Adverse reactions : תופעות לוואי

6       ADVERSE REACTIONS
The following adverse reaction is described elsewhere in the labeling: • Hyponatremia [see Boxed Warning and Warnings and Precautions (5.1)] 
6.1     Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse event 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.
The safety database includes three double-blind, placebo-controlled, multicenter, randomized trials of NOQDIRNA and one open-label extension trial. Study 1 (CS40) (NCT01262456) enrolled only women, Study 2 (CS41) (NCT01223937) enrolled only men, Study 3 (CS29) (NCT00477490) enrolled men and women and Study 4 (CS31) (NCT00615836) was an extension of Study 3 for up to 3 years [see Clinical Studies (14)].
At baseline, 196 women treated with NOQDIRNA 27.7 mcg/day, 173 women given placebo, 195 men treated with NOQDIRNA 55.3 mcg/day, and 213 men given placebo had nocturia due to nocturnal polyuria, with at least 2 nocturnal voids per night. The mean age of women treated with NOQDIRNA 27.7 mcg was 59 years and 42% of women were aged 65 and older. The mean age of men treated with NOQDIRNA 55.3 mcg was 62 years and 50% of men were aged 65 and older. Caucasians comprised 81%, Blacks 17%, and Asians 1% of the nocturia due to nocturnal polyuria population, and 12% were Hispanic.
Concomitant use of anti-muscarinic medications, alpha-blockers, and alpha-reductase inhibitors was permitted for patients on a stable dose prior to study entry. Serious adverse reactions included 2 reports of hyponatremia in men treated with NOQDIRNA 55.3 mcg. These 2 reports occurred in a trial in which all cases of serum sodium <125 mmol/L were reported as serious adverse reactions.
Adverse Reactions Leading to Discontinuation
Among women with nocturia due to nocturnal polyuria, the discontinuation rate due to adverse reactions was 3% for those treated with NOQDIRNA 27.7 mcg and 2% for those in the placebo group. Among men with nocturia due to nocturnal polyuria, the discontinuation rate due to adverse reactions was 4% for those treated with NOQDIRNA 55.3 mcg and 3% in the placebo group.
Table 1 displays the most common adverse reactions leading to discontinuation in patients with nocturia due to nocturnal polyuria.

Table 1: Most Common Adverse Reactions (≥2 Incidences) Leading to Discontinuation in Patients With Nocturia Due to Nocturnal Polyuria (Studies 1, 2 and 3)1
Women                                Men
Adverse Reactions                                     NOQDIRNA                            NOQDIRNA Placebo                            Placebo
27.7 mcg                            55.3 mcg
(N=173)                            (N=213)
(N=196)                             (N=195)
Hyponatremia or blood sodium
1 (<1%)            1 (<1%)             0             4 (2.1%) decreased
1
Includes adverse reactions occurring during up to 3 months of treatment in patients who continued from Study 3 into Study 4
Most Common Adverse Reactions
Table 2 displays the most common adverse reactions in patients with nocturia due to nocturnal polyuria in Studies 1, 2, and 3. The most common adverse reactions reported with both the 27.7 mcg/day and 55.3 mcg/day dosages included dry mouth, hyponatremia or blood sodium decreased, and dizziness.
The high incidence of dry mouth may have been affected by specific query about dry mouth in Study 3 (CS29). In Studies 1 and 2 where the adverse reaction was spontaneously reported, the incidence was ≤4%.
Table 2: Common Adverse Reactions (Reported by >2% of NOQDIRNA-Treated Patients and at a Higher Incidence With Either Dose Than With Placebo) in Patients With Nocturia Due to Nocturnal Polyuria (Studies 1, 2 and 3)1
Women                                Men
Adverse Reactions                      Placebo        NOQDIRNA             Placebo        NOQDIRNA 
(N=173)              27.7 mcg       (N=213)             55.3 mcg
(N=196)                            (N=195)
Dry mouth                                  19 (11%)             23 (12%)       27 (13%)            27 (14%) Hyponatremia or blood sodium
3 (2%)               6 (3%)         1 (<1%)             8 (4%) decreased
Headache                                    5 (3%)               4 (2%)         3 (1%)              7 (4%) Dizziness                                     0                  3 (2%)         1 (<1%)             5 (3%) 1
Includes adverse reactions occurring during up to 3 months of treatment in patients who continued from Study 3 into Study 4


Hyponatremia
Serum sodium was measured during screening, at baseline, and on all study visits during treatment including day 4, week 1, week 2 (males only), week 4 and then every month of the studies. Tables 3 and Table 4 show the incidence of serum sodium concentrations below the normal range based on the pooled analysis of three phase 3 studies.

Table 3: Incidence of Hyponatremia by Sex in Patients with Nocturia due to Nocturnal Polyuria (Studies 1, 2, and 3)1
Women                                                   Men
Placebo                  NOQDIRNA                    Placebo                 NOQDIRNA Serum Sodium                     (N=171)                  27.7 mcg/day                (N=207)                 55.3 mcg/day (mmol/L)
(N=191)                                             (N=192)


130-134                          7 (4%)                         13 (7%)                6 (3%)                    33 (17%) 126-129                          0 (0%)                          7 (4%)                0 (0%)                    1 (<1%) ≤125                             1 (<1%)                         0 (0%)                0 (0%)                     3 (2%) Some subjects received different doses over the course of Study 3 and are in more than one dose-group.
n is number observed post baseline
1
Includes adverse reactions occurring during up to 3 months of treatment in patients who continued from Study 3 into Study 4


Table 4: Incidence of Hyponatremia by Sex and Age in Patients with Nocturia due to Nocturnal Polyuria (Studies 1,           2 and 3)1
Women                        Women                            Men                          Men Serum                <65 years                    ≥ 65 years                     < 65 years                   ≥ 65 years Sodium
Placebo     NOQDIRNA           Placebo      NOQDIRNA           Placebo   NOQDIRNA          Placebo    NOQDIRNA (mmol/L)
(N=95)      27.7 mcg/day       (N=76)       27.7 mcg/day       (N=95)    55.3 mcg/day      (n=112)    55.3 mcg/day (N=113)                          (N=78)                       (N=98)                       (N=94) 

130-134     2 (2%)         4 (4%)           5 (7%)             9 (12%)     5 (5%)      11 (11%)        1 (<1%)      22 (23%) 126-129     0 (0%)         2 (2%)           0 (0%)             5 (6%)      0 (0%)         0 (0%)       0 (0%)        1 (1%) 

≤125         0 (0%)      0 (0%)        1 (1%)            0 (0%)     0 (0%)        0 (0%)        0 (0%)    3 (3%) Some subjects received different doses over the course of study 3 and are in more than one dose-group.
n is number observed post baseline
1
Includes adverse reactions occurring during up to 3 months of treatment in patients who continued from Study 3 into Study 4
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/