Dipentum

Aminosalicyclic Acid and Related Intestinal Antiinflammatory Agents

Administer with food.
Patients should drink an adequate amount of fluids during treatment.

pancreatitis / Delayed / Incidence not known
aplastic anemia / Delayed / Incidence not known
pancytopenia / Delayed / Incidence not known
hemolytic anemia / Delayed / Incidence not known
hepatic necrosis / Delayed / Incidence not known
cirrhosis / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
erythema nodosum / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
myocarditis / Delayed / Incidence not known
pericarditis / Delayed / Incidence not known
bronchospasm / Rapid / Incidence not known
interstitial nephritis / Delayed / Incidence not known
proteinuria / Delayed / Incidence not known
nephrotoxicity / Delayed / Incidence not known
nephrotic syndrome / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known

stomatitis / Delayed / 1.0-1.0
colitis / Delayed / Incidence not known
neutropenia / Delayed / Incidence not known
anemia / Delayed / Incidence not known
eosinophilia / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
leukopenia / Delayed / Incidence not known
lymphopenia / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
jaundice / Delayed / Incidence not known
hyperbilirubinemia / Delayed / Incidence not known
cholestasis / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
depression / Delayed / Incidence not known
peripheral neuropathy / Delayed / Incidence not known
erythema / Early / Incidence not known
hypertension / Early / Incidence not known
orthostatic hypotension / Delayed / Incidence not known
peripheral edema / Delayed / Incidence not known
palpitations / Early / Incidence not known
sinus tachycardia / Rapid / Incidence not known
chest pain (unspecified) / Early / Incidence not known
dyspnea / Early / Incidence not known
interstitial lung disease / Delayed / Incidence not known
dysuria / Early / Incidence not known
hematuria / Delayed / Incidence not known
nephrolithiasis / Delayed / Incidence not known
hot flashes / Early / Incidence not known
blurred vision / Early / Incidence not known
impotence (erectile dysfunction) / Delayed / Incidence not known

diarrhea / Early / 11.1-17.0
abdominal pain / Early / 10.1-10.1
nausea / Early / 5.0-5.0
headache / Early / 5.0-5.0
dyspepsia / Early / 4.0-4.0
arthralgia / Delayed / 4.0-4.0
rash / Early / 2.3-2.3
fatigue / Early / 1.8-1.8
lethargy / Early / 1.8-1.8
drowsiness / Early / 1.8-1.8
infection / Delayed / 1.5-1.5
anorexia / Delayed / 1.3-1.3
pruritus / Rapid / 1.3-1.3
vomiting / Early / 1.0-1.0
vertigo / Early / 1.0-1.0
dizziness / Early / 1.0-1.0
pyrosis (heartburn) / Early / Incidence not known
flatulence / Early / Incidence not known
xerostomia / Early / Incidence not known
tremor / Early / Incidence not known
irritability / Delayed / Incidence not known
paresthesias / Delayed / Incidence not known
insomnia / Early / Incidence not known
alopecia / Delayed / Incidence not known
photosensitivity / Delayed / Incidence not known
muscle cramps / Delayed / Incidence not known
myalgia / Early / Incidence not known
increased urinary frequency / Early / Incidence not known
fever / Early / Incidence not known
chills / Rapid / Incidence not known
tinnitus / Delayed / Incidence not known
xerophthalmia / Early / Incidence not known
menorrhagia / Delayed / Incidence not known

Dipentum

Rx

Oral diazo-bonded 5-aminosalicylate (5-ASA) prodrug; bacterial azoreduction in the intestines releases mesalamine (5-ASA)
Used in adults for the maintenance of remission in ulcerative colitis
Dose-related diarrhea is relatively common

No dosage adjustments are recommended for patients with hepatic impairment; however, monitor these patients during treatment.

Olsalazine is converted to mesalamine, which is known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Dosage adjustments may be needed; however, specific guidelines for olsalazine dosage adjustments in renal impairment are not available. Discontinue olsalazine if renal function deteriorates while on therapy.

