Information
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not
include all the information needed to use Desmopressin Acetate
Tablets safely and effectively. See full prescribing information for Desmopressin Acetate Tablets.
DESMOPRESSIN ACETATE
tablets, for oral use Initial U.S. Approval: 1978
Newsletter
Faster onset of action
Ranitidine has faster onset of action that PPI It start action within 1 hr Ref: Aliment Pharmacol Ther. 2002 Jul;16(7):1317-26. doi: 10.1046/j.1365-2036.2002.01291.x.
Faster onset of action
Ranitidine has faster onset of action that PPI It start action within 1 hr Ref: Aliment Pharmacol Ther. 2002 Jul;16(7):1317-26. doi: 10.1046/j.1365-2036.2002.01291.x.
Faster onset of action
Ranitidine has faster onset of action that PPI It start action within 1 hr Ref: Aliment Pharmacol Ther. 2002 Jul;16(7):1317-26. doi: 10.1046/j.1365-2036.2002.01291.x.
CLINICAL INFORMATION
Hyponatremia
Excessive fluid intake when
urine output is limited by the antidiuretic effect of desmopressin may lead to
water intoxication with hyponatremia. Cases of hyponatremia have been reported
from postmarketing experience in patients treated
with desmopressin acetate.
Unless properly diagnosed and treated, hyponatremia can be
fatal.
All patients receiving Desmopressin Acetate Tablets should
be observed for the following signs or symptoms
associated with hyponatremia: headache, nausea/vomiting, decreased serum sodium,
weight gain, restlessness, fatigue, lethargy, disorientation, depressed
reflexes, loss of appetite, irritability, muscle weakness, muscle spasms or
cramps and abnormal mental status such as hallucinations, decreased
consciousness and confusion. Severe symptoms due to an extreme decrease in
serum sodium and plasma osmolality may include one or a combination of the
following: seizure, coma and/or respiratory arrest.
In order to decrease the risk
of water intoxication with hyponatremia, fluid restriction is recommended. Careful fluid intake restriction is
particularly important in pediatric and geriatric patients because these
patients are at greater risk of developing hyponatremia [see Use in Specific Populations, Pediatric Use (8.4) and Geriatric Use (8.5)]. More frequent monitoring of serum sodium levels is
recommended in the following patients: those with conditions associated with
fluid and electrolyte imbalance, such as cystic fibrosis, heart failure, renal
disorders, habitual or psychogenic polydipsia or those taking
concomitant drugs that may cause hyponatremia [see Drug Interactions (7.1)].
Suspend treatment with
Desmopressin Acetate Tablets for patients with primary nocturnal enuresis during
acute intercurrent illness
characterized by fluid
and/or electrolyte imbalance
(e.g., systemic infections, fever, recurrent vomiting or diarrhea) or
under conditions of extremely hot weather, vigorous exercise or other
conditions associated with increased water intake.
ADVERSE REACTIONS
The following serious reactions are described below
and elsewhere in the labeling:
·
Hyponatremia [see Warnings and Precautions (5.1)].
Adverse Reactions from Clinical
Studies or Postmarketing Reports
The following additional adverse
reactions have been identified during clinical studies or from postmarketing
reports with use of desmopressin. Because some of these reactions are reported
voluntarily from a population of uncertain size,
it is not always possible
to reliably estimate
their frequency or to establish a causal relationship to drug exposure.
Cardiac disorders: hypertension
Gastrointestinal disorders: nausea, vomiting, diarrhea,
constipation, abdominal cramps
General disorders: headache, malaise, drug ineffective, edema,
fatigue
Hepatobiliary disorders: transient increases in AST (1.5 times the upper limit of normal)
Immune system
disorders: severe allergic
reactions, anaphylaxis has occurred with other
formulations of desmopressin
Metabolism and nutrition: dehydration, hyponatremia, water intoxication with hyponatremia
Nervous system disorders: hyponatremic convulsions, hyponatremic
convulsions associated with concomitant use of the following medications:
oxybutinin and imipramine [see Drug
Interactions (7.1)], asthenia, coma,
disturbance in attention, psychomotor hyperactivity, dizziness, somnolence, depressed level of consciousness, falls.
