Salazine (Mesalazine)

Uses

This medication is used to treat a certain bowel disease (ulcerative colitis). It helps to reduce symptoms of ulcerative colitis such as diarrhea, rectal bleeding, and stomach pain. Mesalamine belongs to a class of drugs known as aminosalicylates.This medication may also be used to treat Crohn's disease.

Salazine (Mesalazine) is also used to associated treatment for these conditions: Crohn's Disease (CD), Proctitis, Ulcerative, Proctosigmoiditis, Ulcerative Colitis

How Salazine (Mesalazine) works

Although the mechanism of action of mesalazine is not fully understood, it is believed to possess a topical anti-inflammatory effect on colonic epithelial cells . Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways, i.e., prostanoids, and through the lipoxygenase pathways, i.e., leukotrienes and hydroxyeicosatetraenoic acids, is increased in patients with chronic inflammatory bowel disease, and it is possible that mesalazine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon .

Furthermore, mesalazine also has the potential to inhibit the activation of Nuclear Factor kappa B (NKkB) and consequently the production of key of pro-inflammatory cytokines . It has been proposed that reduced expression of PPAR gamma nuclear receptors (gamma form of peroxisome proliferator-activated receptors) may be implicated in ulcerative colitis . There is evidence that mesalazine produces pharmacodynamic effects through direct activation of PPAR gamma receptors in the colonic/rectal epithelium as well .

Moreover, since increased leukocyte migration, abnormal cytokine production, increased production of arachidonic acid metabolites, particularly leukotriene B4, and increased free radical formation in the inflamed intestinal tissue are all present in patients with inflammatory bowel disease it is also believed that mesalazine has in-vitro and in-vivo pharmacological effects that inhibit leukocyte chemotaxis, decrease cytokine and leukotriene production and scavenge for free radicals .

Dosage

Salazine (Mesalazine) dosage

Adult:

• Acute attack: Initially, up to 4 gm/day in 2-3 divided doses
• Maintenance of remission: Initially, 1.5 gm/day in 2-3 divided doses, adjust subsequently based on response.

Child (5-15 year):

• Acute attack: 15-20 mg/kg (max: 1 gm) tid
• Maintenance of remission: 10 mg/kg (max: 500 mg) 2-3 times daily.

Should be taken on an empty stomach: Take 1 hr before meals. Swallow whole, do not chew/crush.

Side Effects

Abdominal pain, diarrhea, flatulence, nausea, vomiting. Tab: Renal impairment, acute & chronic interstitial nephritis, renal insufficiency; exanthema, drug fever, bronchospasm, pericarditis & myocarditis, pancreatitis, allergic & fibrotic lung reactions including dyspnoea, cough, alveolitis, pulmonary eosinophilia, lung infiltration, pneumonitis, butterfly rash (lupus erythematosus syndrome), pancolitis; myalgia, arthralgia; aplastic anaemia, agranulocytosis, pancytopenia, neutropenia, leucopenia, thrombocytopenia; raised transaminase & parameters of cholestasis, hepatitis, cholestatic hepatitis; alopecia; reversible oligospermia. Enema: Allergic exanthema, drug fever; bronchospasm; lupus erythematosus-like syndrome. Granules: Headache, dizziness; pericarditis. Supp: Allergic skin rash, fever, breathing difficulty.

Toxicity

Oral, mouse: LD₅₀ = 3370 mg/kg; Oral, rat: LD₅₀ = 2800 mg/kg; Skin, rabbit: LD₅₀ = >5 gm/kg .

There have been no documented reports of serious toxicity in man resulting from massive overdosing with mesalamine. Under ordinary circumstances, mesalazine absorption from the colon is limited. Although there is little to no clinical experience with mesalazine overdosage . Salazine (Mesalazine) is an aminosalicylate, and symptoms of salicylate toxicity may be possible, such as tinnitus, vertigo, headache, confusion, drowsiness, sweating, hyperventilation, vomiting, and diarrhea . Severe intoxication with salicylates can lead to disruption of electrolyte balance and blood-pH, hyperthermia, and dehydration .

