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DESMOPRESSIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Desmopressin acetate is a synthetic analogue of 8-arginine vasopressin or antidiuretic hormone (ADH), a natural pituitary hormone affecting renal free water conservation.

Specific Substances

    A) DESMOPRESSIN (SYNONYM)
    1) Desmopressin acetate
    2) Desmopressium
    3) DDAVP
    4) Desmopresina
    5) Desmopresinas
    6) Desmopressiini
    7) Desmopressine
    8) Desmopressinum
    9) Dezmopresszin
    10) CAS 16679-58-6
    LYPRESSIN (SYNONYM)
    1) L-8
    2) Lipresina
    3) Lipressina
    4) LVP
    5) C(46)H(65)N(13)O(12)S(2)
    6) CAS 50-57-7

Available Forms Sources

    A) FORMS
    1) Desmopressin is available in the following formulations:
    a) Oral Tablet: 0.1 mg and 0.2 mg (Prod Info desmopressin acetate oral tablets, 2014).
    b) Nasal Spray: 5 mL bottle (each mL contains 0.1 mg of desmopressin), compression pump delivers 0.1 mL (10 mcg) of desmopressin per spray (Prod Info DDAVP(R) nasal spray, 2015; Prod Info desmopressin acetate 0.01% nasal spray solution, 2015); 2.5 mL bottle (each mL contains 1.5 mg of desmopressin), spray pump delivers 0.1 mL (150 mcg) of desmopressin per spray (Prod Info STIMATE(R) nasal spray, 2007).
    c) Nasal Solution (Rhinal Tube): 2.5 mL bottle packaged with two rhinal tubes for administration (Prod Info DDAVP(R) Rhinal Tube intranasal solution, 2011).
    d) Injection Solution: 4 mcg/ml in 10 mL multi-dose vials (Prod Info desmopressin acetate intravenous injection solution, subcutaneous injection solution, 2014).
    B) USES
    1) Desmopressin is indicated as an antidiuretic hormone replacement therapy in the management of central diabetes insipidus, and for the management of temporary polyuria and polydipsia following head trauma or surgery in the pituitary region (Prod Info desmopressin acetate 0.01% nasal spray solution, 2015; Prod Info DDAVP(R) nasal spray, 2015; Prod Info desmopressin acetate oral tablets, 2014; Prod Info DDAVP(R) Rhinal Tube intranasal solution, 2011).
    2) Desmopressin tablets are also indicated for the management of primary nocturnal enuresis (Prod Info desmopressin acetate oral tablets, 2014).
    3) Desmopressin injection is indicated for patients with hemophilia A or von Willebrand's Disease (Type 1) with factor VIII coagulant activity levels greater than 5% (Prod Info desmopressin acetate intravenous injection solution, subcutaneous injection solution, 2014).
    4) LYPRESSIN: Lypressin is a form of vasopressin (Sweetman, 2004).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Used to treat nocturnal enuresis in children and adults. Used to treat central diabetes insipidus, and to treat hemorrhage in patients with mild to moderate hemophilia A or type I von Willebrand disease.
    B) PHARMACOLOGY: Synthetic vasopressin analog; has antidiuretic activity and increases plasma factor VIII activity.
    C) TOXICOLOGY: Excessive antidiuretic activity or ingestion of free water causes hyponatremia.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) Potentially severe adverse effects reported with therapeutic use have included: hyponatremia and water intoxication in children and infrequently in adults. Nausea, vomiting, allergic reactions, headache, behavior changes, seizures and coma have been associated with hyponatremia. Minor elevations in blood pressure have been reported with therapeutic use.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting, headache, hyponatremia.
    2) SEVERE TOXICITY: Hyponatremia, coma and seizures have developed in children and adolescents using desmopressin nasal spray unsupervised, presumed to be inadvertent overdoses.
    0.2.20) REPRODUCTIVE
    A) In a retrospective chart review of 49 pregnant women receiving desmopressin for the management of diabetes insipidus, there were no safety issues that could be related to desmopressin in either the mother or infant.

