Drug for Treating Nighttime Urination Too Dangerous

The Food and Drug Administration (FDA) approved desmopressin sublingual (under the tongue) tablets with the brand name NOCDURNA in 2018 for the treatment of nocturia (waking up at night to urinate) in adults.[1] The approval is limited to those patients who have nocturnal polyuria (overproduction of urine during the night) and wake up at least twice per night to urinate.

Desmopressin is the only drug approved in the U.S. for treating nocturia.[2] Public Citizen’s Health Research Group has designated desmopressin sublingual tablets as Do Not Use for treatment of nocturia because the drug’s significant risks far outweigh its minimal benefits.

New form of an old drug

Desmopressin is a synthetic version of the naturally occurring hormone vasopressin, which is produced by the pituitary gland, a pea-sized structure located below the brain. Desmopressin, like vasopressin, works in part by stimulating the kidneys to reabsorb water, thereby temporarily reducing the volume of urine that is produced.

Since 1978, the FDA has approved several other nasal-spray, oral-tablet and injectable formulations of desmopressin for uses other than treatment of nocturia.[3] These older versions of desmopressin currently are marketed under the brand name DDAVP, as well as several generic versions.

Nocdurna, the newest version of desmopressin, is approved only for treating nocturia.[4] It is to be administered nightly one hour before bedtime as a single tablet taken sublingually and is available in two dosage strengths: 25 micrograms (mcg) per tablet for women and 50 mcg per tablet for men.

Nocturia overview

Nocturia is a symptom, not a specific disease or disorder. It becomes more common with increasing age. Among adults aged 18 to 49, nocturia occurs more frequently in women than in men, but after age 60 it is more common in men.[5]

Common causes of nocturia include the following:

• Disorders that cause swelling, such as heart failure and kidney disease
• Poorly controlled diabetes
• Use of diuretics (for example, furosemide [LASIX])
• Excessive fluid intake
• Consumption of caffeine or alcohol, especially before bedtime
• Prostate enlargement
• Overactive bladder
• Small bladder size
• Urinary tract infection
• Sleep apnea
• Hypertension (high blood pressure)[6]

Patients often have multiple causes for their nocturia. Some patients have nocturnal polyuria without an identifiable cause. Regardless of the cause, the number of nocturia episodes can fluctuate markedly from night to night in a given patient.[7]

Multiple FDA rejections

Importantly, prior to approving Nocdurna in 2018, the FDA had rejected the drug twice (in 2010 and 2013) for treatment of all types of nocturia regardless of severity or cause and a third time (in 2015) for treatment of nocturia due to nocturnal polyuria because the drug’s risks were deemed to outweigh its benefits.[8]

At a 2015 meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, 10 of 17 committee members concluded that the demonstrated benefits of Nocdurna did not outweigh its risks and did not support approval of the drug for treating nocturia due to nocturnal polyuria (two other members abstained from voting on this pivotal issue).[9] Particular concern was expressed that the drug could trigger dangerously low blood sodium levels.

Disturbingly, the FDA did not require that Ferring Pharmaceuticals, the manufacturer of Nocdurna, conduct new clinical trials to establish the safety and effectiveness of Nocdurna after the agency’s third rejection of the drug in 2015 before reconsidering the drug for approval for a fourth time.

Meager benefits

The effectiveness of Nocdurna for treating nocturia in adults was tested in two three-month, randomized, placebo-controlled clinical trials.[10] One trial tested a desmopressin dosage of 25 mcg nightly compared with a placebo across a total of 237 women, and the other tested a dosage of 50 mcg nightly compared with a placebo across a total of 230 men.

Compared with placebo, Nocdurna resulted, on average, in only approximately one fewer nocturia episode every five days in women and one fewer episode every two to three days in men.[11]

Dangerous adverse effects

Like all other desmopressin drugs, Nocdurna’s greatest danger is that it can cause hyponatremia (low blood sodium or salt levels). The FDA required that the product labeling for Nocdurna include a black-box warning about this risk (see box, below).[12]

FDA-Required Black-Box Warning for Nocdurna

• Desmopressin can cause hyponatremia (low blood sodium or salt level), which can be life-threatening if severe, leading to seizures, coma, respiratory arrest or death.
• Desmopressin is contraindicated (should not be used) in patients who are at increased risk of severe hyponatremia, such as patients with excessive fluid intake, who have illnesses that can cause fluid or electrolyte (salt) imbalances or who are using loop diuretics (for example, furosemide [LASIX]) or systemic (oral or injected) or inhaled glucocorticoids (for example, prednisone [RAYOS] and budesonide [BREZTRI AEROSPHERE, ENTOCORT EC, ORTIKOS, PULMICORT FLEXHALER, PULMICORT RESPULES, SYMBICORT, UCERIS]).

