Lialda Information
Lialda () Indications And Usage
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 () Dosage And Administration
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.
Lialda () Dosage Forms And Strengths
The red-brown ellipsoidal delayed-release tablet containing 1.2 g mesalamine is debossed on one side and imprinted with S476.
Lialda () Contraindications
Lialda () is contraindicated in patients with known hypersensitivity to salicylates or aminosalicylates or to any of the ingredients of Lialda () [see , ].
Lialda () Warnings And Precautions
Array
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 and ]
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.
Lialda () Adverse Reactions
The most serious adverse reactions seen in Lialda () clinical trials or with other products that contain or are metabolized to mesalamine are:
Lialda () Drug Interactions
No investigations of interaction between Lialda () and other drugs have been performed. However, the following interactions between mesalamine medications and other drugs have been reported.
Lialda () Use In Specific Populations
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.
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 ]. 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.
Lialda () Overdosage
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.
Lialda () Description
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: CHNO
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 () Clinical Pharmacology
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 (NFkB) and consequently the production of key pro-inflammatory cytokines. It has been proposed that reduced expression of PPARy nuclear receptors (y-form of peroxisome proliferator-activated receptors) may be implicated in ulcerative colitis. There is evidence that mesalamine produces pharmacodynamic effects through direct activation of PPARy receptors in the colonic/rectal epithelium.
Absorption
The total absorption of mesalamine from Lialda () 2.4 g or 4.8 g given once daily for 14 days to healthy volunteers was found to be approximately 21-22% of the administered dose.
Gamma-scintigraphy studies have shown that a single dose of Lialda () 1.2 g (one tablet) passed intact through the upper gastrointestinal tract of fasted healthy volunteers. Scintigraphic images showed a trail of radio-labeled tracer in the colon, suggesting that mesalamine had distributed through this region of the gastrointestinal tract.
In a single dose study, Lialda () 1.2 g, 2.4 g and 4.8 g were administered in the fasted state to healthy subjects. Plasma concentrations of mesalamine were detectable after 2 hours and reached a maximum by 9-12 hours on average for the doses studied. The pharmacokinetic parameters are highly variable among subjects (Table 3). Mesalamine systemic exposure in terms of area under the plasma concentration-time curve (AUC) was slightly more than dose proportional between 1.2 g and 4.8 g Lialda () . Maximum plasma concentrations (C) of mesalamine increased approximately dose proportionately between 1.2 g and 2.4 g and sub-proportionately between 2.4 g and 4.8 g Lialda () , with the dose normalized value at 4.8 g representing, on average, 74% of that at 2.4 g based on geometric means.
Table 3: Mean (SD) PK Parameters for Mesalamine Following Single Dose Administration of Lialda () Under Fasting Conditions
Administration of a single dose of Lialda () 4.8 g with a high fat meal resulted in further delay in absorption, and plasma concentrations of mesalamine were detectable 4 hours following dosing. However, a high fat meal increased systemic exposure of mesalamine (mean C: ( 91%; mean AUC: ( 16%) compared to results in the fasted state. Lialda () was administered with food in the controlled clinical trials that supported its approval.
In a single and multiple dose pharmacokinetic study of Lialda () , 2.4 g or 4.8 g was administered once daily with standard meals to 28 healthy volunteers per dose group. Plasma concentrations of mesalamine were detectable after 4 hours and were maximal by 8 hours after the single dose. Steady state was achieved generally by 2 days after dosing. Mean AUC at steady state was only modestly greater (1.1- to 1.4-fold) than predictable from single dose pharmacokinetics.
In a single dose pharmacokinetic study of Lialda () , 4.8 g was administered in the fasted state to 71 healthy male and female volunteers (28 young (18-35yrs); 28 elderly (65-75yrs); 15 elderly (>75yrs)). Increased age resulted in increased systemic exposure (approximately 2-fold in C), to mesalamine and its metabolite N-acetyl-5-aminosalicylic acid. Increased age resulted in a slower apparent elimination of mesalamine, though there was high between-subject variability. Systemic exposures in individual subjects were inversely correlated with renal function as assessed by estimated creatinine clearance.
Table 4: Mean (SD) PK Parameters for Mesalamine Following Single Dose Administration of Lialda () 4.8 g under Fasting Conditions to Young and Elderly Subjects
Distribution
Mesalamine is approximately 43% bound to plasma proteins at the concentration of 2.5 μg/mL.
Metabolism
The only major metabolite of mesalamine (5-aminosalicylic acid) is N-acetyl-5-aminosalicylic acid. Its formation is brought about by N-acetyltransferase (NAT) activity in the liver and intestinal mucosa cells, principally by NAT-1.
Elimination
Elimination of mesalamine is mainly via the renal route following metabolism to N-acetyl-5-aminosalicylic acid (acetylation). However, there is also limited excretion of the parent drug in urine. Of the approximately 21-22% of the dose absorbed, less than 8% of the dose was excreted unchanged in the urine after 24 hours, compared with greater than 13% for N-acetyl-5-aminosalicylic acid. The apparent terminal half-lives for mesalamine and its major metabolite after administration of Lialda () 2.4 g and 4.8 g were, on average, 7-9 hours and 8-12 hours, respectively.
Lialda () Nonclinical Toxicology
Carcinogenesis
In a 104-week dietary carcinogenicity study in CD-1 mice, mesalamine at doses up to 2500 mg/kg/day was not tumorigenic. This dose is 2.2 times the maximum recommended human dose (based on a body surface area comparison) of Lialda () . Furthermore, in a 104-week dietary carcinogenicity study in Wistar rats, mesalamine up to a dose of 800 mg/kg/day was not tumorigenic. This dose is 1.4 times the recommended human dose (based on a body surface area comparison) of Lialda () .
Mutagenesis
No evidence of mutagenicity was observed in an Ames test or an mouse micronucleus test.
Impairment of Fertility
No effects on fertility or reproductive performance were observed in male or female rats at oral doses of mesalamine up to 400 mg/kg/day (0.7 times the maximum recommended human dose based on a body surface area comparison).
Lialda () Clinical Studies
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 (1.2g 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
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%).
Lialda () How Supplied/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 54092-476-12 HDPE Bottle with a child-resistant closure of 120 delayed-release tablets.
Store at room temperature 15C to 25C (59F to 77F); excursions permitted to 30C (86F).
See USP Controlled Room Temperature.
Lialda () 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 physcians know all medications they are taking and if they:
- Patients should be instructed to swallow Lialda () delayed-release tablets whole, taking care not to break the outer coating. The outer coating needs to remain intact so that Lialda () is absorbed properly.
Manufactured for Shire US Inc., 725 Chesterbrook Blvd., Wayne, PA 19087, USA by Cosmo S.p.A., Milan, Italy. By license of Giuliani S.p.A., Milan Italy.
U.S. Patent No. 6,773,720.
© 2011 Shire US Inc.
