Many adults, especially those over 60, get up in the middle of the night – sometimes several times – to urinate.
Doctors have a name for this problem. They call it nocturia.
Nocturia can be caused by making more urine during the day than your body can get rid of or being able to store less urine in your bladder. Nocturia is a common problem, which affects about 12% of adults over 60 years of age and more than half the adults over 70 years of age. 1
There are medical reasons that contribute to this problem:
- diseases, such as congestive heart failure and diabetes
- medications that cause increased urination
- drinking too much water in the evening
- poor sleep – people who awake at night often decide to urinate
- problems with the bladder that reduce the amount it can hold, such as infection, obstruction, swelling, or an enlarged prostate
- Weakened pelvic muscles that cause stress incontinence, a common problem for post-menopausal women
Typically, a person makes only 20% of their daily urine at night – so the bladder can hold all of it until morning. However, some people make more than 33% of their daily urine at night – so they need to empty their bladder during the night. This is a type of nocturia called nocturnal polyuria.
Nocturia is a symptom, it’s not a disease or condition. Treatments do not try to fix the cause of the problem – they only cover it up. But nocturia can be a problem, because it can interrupt sleep and increase your chances of falling at night.
Is Noctiva (Desmopressin) the Answer?
The FDA approved Noctiva in March 2017 to treat the symptoms of nocturnal polyuria. It is intended for adults who regularly take at least two trips to urinate each night.
The FDA approved two different doses of Noctiva nasal spray based on two clinical trials of patients who averaged 3.3 trips to urinate every night after going to sleep.
Patients taking Noctiva at either dose awoke to urinate 0.3-0.4 fewer times each night than patients taking placebo.1,2 This would be about one fewer trips to the bathroom every 2-3 nights. This difference was statistically significant, which means it probably was due to the drug, not due to chance. However, the improvement is so small that many patients wouldn’t notice it.
Researchers also looked at the percentage of people taking either dose who cut their trips to the bathroom by at least half. About 50% of patients taking the high dose of Noctiva did so. However, about 30% of patients taking placebo did too, so that isn’t a huge difference.
Given how modest the benefits are of Noctiva, it is important to note that the drug has very serious side effects (see below).
The studies were well designed, with patients randomly assigned to take either Noctiva or placebo (a pill with no active ingredient). Neither the patients nor clinicians knew if they were taking Noctiva or the placebo. The trials only included patients 50 years or older who had at least two trips to the bathroom to urinate each night. For that reason, there is no way to know if the drug is safe or effective for patients under 50.
These same two clinical trials were also presented at a medical conference in August 2018.3,4 Researchers reanalyzed the data presented to the FDA by combining patients from both clinical trials but excluding those who were under 65 years of age.
When patients under 65 years old were excluded, both doses reduced the number of trips to the bathroom. However, the results were similar to the study of the larger dose: Only 1 fewer trips to the bathroom every 2-3 nights. It also showed that the length of time between patients’ bedtime and their first trip to the bathroom was 30-42 minutes longer for patients who took Noctivia compared to placebo. In addition, patients who took Noctivia reported 1 or fewer bathroom trips on 38-44% of nights in the study, compared to 31% of nights for patients who took placebo. The results were similar for patients 75 years and older.
Another research analysis of those same two studies, including patients ages 50 and older and only for the first night of the clinical trials concluded that patients who took Noctiva reported similarly modest improvements in the first night of the study in the number of trips and length of sleep prior to waking up to urinate. In other words, it doesn’t take a few days to take effect but also it doesn’t become more effective over time.
Results presented at a conference are not peer-reviewed the way studies published in a medical journal are. We are concerned that even though these results were statistically significant, the benefits are still very small. The two trials were combined and reanalyzed, which can make the results biased. It is also possible that patients who are younger than 65 or who only get up once each night will be prescribed Noctiva and not benefit at all.
Safety Concerns With Noctiva
With such a small benefit, it is important to think about the risks. Noctiva has a Black Box Warning, which is the most serious kind of warning.5 The Black Box warns that the drug can cause hyponatremia, which is a condition when sodium levels in the blood get too low. It can cause nausea, headache, confusion, fatigue, irritability, and muscle problems. In severe cases, it can cause seizures, coma, and death. The risk of hyponatremia increases with age. In clinical trials, it occurred more often when patients taking the drug were 65+ years old or took the higher dose.