Sudden, severe hyponatremia is a medical emergency because it can cause swelling of the brain, which can lead to confusion, loss of consciousness, seizures, coma and death. Mild-to-moderate hyponatremia usually does not cause symptoms, but even mild hyponatremia has been clearly associated with an increased risk of impaired attention, unsteadiness when walking, falls, and fractures in the elderly.[13],[14]

Across all major randomized clinical trials of Nocdurna, hyponatremia occurred in approximately 4% of subjects who received Nocdurna (at a dosage of either 25 mcg or 50 mcg nightly) and only 1% of those who received a placebo.[15] The incidence of hyponatremia with Nocdurna use was markedly higher in patients aged 65 or older than in those aged 64 or younger.[16]

Desmopressin also can cause fluid retention, which can worsen hypertension (high blood pressure) and heart failure.[17]

What You Can Do

You should not use Nocdurna to treat nocturia. If you have frequent nocturia, work with your doctor to optimize the treatment of any underlying disorders or conditions associated with nocturia that you may have.

You also should avoid consuming caffeine, alcohol, diuretic medications and too much fluid during the few hours before bedtime.
 

References

[1] Food and Drug Administration. Approval letter for NDA 022517, NOCDURNA (desmopressin sublingual tablets). June 21, 2018. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/022517Orig1s000Approv.pdf. Accessed July 12, 2021.

[2] Lee KC. Upcoming new drug therapies for nocturia — A nonsystematic stepwise review. Ann Rev Resear. 2021;6(2):555682. DOI: 10.19080/ARR.2021.06.555682.

[3] Food and Drug Administration. Summary review for regulatory action for NDA 201656, Noctiva (desmopressin acetate) nasal spray. https://www.accessdata.fda.gov/drugsatfda_docs/summary_review/2017/201656Orig1s000SumR.pdf. Accessed July 12, 2021.

[4] Ferring Pharmaceuticals Inc. Label: desmopressin acetate sublingual tablets (NOCDURNA). June 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022517s000lbl.pdf. Accessed July 12, 2021.

[5] Johnson TM. Nocturia: Clinical presentation, evaluation, and management in adults. UpToDate. January 12, 2021.

[6] Ibid.

[7] Ibid.

[8] Food and Drug Administration. Multi-discipline review for NDA 022517, NOCDURNA (desmopressin sublingual tablets). https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/022517Orig1s000MultidisciplineR.pdf. Accessed July 12, 2021.

[9] Food and Drug Administration. Summary minutes of the Endocrinologic and Metabolic Drugs Advisory Committee Meeting, January 12, 2015. https://wayback.archive-it.org/7993/20170404151636/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM435951.pdf. Accessed July 12, 2021.

[10] Ferring Pharmaceuticals Inc. Label: desmopressin acetate sublingual tablets (NOCDURNA). June 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022517s000lbl.pdf. Accessed July 12, 2021.

[11] Food and Drug Administration. Multi-discipline review for NDA 022517, NOCDURNA (desmopressin sublingual tablets). https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/022517Orig1s000MultidisciplineR.pdf. Accessed July 12, 2021.

[12] Ferring Pharmaceuticals Inc. Label: desmopressin acetate sublingual tablets (NOCDURNA). June 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022517s000lbl.pdf. Accessed July 12, 2021.

[13] Renneboog B, Musch W, Vandemergel X, et al. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med. 2006;119(1):71.e1-8.

[14] Tolouian R, Alhamad T, Farazmand M, Mulla ZD. The correlation of hip fracture and hyponatremia in the elderly. J Nephrol. 2012;25(5):789-793.

[15] Ferring Pharmaceuticals Inc. Label: desmopressin acetate sublingual tablets (NOCDURNA). June 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022517s000lbl.pdf. Accessed July 12, 2021

[16] Ibid.

[17] Ibid.