Psychiatric disorders: confusional state, abnormal behavior, emotional disorder, depression, hallucination, insomnia
Renal and urinary disorders: Bladder and urethral
symptoms, including urinary
retention, urine flow
decreased, dysuria
Skin and subcutaneous tissue
disorders: rash, dermatitis allergic, sweating, flushing,
urticaria
Respiratory, thoracic
and mediastinal disorders: dyspnea, epistaxis
DRUG INTERACTIONS
INDICATIONS AND USAGE
USE IN SPECIFIC POPULATIONS
DESCRIPTION
Desmopressin Acetate
Tablets contain desmopressin acetate, a synthetic
vasopressin analog, an antidiuretic hormone affecting renal
water conservation. It is chemically defined as follows:
Mol. wt. 1183.34
SCH2CH2CO-Tyr-Phe-Gln-Asn-Cys-Pro-D-Arg-Gly-NH2 • CH3COOH • 3H2O
1-(3-mercaptopropionic acid)-8-D-arginine vasopressin monoacetate (salt) trihydrate.
Desmopressin acetate tablets
contain either 0.1 or 0.2 mg desmopressin acetate which is equivalent to 0.089 mg desmopressin and 0.178 mg of desmopressin, respectively. Inactive
ingredients include: lactose, potato starch, magnesium stearate and povidone.
CLINICAL PHARMACOLOGY
Pharmacokinetics
Absorption
The mean time to reach maximum plasma
desmopressin levels (tmax)
is approximately 1.1 hours following Desmopressin Acetate Tablet
administration. Increasing oral doses produced dose dependent increases in the
plasma levels of desmopressin. The bioavailability of desmopressin acetate oral tablets is about 5% compared to intranasal formulation, and about 0.16% compared to intravenous formulation.
Distribution
The volume of distribution of desmopressin after intravenous administration of 2 mcg is 26.5 L.
Elimination
The mean terminal half-life after IV dosing
of desmopressin is 2.8 hours.
Metabolism
In vitro studies in human liver microsome preparations have shown that desmopressin is not a substrate for the human CYP450
system.
Excretion
Desmopressin is mainly excreted
in the urine. After intravenous administration of 2 mcg,
52% of the dose was recovered in the
urine within 24 hours as unchanged desmopressin.
Specific Populations
Renal Impairment
Desmopressin is mainly excreted
in the urine. A pharmacokinetic study was conducted in subjects with
normal kidney function as well as mild, moderate, and severe renal impairment
(n=24, 6 subjects in each group) with a single 2 mcg dose of desmopressin
acetate injection. The terminal half-life was 2.8 hours
in subjects with normal renal function, 4.0 hours in mild renal
impairment,
6.6 hours in moderate
renal impairment and 8.7 hours
in severe renal impairment. In patients with mild, moderate and severe renal
impairment, mean desmopressin exposure was 1.5 fold, 2.4 fold and 3.6 fold
higher, respectively, compared to that of subjects with normal renal function [see Contraindications (4), Use in Specific
Populations (8.6)].
Drug Interactions
In vitro studies in human liver
microsome preparations have shown that desmopressin does not
inhibit the human CYP450 system. No in vivo interaction studies have been
performed with Desmopressin Acetate Tablet.
NONCLINICAL TOXICOLOGY
CLINICAL STUDIES
Central
Diabetes Insipidus
Clinical studies were conducted [see Clinical
Pharmacology (12.2)].