Precaution

Use with caution, usually starting at the low end of the dosage range, because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy.

Hypersensitivity: Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to mesalamine.

Renal Function: Patients with history of renal function impairment or disease may have worsening of renal function.

Hepatic Function: Use with caution. There have been reports of hepatic failure in patients with preexisting liver disease.

Sulfite Sensitivity: Some products may contain sulfites, which may cause allergic reactions in susceptible individuals.

Interaction

Antacids: Because the dissolution of the coating of Apriso granules depends on pH, do not administer with antacids.

Nephrotoxic agents (including NSAIDs): Increased risk of renal adverse reactions.

Thiopurines (eg, azathioprine, mercaptopurine): Risk of leukopenia may be increased.

Warfarin: Decreased anticoagulant effect of warfarin has been reported in 1 patient.

Laboratory Test Interactions: None well documented.

Food Interaction

• Take with or without food. The absorption is unaffected by food.

Volume of Distribution

The apparent volume of distribution (Vd) of the drug in adults is approximately 0.2 L/kg .

Elimination Route

Depending on the formulation administered, prescribing information for orally administered delayed-released tablets of 2.4g or 4.8g of mesalazine given once daily for 14 days to healthy volunteers was to found to be about 21% to 22% of the administered dose while prescribing information for an orally administered controlled-release capsule formulation suggests 20% to 30% of the mesalazine in the formulation is absorbed . In contrast, when mesalamine is administered orally as an unformulated 1-g aqueous suspension, mesalazine is approximately 80% absorbed .

Half Life

The apparent elimination half-life documented for oral delayed-release mesalazine tablets is 7 to 12 hours . The elimination half-life recorded for the active N-acetyl-5-aminosalicylic acid metabolite generated from the administration of oral delayed-release mesalazine tablets is 12 to 23 hours .

Clearance

The mean (SD) renal clearance in L/h for mesalazine following the single dose administration of mesalazine delayed-release tablets 4.8g under fasting conditions to young and elderly subjects was documented as 2.05 (1.33) in young subjects aged 18 to 35 years old, 2.04 (1.16) in elderly subjects aged 65 to 75 years old, and 2.13 (1.20) in elderly subjects older than 75 years .

Elimination Route

Elimination of mesalazine is mainly via the renal route following metabolism to N-acetyl-5-aminosalicylic acid (acetylation) . However, there is also limited excretion of the parent mesalazine drug in the urine .

After the oral administration of the extended-release formulation of mesalazine, of the approximately 21% to 22% of the drug 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 .

When given the controlled-release formulation, about 130 mg free mesalazine was recovered in the feces following a single 1-g dose, which was comparable to the 140 mg of mesalazine recovered from the molar equivalent sulfasalazine tablet dose of 2.5 g F3001]. Elimination of free mesalazine and salicylates in feces increased proportionately with the dose given. N-acetylmesalazine was the primary compound excreted in the urine (19% to 30%) following the controlled-release dosing .

Pregnancy & Breastfeeding use

Pregnancy Category B. Either animal-reproduction studies have not demonstrated a foetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the 1st trimester (and there is no evidence of a risk in later trimesters).

Lactation: Excreted in breast milk.

Contraindication

Hypersensitivity to salicylates, aminosalicylates, or any component of the product.

Special Warning

Renal Impairment: CrCl <20 Dosage Avoid.

Hepatic Impairment: Avoid in severe impairment.

Acute Overdose

Products are salicylates; symptoms of salicylate toxicity may include confusion, deafness, dehydration, diarrhea, drowsiness, dyspnea, electrolyte and blood pH imbalance, headache, hematemesis, hyperpnea, hyperthermia, hyperventilation, lethargy, seizures, sweating, tachypnea, tinnitus, vertigo, vomiting.

Storage Condition

Tablet: store at below 25° C.

Capsule: protect from light and store at 15-30° C.

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