The clinical significance of this has not been determined and there is limited experience of nursing women using mesalamine.
Caution should be exercised if LIALDA is administered to a nursing woman.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Renal impairment may occur.
Assess renal function at the beginning of treatment and periodically during treatment.
( 5.1 ) Mesalamine-induced acute intolerance syndrome has been reported.
Observe patients closely for worsening of these symptoms while on treatment.
( 5.2 ) Use caution when treating patients who are hypersensitive to sulfasalazine.
( 5.3 ) Mesalamine-induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported.
( 5.3 ) Hepatic failure has been reported in patients with pre-existing liver disease.
Use caution when treating patients with liver disease.
( 5.4 ) Upper GI tract obstruction may delay onset of action.
( 5.5 ) Use of mesalamine may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection.
(5.6) 5.1 Renal Impairment Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis, and, rarely, renal failure, has been reported in patients given products such as LIALDA that contain mesalamine or are converted to mesalamine.
It is recommended that patients have an evaluation of renal function prior to initiation of LIALDA therapy and periodically while on therapy.
Exercise caution when using LIALDA in patients with known renal dysfunction or a history of renal disease.
In animal studies, the kidney was the principal organ for toxicity.
[See Drug Interactions (7.1) and Nonclinical Toxicology (13.2) ] 5.2 Mesalamine-Induced Acute Intolerance Syndrome Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from an exacerbation of ulcerative colitis.
Although the exact frequency of occurrence has not been determined, it has occurred in 3% of patients in controlled clinical trials of mesalamine or sulfasalazine.
Symptoms include cramping, acute abdominal pain and bloody diarrhea, and sometimes fever, headache, and rash.
Observe patients closely for worsening of these symptoms while on treatment.
If acute intolerance syndrome is suspected, promptly discontinue treatment with LIALDA.
5.3 Hypersensitivity Reactions Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to LIALDA tablets or to other compounds that contain or are converted to mesalamine.
Mesalamine-induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported with LIALDA and other mesalamine medications.
Caution should be taken in prescribing this medicine to patients with conditions predisposing them to the development of myocarditis or pericarditis.
5.4 Hepatic Impairment There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine.
Caution should be exercised when administering LIALDA to patients with liver disease.
5.5 Upper GI Tract Obstruction Pyloric stenosis or other organic or functional obstruction in the upper gastrointestinal tract may cause prolonged gastric retention of LIALDA which would delay mesalamine release in the colon.
5.6 Interference with Laboratory Tests Use of mesalamine may lead to spuriously elevated test results when measuring urinary normetanephrine by liquid chromatography with electrochemical detection because of the similarity in the chromatograms of normetanephrine and mesalamine’s main metabolite, N-acetylaminosalicylic acid (N-Ac-5-ASA).
An alternative, selective assay for normetanephrine should be considered.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Instruct patients not to take LIALDA if they have hypersensitivity to salicylates (e.g., aspirin) or other mesalamines.
Inform patients to let their physicians know all medications they are taking and if they: are allergic to sulfasalazine, salicylates or mesalamine; are taking non-steroidal anti-inflammatory drugs (NSAIDs) or other nephrotoxic agents; are taking azathioprine, or 6-mercaptopurine; experience cramping, abdominal pain, bloody diarrhea, fever, headache or rash; have a history of myocarditis or pericarditis; have kidney or liver disease; have a history of stomach blockage; are pregnant, intend to become pregnant or are breast-feeding.
Patients should be instructed to swallow LIALDA delayed-release tablets whole, taking care not to break the outer coating.
Manufactured for Shire US Inc., 725 Chesterbrook Blvd., Wayne, PA 19087, USA by Cosmo S.p.A., Milan, Italy.
By license of Nogra Pharma Limited, Dublin, Ireland.
U.S.
Patent No.
6,773,720.
© 2013 Shire US Inc.
REPACKAGED BY: KAISER FOUNDATION HOSPITALS LIVERMORE, CA 94551
DOSAGE AND ADMINISTRATION
2 The recommended dosage for the induction of remission in adult patients with active, mild to moderate ulcerative colitis is two to four 1.2 g tablets taken once daily with a meal for a total daily dose of 2.4 g or 4.8 g.
The recommended dosage for the maintenance of remission is two 1.2 g tablets taken once daily with a meal for a total daily dose of 2.4 g.
For induction of remission of active, mild to moderate ulcerative colitis, two to four 1.2 g tablets taken once daily with food.
( 1 , 2 ) For maintenance of remission of ulcerative colitis, two 1.2 g tablets taken once daily with food.
( 1 , 2 )