Amlodipine; Celecoxib: (Moderate) Monitor patients for signs of worsening renal function during coadministration of olsalazine and celecoxib. Coadministration may increase the risk for drug-induced nephrotoxicity. Olsalazine is converted to mesalamine in the gastrointestinal tract; nephrotoxicity has been observed during mesalamine treatment.
Azathioprine: (Moderate) 5-aminosalicylates (e.g., sulfasalazine, mesalamine, olsalazine) may interact with azathioprine and increase the risk of azathioprine-related toxicity. The inhibition of thiopurine methyltransferase activity, one of the enzymes responsible for azathioprine metabolism, by 5-aminosalicylates has been described via in vitro and in vivo study. Theoretically, this interaction could result in a higher risk of bone marrow suppression or other azathioprine dose-related side effects. If concurrent therapy cannot be avoided, closely monitor platelet and complete blood cell counts.
Celecoxib: (Moderate) Monitor patients for signs of worsening renal function during coadministration of olsalazine and celecoxib. Coadministration may increase the risk for drug-induced nephrotoxicity. Olsalazine is converted to mesalamine in the gastrointestinal tract; nephrotoxicity has been observed during mesalamine treatment.
Celecoxib; Tramadol: (Moderate) Monitor patients for signs of worsening renal function during coadministration of olsalazine and celecoxib. Coadministration may increase the risk for drug-induced nephrotoxicity. Olsalazine is converted to mesalamine in the gastrointestinal tract; nephrotoxicity has been observed during mesalamine treatment.
Dalteparin: (Moderate) Coadministration of 5-aminosalicylates and low molecular weight heparins may result in an increased risk of bleeding (i.e., hematomas) following neuraxial anesthesia. Discontinue 5-aminosalicylates prior to the initiation of a low molecular weight heparins. If this is not possible, it is recommended to monitor patients closely for bleeding.
Enoxaparin: (Moderate) Coadministration of 5-aminosalicylates and low molecular weight heparins may result in an increased risk of bleeding (i.e., hematomas) following neuraxial anesthesia. Discontinue 5-aminosalicylates prior to the initiation of a low molecular weight heparins. If this is not possible, it is recommended to monitor patients closely for bleeding.
Heparin: (Moderate) Coadministration of 5-aminosalicylates and heparin may result in an increased risk of bleeding (i.e., hematomas) following neuraxial anesthesia. Discontinue 5-aminosalicylates prior to the initiation of heparin. If this is not possible, it is recommended to monitor patients closely for bleeding.
Low Molecular Weight Heparins: (Moderate) Coadministration of 5-aminosalicylates and low molecular weight heparins may result in an increased risk of bleeding (i.e., hematomas) following neuraxial anesthesia. Discontinue 5-aminosalicylates prior to the initiation of a low molecular weight heparins. If this is not possible, it is recommended to monitor patients closely for bleeding.
Mercaptopurine, 6-MP: (Moderate) Increased bone marrow suppression may occur if mercaptopurine is coadministered with olsalazine. If concomitant use is necessary, use the lowest possible doses of each drug and closely monitor the patient for myelosuppression. 5-Aminosalicylates, such as olsalazine, have been shown to inhibit the thiopurine methyltransferase (TPMT) enzyme in vitro. Mercaptopurine is inactivated via the TPMT enzyme.
Thioguanine, 6-TG: (Moderate) Use these drugs together with caution; concomitant use may result in reduced metabolism of thioguanine via TPMT and an increased risk for thioguanine-induced toxicity. Monitor patients for signs and symptoms of hematologic and hepatic toxicity. There is in vitro evidence that 5-aminosalicylate derivatives inhibit thiopurine methyltransferase (TPMT), the enzyme that metabolizes thioguanine. Increased thioguanine concentrations can lead to an increased risk for severe thioguanine-induced myelosuppression. In cases of bone marrow suppression, a dose reduction of thioguanine may be necessary.
Warfarin: (Moderate) Olsalazine does not interfere with the protein binding of warfarin, however increased prothrombin time (PT) in patients taking concomitant warfarin has been reported. Closely monitor a patient's PT and INR during and following concomitant olsalazine therapy; dosage adjustments of anticoagulants may be necessary. In elderly patients taking olsalazine with anticoagulants, consider regularly monitoring complete blood cell counts and platelet counts, as an increased risk for blood dyscrasia has been reported in geriatric adults.

Dipentum Oral Cap: 250mg

1 gram/day PO.

1 gram/day PO.

Safety and efficacy have not been established; however, off-label use has been reported.

2 years and older: Safety and efficacy have not been established; however, off-label use has been reported.
Less than 2 years: Safety and efficacy have not been established.

Safety and efficacy have not been established.

