Drug for Treating Nighttime Urination Too Dangerous

On March 3, 2017, the Food and Drug Administration (FDA) approved desmopressin nasal spray (NOCTIVA) 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. This is the first and only drug approved in the U.S. for nocturia.[2]

Public Citizen’s Health Research Group has designated desmopressin nasal spray 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,[3] 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 one or more of the following uses: to treat vasopressin hormone deficiency, to manage nighttime bed-wetting in children and to prevent or treat bleeding in patients with certain inherited blood clotting disorders, including hemophilia A.[4] These older versions of desmopressin are marketed under the brand names DDAVP, MINIRIN and STIMATE, as well as several generic versions.

Noctiva, the newest version of desmopressin, is only approved for nocturia.[5] Unlike other nasal-spray forms of the drug, it contains a chemical that is intended to enhance absorption of the drug through the inner lining of the nose.[6] Noctiva is to be administered nightly about 30 minutes before bedtime as a single spray in one nostril and is available in two dosage strengths: 0.75 micrograms (mcg) and 1.5 mcg per spray.[7]

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 men, but after age 60 it is more common in men.[8]

Common causes of nocturia include the following:[9]

• 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)

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.[10]

Noctiva’s meager benefits

The effectiveness of Noctiva was initially tested in two identical randomized clinical trials that together enrolled more than 600 adults aged 50 or older who had a six-month history of at least two nocturia episodes per night, on average.[11],[12],[13] Subjects were randomly assigned to receive either Noctiva at an initial nightly dose of 0.5 mcg (which could be increased to 0.75 mcg) or a placebo nasal spray for seven weeks. Both trials failed to show that Noctiva was effective in reducing the frequency of nocturia episodes.

The manufacturer of Noctiva then decided to conduct two additional clinical trials using a higher dose of the drug.[14] Combined, these two additional trials enrolled more than 1,300 subjects aged 50 or older who had a six-month history of at least two nocturia episodes per night, on average. The subjects were randomly assigned to receive either Noctiva — at a nightly dose of 0.75, 1.0 or 1.5 mcg — or a placebo for 12 weeks. Compared with a placebo, Noctiva at doses of 0.75 and 1.0 mcg resulted, on average, in only one fewer nocturia episode every five days. For the 1.5 mcg dose, the effect was only slightly better: an average reduction of one nocturia event every two to three days compared with placebo. The clinical meaningfulness of such modest differences is unclear.

Alongside these minimal benefits, the drug poses serious risks.

Dangerous adverse effects

Like other desmopressin drugs, Noctiva’s greatest danger is that it can cause hyponatremia (low blood sodium or salt levels). The FDA requires that the product labeling for Noctiva include a black-box warning about this risk.[15] 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 may be associated with an increased risk of impaired attention, unsteadiness when walking, falls and fractures in the elderly.[16],[17]

During the two randomized clinical trials that tested the higher doses of Noctiva, hyponatremia occurred in 14 percent of subjects receiving the 1.5 mcg dose of the drug, 10 percent of those receiving the 0.75 mcg dose of the drug and only 5 percent of those receiving a placebo.[18] Severe hyponatremia occurred in five subjects (1 percent) receiving the 1.5 mcg dose of Noctiva but only one subject (0.2 percent) receiving a placebo.[19] The risk of hyponatremia with Noctiva use was higher in patients age 65 or older than in those age 64 or younger.[20] This risk is very likely to be greater outside the carefully controlled circumstances of a clinical trial.

Across all clinical trials of Noctiva, five subjects receiving the drug died, whereas no subjects receiving a placebo died.[21] For three of these cases, the FDA concluded that the death was likely unrelated to the medication. For the other two cases, the agency could not rule out that Noctiva played a role in the deaths.

During clinical trials, hypertension (high blood pressure) — a risk factor for adverse cardiovascular disease, including heart attacks and stroke — occurred slightly more frequently in subjects receiving Noctiva than in those receiving a placebo.[22]

What You Can Do

You should avoid starting Noctiva if you are not currently taking it. If you are already taking it, consult with your doctor before discontinuing the drug. Work with your doctor to optimize the treatment of any underlying disorders 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 201656, NOCTIVA (desmopressin) nasal spray. March 3, 2016. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/201656Orig1s000Ltr.pdf. Accessed August 30, 2017.

[2] Food and Drug Administration. FDA briefing document for the Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC). October 19, 2016. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM525329.pdf. Accessed August 30, 2017.

[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 August 30, 2017.

[4] Ibid.

[5] Serenity Pharmaceuticals. Label: desmopressin acetate nasal spray (NOCTIVA). March 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/201656lbl.pdf. Accessed August 31, 2017.

[6] Food and Drug Administration. FDA briefing document for the Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC). October 19, 2016. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM525329.pdf. Accessed August 30, 2017.

[7] Serenity Pharmaceuticals. Label: desmopressin acetate nasal spray (NOCTIVA). March 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/201656lbl.pdf. Accessed August 31, 2017.

[8] Johnson TM. Nocturia: Clinical presentation, evaluation, and management in adults. UpToDate. August 8, 2017. https://www.uptodate.com/contents/nocturia-clinical-presentation-evaluation-and-management-in-adults. Accessed August 31, 2017.

[9] Ibid.

[10] Ibid.

[11] Food and Drug Administration. FDA briefing document for the Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC). October 19, 2016. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM525329.pdf. Accessed August 30, 2017.

[12] ClinicalTrials.gov. NCT00937859: Treatment of patients with nocturia. https://clinicaltrials.gov/ct2/show/NCT00937859. Accessed August 31, 2017.

[13] ClinicalTrials.gov. NCT00937378: Treatment of patients with nocturia (non-PK study). https://clinicaltrials.gov/ct2/show/NCT00937378. Accessed August 31, 2017.

[14] Food and Drug Administration. FDA briefing document for the Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC). October 19, 2016. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM525329.pdf. Accessed August 30, 2017.

[15] Serenity Pharmaceuticals. Label: desmopressin acetate nasal spray (NOCTIVA). March 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/201656lbl.pdf. Accessed August 31, 2017.

[16] 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.

[17] 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.

[18] Food and Drug Administration. FDA briefing document for the Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC). October 19, 2016. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM525329.pdf. Accessed August 30, 2017.

[19] Ibid.

[20] Ibid.

[21] Ibid.

[22] Serenity Pharmaceuticals. Label: desmopressin acetate nasal spray (NOCTIVA). March 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/201656lbl.pdf. Accessed August 31, 2017.