Primary Nocturnal Enuresis in Pediatric Patients
Two double-blind, randomized,
placebo-controlled studies were conducted in a total of 329 patients with primary nocturnal enuresis with data available for efficacy. Patients
were 5-17 years old, and 72% were males. Patients
were evaluated over a two-week baseline period in which the average number of
wet nights was 10 (range 4-14). Patients were then randomized to receive
0.2, 0.4, or 0.6 mg of desmopressin acetate or placebo. The pooled results
after two weeks are shown in Table 1:
Table 1. Response to Desmopressin Acetate
Tablets and Placebo
at Two Weeks of Treatment Mean (SE) Number of Wet
Nights/2 Weeks
|
|
Placebo
(n =
85) |
0.2 mg/day (n = 79) |
0.4 mg/day (n = 82) |
0.6 mg/day (n = 83) |
|
Baseline |
10 (0.3) |
11 (0.3) |
10 (0.3) |
10 (0.3) |
|
Reduction from Baseline |
1 (0.3) |
3 (0.4) |
3 (0.4) |
4 (0.4) |
|
Percent Reduction from
Baseline |
10% |
27% |
30% |
40% |
|
p-value vs placebo |
—— |
<0.05 |
<0.05 |
<0.05 |
Patients treated
with Desmopressin Acetate
Tablets showed a statistically significant reduction in the
number of wet nights compared to placebo-treated patients. A greater response
was observed with increasing doses up to 0.6 mg.
Primary Nocturnal Enuresis in Pediatric Patients
Aged 12 and Older and
Adults
A double-blind, randomized,
parallel-group study was conducted in 66 patients with primary nocturnal
enuresis who were determined to be responders to therapy with Desmopressin
Acetate Nasal Spray (e.g., >50% reduction in the number of wet nights/week)
and continued to have at least one wet night per week during the washout
period. The median age of the subjects was 17 with a range of 12 to 45 years, 56% were males, and they had an average
of 5 wet nights per week
(range 2-7) at baseline. Patients were randomized to receive 0.2 or 0.4 mg of
Desmopressin Acetate Tablets. Treatment outcome was measured as a mean
reduction in the number of wet
nights per week at the end of the four week treatment period
relative to the baseline observation period. The results by age
group are shown in Table 2:
Table 2. Response to Desmopressin Acetate
Tablets at Four Weeks of Treatment Mean (SD)
Number of Wet Nights/Week
|
Age |
12-17 years of age |
18-45 years of age |
||
|
|
0.2 mg/day (n = 13) |
0.4 mg/day (n = 17) |
0.2 mg/day (n = 18) |
0.4 mg/day (n = 15) |
|
Baseline |
5.5 (1.0) |
4.5 (1.4) |
5.7 (1.1) |
4.7 (1.4) |
|
Reduction from Baseline* |
1.7 (0.5) |
3.6 (0.4) |
3.7 (0.4) |
3.8 (0.4) |
|
Percent Reduction from
Baseline |
31% |
80% |
65% |
81% |
*Least square mean (SE) adjusted
for baseline
Renal Concentration Capacity Test in Pediatric Patients
A multi-center, randomized,
double-blind, double-dummy, four-period, cross-over trial was performed in 153
patients aged 3 to 18 years to compare Desmopressin Acetate Tablets (0.6 mg),
Desmopressin Acetate Nasal Spray (20 mcg) and placebo. Patients were given
medication in the evening before bedtime, with fluid restriction maintained
from one hour before dosing to 8 hours after dosing. Any urine sample within
one hour of drug administration was discarded. Urine osmolality was measured in the first
voided specimen, at least one hour but not more than 12 hours
after drug administration. The results of the test are shown in Table 3:
Table 3. Urine Osmolality (mOsm/kg)
in Pediatric Patients
Treated with Desmopressin Acetate Tablets, Nasal Spray
and Placebo (ITT population)
|
|
Tablet 0.6 mg (3×0.2 mg) |
Nasal Spray 20 μg (2×10μg) |
Placebo |
|
N |
137 |
144 |
141 |
|
Mean (SD) |
930 (149) |
962
(187) |
718 (238) |
|
Tablet vs.
Nasal Spray |
-41 (-62, -19) |
|
|
|
LSMean difference (95% Cl) |
|||
Central Diabetes Insipidus
Desmopressin Acetate
Tablets are indicated as antidiuretic replacement therapy in the management of central diabetes
insipidus.
Primary Nocturnal Enuresis
Desmopressin Acetate
Tablets are indicated
in patients aged 6 years
and older for the management of primary nocturnal enuresis.
DOSAGE AND ADMINISTRATION
Renal Concentration Capacity Test
Desmopressin Acetate
Tablets are indicated
in pediatric patients
aged 3 years and older to evaluate the capacity of the kidneys to
concentrate urine.
