"The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has recommended the marketing of selexipag (Uptravi, Actelion Registration Ltd) for the treatment of adults with pulmonary arterial hypertension (PAH)./"...
The following risks are discussed in more detail in others sections:
- Hypotension and Worsening Renal Function [see WARNINGS AND PRECAUTIONS]
- Electrolyte and Metabolic Abnormalities [see WARNINGS AND PRECAUTIONS]
- Ototoxicity [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 practice.
In pre-approval studies, DEMADEX has been evaluated for safety in approximately 4000 subjects; over 800 of these subjects received DEMADEX for at least 6 months, and over 380 were treated for more than 1 year. Among these subjects were 564 who received DEMADEX during United States-based trials in which 274 other subjects received placebo.
Discontinuation of therapy due to adverse reactions occurred in 3.5% of United States patients treated with DEMADEX and in 4.4% of patients treated with placebo.
In United States placebo-controlled trials excessive urination occurred in 6.7% of patients compared with 2.2% of patients receiving placebo. The daily doses of DEMADEX used in these trials ranged from 1.25 mg to 20 mg, with most patients receiving 5 mg to 10 mg; the duration of treatment ranged from 1 to 52 days, with a median of 41 days.
In the placebo-controlled hypertension studies excessive urination was dose related; 1% of patients receiving placebo, 4% of those treated with 5 mg of daily DEMADEX, and 15% of those treated with 10 mg. Excessive urination was generally not reported as an adverse event among patients who received DEMADEX for cardiac, renal, or hepatic failure.
There was no effect of age or sex on the incidence of adverse reactions.
In controlled studies in the United States, DEMADEX was administered to hypertensive patients at doses of 5 mg or 10 mg daily. After 6 weeks at these doses, the mean decrease in serum potassium was approximately 0.1 mEq/L. The percentage of patients who had a serum potassium level below 3.5 mEq/L at any time during the studies was 1.5% on DEMADEX and 3% on placebo. In patients followed for 1 year, there was no progressive change in mean serum potassium levels. In patients with congestive heart failure, hepatic cirrhosis, or renal disease treated with DEMADEX at doses higher than those studied in United States antihypertensive trials, hypokalemia was observed with greater frequency, in a dose-related manner.
Blood Urea Nitrogen (BUN), Creatinine and Uric Acid
DEMADEX produces small dose-related increases in each of these laboratory values. In hypertensive patients who received 10 mg of DEMADEX daily for 6 weeks, the mean increase in blood urea nitrogen was 1.8 mg/dL (0.6 mmol/L), the mean increase in serum creatinine was 0.05 mg/dL (4 mmol/L), and the mean increase in serum uric acid was 1.2 mg/dL (70 mmol/L). Little further change occurred with long-term treatment, and all changes reversed when treatment was discontinued.
Hypertensive patients who received 10 mg of daily DEMADEX experienced a mean increase in serum glucose concentration of 5.5 mg/dL (0.3 mmol/L) after 6 weeks of therapy, with a further increase of 1.8 mg/dL (0.1 mmol/L) during the subsequent year. In long-term studies in diabetics, mean fasting glucose values were not significantly changed from baseline.
The following adverse reactions have been identified during the post-approval use of DEMADEX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or establish a causal relationship to drug exposure.
Gastrointestinal system: Pancreatitis, abdominal pain
Nervous System: Paresthesia, confusion, visual impairment, loss of appetite
Hepatobiliary: Increase in liver transaminases, gamma-glutamyltransferase
Urogenital: Acute urinary retention
Read the Demadex (torsemide) Side Effects Center for a complete guide to possible side effects
Nonsteroidal Anti-Inflammatory Drugs
Because DEMADEX and salicylates compete for secretion by renal tubules, patients receiving high doses of salicylates may experience salicylate toxicity when DEMADEX is concomitantly administered.
Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and torsemide has been associated with the development of acute renal failure. The antihypertensive and diuretic effects of DEMADEX can be reduced by NSAIDs.
Partial inhibition of the natriuretic effect of DEMADEX by concomitant administration of indomethacin has been demonstrated for DEMADEX under conditions of dietary sodium restriction (50 mEq/day) but not in the presence of normal sodium intake (150 mEq/day).
Cytochrome P450 2C9 Inhibitors And Inducers
Torsemide is a substrate of CYP2C9. Concomitant use of CYP2C9 inhibitors (e.g., amiodarone, fluconazole, miconazole, oxandrolone) can decrease torsemide clearance and increase torsemide plasma concentrations. Concomitant use of CYP2C9 inducers (e.g., rifampin) increase torsemide clearance and decrease plasma torsemide concentrations. Monitor diuretic effect and blood pressure when used in combination with CYP2C9 inhibitor or inducer. Adjust torsemide dose if necessary.
Because of its inhibition of CYP2C9 metabolism, torsemide may affect the efficacy and safety of sensitive CYP2C9 substrates, such as celecoxib, or of substrates with a narrow therapeutic range, such as warfarin or phenytoin. Monitor patients and adjust dosages if necessary.
Concomitant use of torsemide and cholestyramine has not been studied in humans but, in a study in animals, coadministration of cholestyramine decreased the absorption of orally administered torsemide. If DEMADEX and cholestyramine should be coadministered, administer DEMADEX at least one hour before or 4 to 6 h after cholestyramine administration.
Organic Anion Drugs
Coadministration of organic anion drugs (e.g., probenecid) that undergo significant renal tubular secretion have the potential to reduce secretion of DEMADEX into the proximal tubule and thereby decreases the diuretic activity of DEMADEX. Monitor diuretic effect and blood pressure during coadministration.
Loop diuretics increase the ototoxic potential of other ototoxic drugs, including aminoglycoside antibiotics and ethacrynic acid. This effect has been reported with concomitant use of torsemide and gentamycin. Avoid concomitant use of DEMADEX and aminoglycoside antibiotics, if possible.
DEMEDEX can increase the risk of renal toxicity related to administration of radiocontrast agents.
Corticosteroids And ACTH
Concomitant use with DEMEDEX may increase risk of hypokalemia
Read the Demadex Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 3/17/2017
Additional Demadex Information
Demadex - User Reviews
Demadex User Reviews
Now you can gain knowledge and insight about a drug treatment with Patient Discussions.
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.
Get tips on handling your hypertension.