Laboratory Monitoring

    A) Monitor serial serum electrolytes (especially sodium), serum osmolality, urine output (volume and osmolarity), and fluid status after overdose and in patients with vomiting, headache, depressed mental status, or seizures after therapeutic use.
    B) Monitor mental status and vital signs.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is primarily symptomatic and supportive. Treat mild hyponatremia with water restriction and/or 0.9% sodium chloride.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Manage severe hyponatremia with 0.9% sodium chloride; 3% NaCl may be necessary only with very serious toxicity. Treat seizures with benzodiazepines; recurrent seizures may require the addition of barbiturates or propofol.
    C) DECONTAMINATION
    1) PREHOSPITAL: Based on limited data, it is not known if activated charcoal would be of benefit following oral exposure of desmopressin.
    2) HOSPITAL: Consider activated charcoal for recent large ingestion in patients who can protect their airway. No decontamination after intranasal or subcutaneous use.
    D) AIRWAY MANAGEMENT
    1) Endotracheal intubation and mechanical ventilation may be necessary if coma or recurrent seizures secondary to hyponatremia develop.
    E) ANTIDOTE
    1) None
    F) HYPONATREMIA
    1) Evaluate for hyponatremia and associated symptoms. Patients with mild symptoms can be managed with water restriction. Patents with moderate to severe symptoms should receive 0.9% sodium chloride (rarely 3% NaCl in patients with very severe symptoms). The goal is slow correction; the serum sodium should not increase more than 2 mEq/L/hour in any 4 hour period or more than 15 mEq/L per day. Rapid correction may cause central pontine myelinolysis. Monitor serum electrolytes, fluid intake and output, and urine volume and electrolytes.
    G) SEIZURES
    1) Administer intravenous benzodiazepines, add barbiturates or propofol if unresponsive. Monitor serum sodium and correct hyponatremia.
    H) BLOOD PRESSURE
    1) Transient increases and decreases in blood pressure may occur which usually do NOT require treatment.
    I) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: Symptomatic patients or those ingesting more than a therapeutic dose should be referred to a healthcare facility for evaluation and treatment, and monitored for at least 8 hours.
    2) ADMISSION CRITERIA: Patients with symptomatic hyponatremia should be admitted.
    J) PITFALLS
    1) Monitor serial serum sodium and restrict free water intake. Duration of antidiuretic effects is 5 to 24 hours, and onset of hyponatremia may be delayed.
    K) PHARMACOKINETICS
    1) Limited absorption (5% oral; 3% to 4% intranasal); onset of antidiuretic effect 1 hour, duration 6 to 12 hours (oral) and 5 to 24 hours (intranasally). Excretion primarily renal. Half life 75 minutes.
    L) DIFFERENTIAL DIAGNOSIS
    1) Other causes of hyponatremia include SIADH, psychogenic polydypsia, Addison disease, diuretic use, vomiting.

Range Of Toxicity

    A) Unsupervised use of the nasal formulation by children and adolescents has caused hyponatremia and seizures, the exact dose used is unclear. Profound hyponatremia, water intoxication, and seizures, have been reported at therapeutic doses in children with unrestricted free water intake.
    B) THERAPEUTIC DOSE: INTRAVENOUS: 0.3 mcg/kg over 15 min. INTRAVENOUS/SUBCUTANEOUS: 2 to 4 mcg/day in 2 divided doses. INTRANASALLY: 10 to 40 mcg/day (0.1 to 0.4 mL). ORAL: 0.1 to 0.8 mg/day in divided doses.

Clinical Effects

Summary Of Exposure

    A) USES: Used to treat nocturnal enuresis in children and adults. Used to treat central diabetes insipidus, and to treat hemorrhage in patients with mild to moderate hemophilia A or type I von Willebrand disease.
    B) PHARMACOLOGY: Synthetic vasopressin analog; has antidiuretic activity and increases plasma factor VIII activity.
    C) TOXICOLOGY: Excessive antidiuretic activity or ingestion of free water causes hyponatremia.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) Potentially severe adverse effects reported with therapeutic use have included: hyponatremia and water intoxication in children and infrequently in adults. Nausea, vomiting, allergic reactions, headache, behavior changes, seizures and coma have been associated with hyponatremia. Minor elevations in blood pressure have been reported with therapeutic use.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting, headache, hyponatremia.
    2) SEVERE TOXICITY: Hyponatremia, coma and seizures have developed in children and adolescents using desmopressin nasal spray unsupervised, presumed to be inadvertent overdoses.

Heent

    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) Symptoms of upper respiratory irritation (nostril pain, rhinitis, and epistaxis) have been reported with intranasal desmopressin therapy (Prod Info DDAVP(R) nasal spray, 2006).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) MYOCARDIAL INFARCTION
    1) WITH THERAPEUTIC USE
    a) Although desmopressin did NOT appear to increase the risk of thrombosis in one study of surgical patients (Mannucci et al, 1994), coronary thrombosis has occurred following therapeutic use in patients with and without ischemic heart disease (Hartmann & Reinhart, 1995; Stratton et al, 2001).
    b) RISK FACTOR: Its been suggested that patients with clinical features of hemolytic uremic syndrome (HUS) may be at greater risk for developing spontaneous thrombosis with the use of DDAVP (Stratton et al, 2001).
    c) CASE REPORT: A 40-year-old male with mild hemophilia A died as a result of a fatal myocardial infarction shortly after desmopressin was begun prophylactically for a surgical procedure. Within 5 minutes of beginning the infusion the patient developed a loss of consciousness, dyspnea, and cardiac arrest. The authors reported a probable relationship between coronary thrombus and desmopressin use. Autopsy revealed a fresh platelet thrombosis in the left coronary artery (Hartmann & Reinhart, 1995).
    B) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Slight elevations in blood pressure have been reported with therapeutic use of desmopressin and appear to be dose dependent (Prod Info DDAVP(R) injection, 2006). The manufacturer suggests caution in administering desmopressin in patients with a known history of coronary artery disease or hypertension.
    C) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) ORAL: Despite its limited antihypertensive activity, large doses of desmopressin should be avoided in patients taking other antihypertensive agents (Prod Info DDAVP(R) injection, 2006).
    b) PARENTERAL: Decreased blood pressure has occurred rarely following intravenous desmopressin (Prod Info DDAVP(R) injection, 2006).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FAILURE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT (PEDIATRIC): Respiratory arrest and seizure activity developed in a child with hyponatremia associated with desmopressin use. The child had a family history of hemophilia and received desmopressin for excessive bleeding 12 hours after a tonsillectomy (Francis et al, 1999). The patient (13.1 kg) received 0.3 mcg/kg desmopressin IV to control bleeding (estimated blood loss was 300 to 400 mL); serum sodium was 114 mmol/L. Following sodium replacement and supportive care the child made a complete recovery.