Limitations of Use:
Desmopressin Acetate Tablets
are not indicated for:
·
Treatment of nephrogenic diabetes insipidus
·
Use in adults with secondary nocturia
·
Use as a diagnostic agent for the renal concentration capacity test in febrile patients (>38.0°C) due to the risk of
inaccurate results.
Central Diabetes Insipidus Recommended Dosage
·
Instruct patients about
appropriate fluid restriction during Desmopressin Acetate
Tablet treatment [see Warnings and
Precautions (5.1)].
·
Individualize the dosage of Desmopressin Acetate Tablets for each
patient and adjust the dosage according to the diurnal
pattern of response.
Estimate patient response
by: duration of sleep and
water turnover.
·
Recommended starting dose for patients
is 0.05 mg desmopressin acetate
(half of the 0.1 mg Desmopressin Acetate Tablet)
orally two times a day.
·
Titrate the daily dosage as needed
to obtain an adequate antidiuretic response. The usual
dosage range is 0.1 mg daily to 1.2 mg daily orally divided into two or three daily doses.
Monitor response by measuring urine volume and osmolality. Monitoring measurements of plasma
osmolality may also be useful
Primary Nocturnal Enuresis Recommended Dosage
·
Instruct patients about
appropriate fluid restriction during Desmopressin Acetate
Tablet treatment. Limit fluid intake to a minimum from 1 hour before
administration, until the next
morning, or at least 8 hours after administration [see Warnings and Precautions (5.1)].
·
Individualize the dosage
of Desmopressin Acetate
Tablets for each patient and adjust the dosage according to response.
·
The recommended starting
dose for patients
aged 6 years and older is 0.2 mg orally
daily at bedtime.
·
Based upon clinical
response, the dose may be titrated up to 0.4 mg daily and, if needed, to the maximum dose of 0.6 mg daily.
Renal Concentration Capacity Test Recommended Dosage
·
Ensure the patient
is afebrile prior to testing
[see Indications and Usage
(1.4)]
·
Pediatric patients aged 3 years
and older: administer 0.6 mg desmopressin acetate (three 0.2
mg Desmopressin Acetate Tablets) orally at bedtime after bladder emptying.
·
Discard any urine passed within
one hour from drug administration. Take a sample
of urine from the first
voided specimen, at least one hour but not more than 12 hours after drug
administration, to measure urine osmolality.
Switching Between Desmopressin Acetate Formulations
·
Begin Desmopressin Acetate
Tablets for patients
previously on intranasal desmopressin acetate:
o
12 hours after
the last intranasal dose for CDI patients
o
24 hours after
the last intranasal dose for PNE
patients.
·
Monitor patients closely
during the initial
dose titration period.
WARNINGS AND PRECAUTIONS
DOSAGE FORMS AND STRENGTHS
Desmopressin Acetate
Tablets:
·
0.1 mg: White,
oval, convex tablet,
scored on one side, with engraving “0.1”
on the other side
·
0.2 mg: White,
round, convex tablet,
scored on one side, with engraving “0.2”
on the other side
CONTRAINDICATIONS
Desmopressin Acetate
Tablets are contraindicated in individuals with:
·
Known hypersensitivity to desmopressin acetate
or to any of the components of Desmopressin Acetate Tablets [see Adverse Reactions (6)].
·
Renal impairment
defined as estimated creatinine clearance (CLcr)
less than 50 mL/min) [see Use in Specific
Populations, Renal Impairment (8.6) and Clinical Pharmacology (12.3)].
·
Hyponatremia or a history of hyponatremia [see Warnings
and Precautions (5.1)].
Other Drugs that may Increase Risk of Hyponatremia
The concomitant administration
of Desmopressin Acetate Tablets with other drugs that may increase the risk of water intoxication with hyponatremia, (e.g.,
tricyclic antidepressants, selective serotonin re-uptake inhibitors,
chlorpromazine, opiate analgesics, NSAIDs, lamotrigene and carbamazepine)
requires more frequent serum sodium
monitoring [see Warnings and
Precautions (5.1), Adverse Events (6)].
