Other causes include Mallory-Weiss tears, cancer, and angiodysplasia.A number of medications are found to cause upper GI bleeds. NSAIDs or COX-2 inhibitors increase the risk about fourfold. SSRIs, corticosteroids, and anticoagulants may also increase the risk. The risk with dabigatran is 30% greater than that with warfarin. Lower gastrointestinal
Lower gastrointestinal bleeding is typically from the colon, rectum or anus. Common causes of lower gastrointestinal bleeding include hemorrhoids, cancer, angiodysplasia, ulcerative colitis, Crohns disease, and aortoenteric fistula. It may be indicated by the passage of fresh red blood rectally, especially in the absence of bloody vomiting. Lower gastrointestinal bleeding could also lead to melena if the bleeding occurs in the small intestine or proximal colon. Signs and symptoms
Gastrointestinal bleeding can range from small non-visible amounts, which are only detected by laboratory testing, to massive bleeding where bright red blood is passed and shock develops. Rapid bleeding may cause syncope. The presence of bright red blood in stool, known as hematochezia, typically indicates lower gastrointestinal bleeding. Digested blood from the upper gastrointestinal tract may appear black rather than red, resulting in "coffee ground" vomit or melena. Other signs and symptoms include feeling tired, dizziness, and pale skin color.A number of foods and medications can turn the stool either red or black in the absence of bleeding. Bismuth found in many antacids may turn stools black as may activated charcoal. Blood from the vagina or urinary tract may also be confused with blood in the stool.
A rare but potentially fatal adverse effect may be PML, which has been observed under treatment with dimethyl fumarate. Overdose
No specific antidote is known. Adverse effects caused by overdosing diroximel fumarate are treated symptomatically. Interactions
Diroximel fumarate does not interact with cytochrome P450 enzymes or P-glycoprotein. Its active metabolite, monomethyl fumarate, has a relatively low plasma protein binding of 27 to 45%. Therefore, its potential for pharmacokinetic interactions is considered to be low.Inactivated vaccines can be given under diroximel fumarate therapy, based on experience with other immunosuppressant drugs, such as studies with tetanus, pneumococcal and meningococcal vaccines. No studies regarding the effectiveness of these vaccines under diroximel fumarate have been conducted. No data are available regarding combination with live vaccines, chemotherapy or immunosuppressants. Nephrotoxicity could be increased when the drug is combined with aminoglycoside antibiotics, diuretics, NSAIDs or lithium. Pharmacology
Mechanism of action
The drugs mechanism of action is not well understood. In preclinical studies it activated nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor that is up-regulated under oxidative stress. Pharmacokinetics
The pharmacokinetics of diroximel fumarate has been found to be practically identical to that of dimethyl fumarate. Both are prodrugs of monomethyl fumarate.Taking the drug with a high-calorie, high-fat meal slows down absorption, but has no relevant effect on overall absorption. The US label recommends not taking the drug together with high-calorie and high-fat meals.After ingestion, the substance is cleaved by esterase enzymes before reaching the systemic circulation, resulting in monomethyl fumarate (MMF), the active metabolite, and hydroxyethyl succinimide (HES), which is inactive.