"The U.S. Food and Drug Administration today approved Hysingla ER (hydrocodone bitartrate), an extended-release (ER) opioid analgesic to treat pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternat"...
The following serious adverse reactions are discussed elsewhere in the labeling:
- Cardiovascular thrombotic events [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
- Gastrointestinal effects [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
- Hepatic effects [see WARNINGS AND PRECAUTIONS]
- Hypertension [see WARNINGS AND PRECAUTIONS]
- Congestive heart failure and edema [see WARNINGS AND PRECAUTIONS]
- Renal effects [see WARNINGS AND PRECAUTIONS]
- Anaphylactic reactions [see WARNINGS AND PRECAUTIONS]
- Central nervous system effects [see WARNINGS AND PRECAUTIONS]
- Skin reactions [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Five hundred and fifty-four patients (554) received TIVORBEX 20 mg or 40 mg for up to 48 hours in two double-blind, placebo-controlled, clinical trials of acute pain following bunionectomy. The most frequent adverse reactions in these trials are summarized below.
Table 1 : Summary of Adverse Reactions ( ≥ 2% in
TIVORBEX 20 mg or 40 mg group) - Phase 3 Studies in Patients With Postsurgical
|Any Treatment Emergent AE||TIVORBEX 40 mg three times daily* (%)
|TIVORBEX 40 mg twice daily* (%)
|TIVORBEX 20 mg three times daily* (%)
|Post procedural edema||24||22||26||32|
|Post procedural hemorrhage||5||11||5||6|
|Post procedural swelling||1||3||1||1|
|Abdominal pain, upper||2||1||2||1|
|*One tablet of hydrocodone/acetaminophen 10 mg/325 mg was permitted every 4 to 6 hours as rescue medication for pain management. There was a greater use of concomitant opioid rescue medication in placebo-treated patients than in TIVORBEX-treated patients [see Clinical Studies].|
Adverse Reactions From Spontaneous Reports
The following adverse reactions have been identified during post approval use of indomethacin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal: anorexia, bloating (includes distension), flatulence, peptic ulcer, gastroenteritis, rectal bleeding, proctitis, single or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestines intestinal ulceration associated with stenosis and obstruction, gastrointestinal bleeding without obvious ulcer formation and perforation of pre-existing sigmoid lesions (diverticulum, carcinoma, etc) development of ulcerative colitis and regional ileitis ulcerative stomatitis, toxic hepatitis and jaundice (some fatal cases have been reported), intestinal strictures (diaphragms).
Hematologic: leukopenia, bone marrow depression, anemia secondary to obvious or occult gastrointestinal bleeding, aplastic anemia, hemolytic anemia, agranulocytosis, thrombocytopenic purpura, disseminated intravascular coagulation.
Central Nervous System: anxiety (includes nervousness), muscle weakness, involuntary muscle movements, insomnia, confusion, psychic disturbances including psychotic episodes, mental confusion, drowsiness, light-headedness, syncope, paresthesia, aggravation of epilepsy and parkinsonism, depersonalization, coma, peripheral neuropathy, convulsion, dysarthria.
Special Senses: ocular — corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients on prolonged therapy with indomethacin; blurred vision, diplopia, hearing disturbances, deafness.
Skin and Appendages: pruritus, rash, urticaria, petechiae or ecchymosis, exfoliative dermatitis, erythema nodosum, loss of hair, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis.
Causal relationship unknown
Other reactions have been reported but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, the possibility cannot be excluded. Therefore, these observations are being listed to serve as alerting information to physicians:
Hematologic: Although there have been several reports of leukemia, the supporting information is weak
Genitourinary: Urinary frequency
Musculoskeletal and Connective Tissue: A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group Ab hemolytic streptococcus, has been described in persons treated with nonsteroidal anti-inflammatory agents, including indomethacin, sometimes with fatal outcome [see WARNINGS AND PRECAUTIONS].
Read the Tivorbex (indomethacin capsules) Side Effects Center for a complete guide to possible side effects
ACE-Inhibitors And Angiotensin II Antagonists
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors and angiotensin II antagonists. Indomethacin can reduce the antihypertensive effects of captopril and losartan. These interactions should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors or angiotensin II antagonists. In some patients with compromised renal function, the co-administration of an NSAID and an ACE-inhibitor or an angiotensin II antagonist may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible [see WARNINGS AND PRECAUTIONS].
When administered with aspirin, indomethacin's protein binding is reduced, although the clearance of free indomethacin is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of indomethacin and aspirin is not generally recommended because of the potential of increased adverse effects.
The use of indomethacin in conjunction with aspirin or other salicylates is not recommended. Controlled clinical studies have shown that the combined use of indomethacin and aspirin does not produce any greater therapeutic effect than the use of indomethacin alone. In a clinical study of the combined use of indomethacin and aspirin, the incidence of gastrointestinal side effects was significantly increased with combined therapy.
In a study in normal volunteers, it was found that chronic concurrent administration of 3.6 g of aspirin per day decreases indomethacin blood levels approximately 20%.
Beta-Adrenoceptor Blocking Agents
Blunting of the antihypertensive effect of beta-adrenoceptor blocking agents by NSAIDs including indomethacin has been reported. Therefore, when using these blocking agents to treat hypertension, patients should be observed carefully in order to confirm that the desired therapeutic effect has been obtained.
Administration of NSAIDs concomitantly with cyclosporine has been associated with an increase in cyclosporine-induced toxicity, possibly due to decreased synthesis of renal prostacyclin. Use caution when NSAIDs are administered concomitantly with cyclosporine. Carefully monitor patients with impaired renal function.
In normal volunteers receiving indomethacin, the administration of diflunisal decreased the renal clearance and significantly increased the plasma levels of indomethacin. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. Therefore, diflunisal and indomethacin should not be used concomitantly.
Indomethacin given concomitantly with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Therefore, when indomethacin and digoxin are used concomitantly, serum digoxin levels should be closely monitored.
Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis.
Indomethacin reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced by furosemide administration, or salt or volume depletion. These facts should be considered when evaluating plasma renin activity in hypertensive patients.
It has been reported that the addition of triamterene to a maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.
Indomethacin and potassium-sparing diuretics each may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium kinetics and renal function should be considered when these agents are administered concurrently.
Most of the above effects concerning diuretics have been attributed, at least in part, to mechanisms involving inhibition of prostaglandin synthesis by indomethacin.
NSAIDs, including indomethacin, have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, observe patients carefully for signs of lithium toxicity. See the Prescribing Information for lithium preparations before use of such concomitant therapy. In addition, the frequency of monitoring serum lithium concentration should be increased at the outset of such combination drug treatment.
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Use caution when NSAIDs are administered concomitantly with methotrexate.
The concomitant use of indomethacin with other NSAIDs is not recommended due to the increased possibility of gastrointestinal toxicity, with little or no increase in efficacy.
Caution should be exercised when NSAIDs, such as indomethacin, and anticoagulants are administered concomitantly. The effects of anticoagulants (such as warfarin) and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than that with use of either drug alone.
When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. Therefore, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 3/5/2014
Additional Tivorbex Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Chronic Pain/Back Pain
Find tips and advances in treatment.