Other Vasoconstrictors
Desmopressin acetate can
elevate blood pressure. Use of large doses of Desmopressin Acetate Tablets with other vasoconstrictors may require a reduction of the Desmopressin Acetate Tablet
dosage [see Adverse Reactions (6)].
Pregnancy
Risk summary
Prolonged experience with
desmopressin in pregnant women over several decades, based on the available
published data and case reports, did not identify a drug associated risk of
major birth defects, miscarriage or adverse maternal or fetal outcomes. In
addition, in vitro studies with human placenta
demonstrate poor placental
transfer of desmopressin. No adverse developmental outcomes were observed in
animal reproduction studies with administration of desmopressin during
organogenesis to pregnant rats and rabbits at doses approximately <1 and 38
times, respectively, the maximum recommended human dose based on body surface
area (mg/m2) (see Data).
The estimated background risk of major birth defects
and miscarriage for the indicated population are unknown. In the US general population, the
estimated background risk of major birth defects and miscarriage in clinically
recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
Desmopressin acetate
at up to 50 ng/kg/day was given by subcutaneous injection
to pregnant rats, from gestation day 1 to 20 during
the period of early embryonic development and organogenesis without teratogenic
effects. Desmopressin acetate at up
to 10 mcg/kg/day was given to pregnant rabbits by subcutaneous injection from
gestation day 6 to 18 during fetal organogenesis without teratogenic effects.
These doses of desmopressin acetate represent approximately <1 times (rat) and
38 times (rabbit) the maximum recommended human dose based on body surface area
(mg/m2).
Lactation
Risk Summary
Breastfeeding is not expected
to result in clinically relevant
exposure of the infant to desmopressin
following maternal administration. Desmopressin is present in small amounts in
human milk (see
Data). There is no information on the effects of desmopressin on the
breastfed infant or on milk production. The developmental and health benefits of
breastfeeding should be considered along with the mother’s need for
Desmopressin Acetate Tablets and any potential adverse effects on the breastfed
child from Desmopressin Acetate Tablets or from the underlying maternal
condition.
Data
Risk Summary
Breastfeeding is not expected
to result in clinically relevant
exposure of the infant to desmopressin
following maternal administration. Desmopressin is present in small amounts in
human milk (see
Data). There is no information on the effects of desmopressin on the
breastfed infant or on milk production. The developmental and health benefits of
breastfeeding should be considered along with the mother’s need for
Desmopressin Acetate Tablets and any potential adverse effects on the breastfed
child from Desmopressin Acetate Tablets or from the underlying maternal
condition.
Data
Human Data
The breast milk of lactating women was collected over 8 hours following desmopressin (300 mcg) administration using nasal spray. Based on the measured concentrations of desmopressin, the amounts of desmopressin that may be transferred to a breastfed infant correspond to 0.0001- 0.005% of the dose administered.
Pediatric Use
Central Diabetes
Insipidus
Desmopressin Acetate Tablets are
indicated as antidiuretic replacement therapy in the management of central
diabetes insipidus in pediatric patients. Use of Desmopressin Acetate Tablets for this indication is supported by evidence from adults and pediatric patients
with central diabetes
insipidus. Use in pediatric patients requires careful fluid intake restriction
to prevent possible water intoxication with hyponatremia [see Warnings and Precautions (5.1)].
Primary Nocturnal
Enuresis
Desmopressin Acetate Tablets
are indicated for the management of primary nocturnal enuresis in pediatric patients
6 years of age and older. Use of Desmopressin Acetate Tablets for this indication is supported by evidence from
clinical trials in pediatric and adult patients with primary nocturnal
enuresis. Temporarily suspend treatment with Desmopressin Acetate Tablets
during acute intercurrent illness characterized by fluid and/or electrolyte
imbalance (e.g., systemic infections, fever, recurrent vomiting or diarrhea) or
under conditions of extremely hot weather, vigorous exercise or other conditions associated with increased water intake [see Warnings
and Precautions (5.1)].
Desmopressin Acetate Tablets
are not indicated in pediatric patients
less than 6 years of age.