Although the mechanism of action of olsalazine has not been fully elucidated, it appears to be local rather than systemic. Olsalazine is converted to mesalamine (5-ASA) in the GI tract by colonic bacteria. The antiinflammatory mechanism of mesalamine is believed to occur, at least in part, through the inhibition of prostaglandin production in the bowel mucosa by inhibition of cyclooxygenase. This effectively diminishes the production of arachidonic acid metabolites, thereby reducing colonic inflammation. Production of arachidonic metabolites appears to be increased in patients with inflammatory bowel disease. Mesalamine also inhibits leukotriene synthesis, possibly through the inhibition of lipoxygenase, which catalyzes the production of arachidonic acid. This activity has been suggested as a major component of the drug's antiinflammatory effects. Inhibition of colonic mucosal sulfidopeptide leukotriene synthesis and chemotactic stimuli for polymorphonuclear leukocytes also may occur. Other possible mechanisms include alterations in colonic fluid balance, immunosuppression, and alteration of the GI bacterial flora.

Olsalazine is administered orally. The pharmacokinetics of olsalazine are similar in both healthy volunteers and in patients with ulcerative colitis. Very little of a dose is systemically absorbed. Olsalazine is 99% bound to plasma proteins. Olsalazine has a very short serum half-life, approximately 0.9 hour. Approximately 0.1 % of an oral dose of olsalazine is metabolized in the liver to olsalazine-O-sulfate (olsalazine-S). Olsalazine-S, in contrast to olsalazine, has a long half-life of 7 days. Olsalazine-S accumulates to steady state within 2 to 3 weeks. Olsalazine-S is more than 99% bound to plasma proteins and its long half-life is mainly due to slow dissociation from the protein binding site. Less than 1% of both olsalazine and olsalazine-S appears undissociated in plasma. N-acetyl-5-ASA (Ac-5-ASA), the major metabolite of 5-ASA found in plasma and urine, and is acetylated (deactivated) in at least 2 sites, the colonic epithelium and the liver. Ac-5-ASA is found in the serum, with peak values of 1.7 to 8.7 micromol/L after a single 1 gram dose. and approximately 20% of the total 5-ASA is recovered in the urine, where it is found almost exclusively as Ac-5-ASA. The remaining 5-ASA is partially acetylated and is excreted in the feces. No accumulation of 5-ASA or Ac-5-ASA in plasma has been detected.
 
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: None

Experts recommend that patients maintained on olsalazine pre-pregnancy continue their treatment regimens during pregnancy.[27628] [45899] [64164] The use of olsalazine during pregnancy appears to pose no significant harm to the developing fetus, and the maternal benefits of therapy appear to outweigh any potential for risk to the fetus. Mesalamine, the active metabolite of olsalazine, is known to cross the placental barrier. However, following administration of olsalazine only a small portion of a dose is absorbed systemically and then is rapidly excreted in the urine. Published data from meta-analyses, cohort studies and case series on the use of mesalamine, the active metabolite of olsalazine, during pregnancy have not reliably informed an association with mesalamine and major birth defects, miscarriage, or adverse maternal or fetal outcomes. The human data include case series, controlled prospective trials, and population-based cohort studies.[45899] [64164] In animal reproduction studies, olsalazine produced fetal developmental toxicity as indicated by reduced fetal weights, retarded ossifications, and immaturity of the fetal visceral organs when given during organogenesis to pregnant rats in doses 5 to 20 times the human dose (100 to 400 mg/kg).[32546] Guidelines state that medical therapy for IBD does not decrease fertility.[64164]

The manufacturer recommends against olsalazine use during breast-feeding unless the benefits outweigh the risks.[32546] Experts, however, consider the use of olsalazine compatible with breast-feeding.[64164] Mesalamine (5-ASA), the active metabolite of olsalazine, is excreted into breast milk in small amounts. Monitor a nursing infant for alterations in bowel function, such as persistent changes in stool frequency. Infant diarrhea has been infrequently reported with the maternal use of 5-ASA.[45899] [64164] Oral administration of olsalazine to lactating rats in doses 5 to 20 times the human dose produced growth retardation in their pups [32546]; however, due to differences in animal physiology during lactation, the implications to human lactation are unknown. Among the 5-ASA agents, the drugs mesalamine, balsalazide, and olsalazine are preferred to sulfasalazine during lactation due to the unknown side effects of sulfasalazine's sulfapyridine metabolite, which is excreted into milk at higher concentrations than the parent drug and has hemolytic and antimicrobial properties.[45899] [59766] [59767] [64164]