To reduce the risk of hyponatremia, the label says that older patients should take the lower dose.
In the clinical trials, 11% of patients developed mild hyponatremia, and 1% had a severe case.1,2 These patients were examined every other week. Clinicians that prescribe Noctiva will need to monitor patients to diagnose hyponatremia before it can cause long-term harm. Monitoring will be even more important for patients who also take drugs that cause water retention or also have a risk for low blood sodium. Common drugs with those side effects include some types of antidepressants and seizure medications, opioids, and non-steroidal anti-inflammatories.
More common side effects of Noctiva are nasal discomfort, colds, congestion, sneezing, raised blood pressure, back pain, nosebleeds, bronchitis and dizziness.
A major shortcoming is that the clinical trials excluded patients with many of the conditions that can cause nocturia. Patients with these conditions may have more side effects, different side effects, or even less benefit from the drug.
The studies did not look at whether Noctiva affected the underlying conditions. It might possibly make these conditions worse.
The drug label warns that patients with congestive heart failure or uncontrolled hypertension should not use Noctiva. It also warns that nasal conditions can increase the amount of drug that is absorbed into the body, which increases risk for hyponatremia.
What is Noctiva Made of?
Noctiva contains desmopressin. Other medications also use desmopressin to treat problems due to too much urine. The FDA approved the first medication containing desmopressin in 1978. Some clinicians prescribe these other products with desmopressin “off-label” for nocturia. “Off label” means these other drugs were not approved for nighttime urination. Since they are available as generic drugs, they will likely be considerably less expensive than Noctiva.
Noctiva has a lower dose of desmopressin than these other products.1,2 However, Noctiva also contains another drug to help the body absorb more desmopressin, which results in your body using a “higher dose.” As a result, it might be similar to these other drugs already on the market.
Before starting Noctiva, clinicians should try to identify other causes for these symptoms. They should find out if a patient produces too much urine at night by collecting urine samples over 24 hours. Treating the cause of the symptoms will often be more effective than taking a drug like desmopressin.
Noctiva is the first drug that FDA has approved for frequent nighttime urination. Unfortunately, the low dose (0.83 mcg) probably is not effective enough to feel beneficial and the high dose (1.66 mcg) can cause serious side effects.
It is often not a good idea to treat symptoms instead of diseases. For example, clinicians could prescribe a drug like Noctiva without considering why the patient has symptoms. This could delay diagnosis of a disease that is causing the symptoms.
Instead of Noctiva, it would be more effective to treat the cause of nighttime urination. Patients should talk to their doctors to consider possible causes before considering Noctiva.
Do the benefits of Noctiva outweigh the risks for most patients? Since the benefits are small and the risks can be serious, Noctiva is probably not the best solution for most patients. Some patients may benefit from it without any harmful side effects, but the research doesn’t help us predict who those patients would be.
Some public health experts question why this common issue of nighttime urination was given the medical label “nocturia.” They point out that the “medicalization” of common problems (another good example is “restless leg syndrome”) inevitably results in drugs with limited benefits being widely advertised and sold to thousands of patients who were persuaded that they had a disease. Nighttime urination is certainly a problem for many people. However, how is it helpful to patients to make up a Latin-sounding term to describe it?
- Food and Drug Administration. FDA briefing document: Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC). Silver Spring, MD: US Food and Drug Administration; 2016. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM525329.pdf.
- Serenity Pharmaceuticals, LLC. SER120 Nasal spray advisory committee briefing document. Serenity; 2016. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM525331.pdf.
- Kobashi K, Brucker BM, Yang A, Francis L, Newman DK. Extended first uninterrupted sleep period for older adults following treatment with AV002, an emulsified microdose vasopressin Analog. Presented at International Continence Society; August 29, 2018; Philadelphia, PA. https://www.ics.org/2018/abstract/7.
- Campeau L, Yang A, Francis L, Newman DK. Rapid Nocturia efficacy of AV002, an emulsified microdose vasopressin analog. Presented at International Continence Society; August 29, 2018; Philadelphia, PA. https://www.ics.org/2018/abstract/18.
- Noctiva [Labeling]. Milford, PA: Serenity; 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/201656lbl.pdf.