Renal Concentration Capacity Test
Desmopressin Acetate
Tablets are indicated
to evaluate the capacity of the kidneys
to concentrate urine in
pediatric patients aged 3 years and older. Use of Desmopressin Acetate Tablets
for this indication is supported by evidence from a clinical trial in pediatric
patients.
Desmopressin Acetate
Tablets are not indicated in pediatric patients
less than 3 years of age.
Geriatric Use
Clinical studies of Desmopressin Acetate Tablets in the elderly
have shown an increased risk of
hyponatremia with age and declining creatinine clearance.
Because elderly patients are more likely to have
decreased renal function, care should be taken in dose selection and monitoring renal function is recommended [see Section
Clinical Pharmacology (12),
Contraindications (4)].
Use of Desmopressin Acetate
Tablets in geriatric
patients requires careful
fluid intake restriction to prevent possible water intoxication with hyponatremia [see Warnings
and Precautions (5.1)].
Renal Impairment
Desmopressin acetate
is substantially excreted
by the kidney, and the risk of adverse events may
be greater in patients with renal impairment than patients with normal renal
function.
Desmopressin Acetate Tablets
are contraindicated in patients with estimated CLcr by Cockcroft- Gault equation less than 50 mL/min
[see Clinical Pharmacology (12.1, 12.3), Contraindications (4)].
OVERDOSAGE
Signs of overdose may include
confusion, drowsiness, continuing headache, problems with passing urine and
rapid weight gain due to fluid retention. [see
Warnings and Precautions (5.1)]. In case of overdosage, reduce
the dosage, decrease
the frequency of administration, or discontinue
Desmopressin Acetate Tablets. There is no known specific antidote for
desmopressin acetate.
Mechanism of Action
The antidiuretic effects of
desmopressin are mediated by stimulation of vasopressin 2 (V2) receptors,
thereby increasing water re-absorption in the kidney, and hence reducing urine
production. Desmopressin is a replacement hormone for antidiuretic hormone in the treatment of central diabetes insipidus.
Pharmacodynamics
The use of desmopressin in
patients with central diabetes insipidus reduces urinary output, increases urine osmolality, and decreases plasma
osmolality. Dose response
studies in patients with diabetes insipidus have
demonstrated that oral doses of 0.025 mg to 0.4 mg produced clinically significant antidiuretic effects. In most patients, doses of 0.1 mg
to 0.2 mg produced optimal antidiuretic effects lasting up to eight hours. With doses of 0.4 mg, antidiuretic effects
were observed for up to 12
hours; measurements beyond 12 hours were not recorded. Following administration
of desmopressin acetate tablets, the onset of antidiuretic effect occurs at
around 1 hour, and it reaches a maximum at about 4 to 7 hours based on the measurement of increased urine osmolality.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies with desmopressin acetate
have not been performed to evaluate carcinogenic potential, mutagenic potential or effects on fertility.
HOW SUPPLIED/STORAGE AND HANDLING
Desmopressin Acetate
Tablets are available as:
·
0.1 mg tablet: White, oval,
convex tablet, scored
on one side, with engraving “0.1” on the other side
NDC 55566-5060-1, Bottle of 100 tablets
·
0.2 mg tablet: White, round,
convex tablet, scored on one side, with engraving “0.2”
on the other side
NDC 55566-5061-1, Bottle of 100 tablets
Store at Controlled Room Temperature 20 to 25°C (68 to 77°F) [see USP]. Avoid
exposure to excessive heat or
light.
PATIENT COUNSELING INFORMATION
Hyponatremia and Fluid Restriction
· Inform patients that
Desmopressin Acetate Tablets may cause severe hyponatremia, which may be life-threatening, if it is not promptly
diagnosed and treated.
Inform patients about the
signs and symptoms associated with hyponatremia and advise them to contact a
healthcare provider if these occur [see
Warnings and Precautions (5.1)].
· Advise patients
to limit fluid
intake to a minimum starting
one hour prior
to Desmopressin Acetate Tablet
administration and for eight hours following Desmopressin Acetate Tablet
administration. [see Warnings and
Precautions (5.1)].