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizure activity has been observed, most frequently in children, as a result of hyponatremia during therapeutic use of desmopressin (Kallio et al, 1993; Robson et al, 1997; Donoghue et al, 1998).
    b) CASE REPORT (PEDIATRIC): A 3-year-old child with a family history of hemophilia received desmopressin for severe bleeding after a tonsillectomy. Approximately 12 hours after the second procedure (to control bleeding), respiratory arrest and a grand mal seizure were reported; serum sodium level was 114 mmol/L. Complete recovery occurred following supportive care and sodium replacement (Francis et al, 1999).
    c) CASE REPORT (PEDIATRIC): Generalized tonic-clonic seizures occurred in a 10-year-old boy following 3 weeks of intranasal desmopressin therapy. Initial serum sodium was 117 mmol/L; recovery was complete following supportive treatment (Donoghue et al, 1998).
    d) CASE REPORT (ADOLESCENT): A 16-year-old female with a history of Prader-Willi syndrome and nocturnal enuresis developed generalized seizures and coma after therapy with intranasal desmopressin (40 mcg daily) for 9 months. Two days prior to hospitalization, the patient complained of severe headache. Serum sodium was 116 mEq/L after an initial bolus of 3% saline. With supportive care, the patient's mental status returned to baseline within 5 days of hospital admission (Robson et al, 1997).
    e) CASE REPORT (ADULT): A 37-year-old female with primary nocturnal enuresis was receiving intranasal desmopressin (30 mcg at bedtime) for 2 days was found unconscious with evidence of vomiting. Earlier that day, she complained of not feeling well and a headache. At the hospital, the patient suffered 2 generalized seizures, and initial labs revealed serum sodium of 114 mmol/L. The diagnosis of water intoxication with secondary severe hyponatremia was made, and with appropriate treatment (phenobarbital, hypertonic saline, diuretics and fluid restriction) the patient made a full recovery (Odeh & Oliven, 2001).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 15-year-old boy who was allowed to use desmopressin unsupervised, and drank excessive amounts of water, presented with coma and seizures secondary to water intoxication. Toxicity persisted for 36 hours after presentation, and was presumed secondary to inadvertent desmopressin overdose from overzealous use (Segal-Kuperschmit et al, 1997).
    b) CASE REPORT: A 6-year-old girl developed seizures and coma secondary to water intoxication after unsupervised use of desmopressin. It was felt this developed secondary to inadvertent excessive dosing (Apakama & Bleetman, 1999).
    B) CEREBRAL ARTERY OCCLUSION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT (PEDIATRIC): A 7-month-old girl with a history of end-stage renal disease who was undergoing bilateral nephrectomy developed an intraoperative cerebral infarct. Preoperatively the patient received intravenous desmopressin. Ptosis and leg weakness were apparent after surgery and an MRI revealed an area of ischemia in the superolateral aspect of the left frontal lobe. Ptosis and leg weakness resolved completely after a few hours, and the right arm regained some voluntary activity over the next few weeks. The authors were uncertain of the mechanism involved in the vascular injury; volume depletion was considered an unlikely cause (Grunwald & Sather, 1995).
    b) CASE REPORT (PEDIATRIC): A 7-year-old male with a history of varicella infection (2 weeks prior to onset of symptoms) was started on intranasal desmopressin therapy for enuresis, and within 48 hours developed a left-sided CVA. Following supportive care and physical therapy the patient made a complete recovery. The authors could not determine the exact role of desmopressin in this case, but suggested it may have contributed to the cerebral lesion based on its ability to cause platelet aggregation (Wieting et al, 1997).
    C) INTRACRANIAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT (ADULT): Acute subdural hemorrhage secondary to profound thrombocytopenia occurred in a 48-year-old female following a total abdominal hysterectomy. The patient had a history of hypertension and chronic renal insufficiency, and was given prophylactic intravenous desmopressin (0.24 mcg/kg) preoperatively. Based on the poor prognosis, surgery was not performed; death occurred on postoperative day 3 (Sun & Chien, 1998).
    D) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Transient headache has been reported with large doses of desmopressin. Headache along with nausea and vomiting may be early symptoms of water intoxication (Prod Info DDAVP(R) injection, 2006; Robson et al, 1997; Kallio et al, 1993).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Transient symptoms of nausea and abdominal cramping have been reported with large doses of desmopressin(Prod Info DDAVP(R) injection, 2006).
    b) Early symptoms of water intoxication associated with desmopressin therapy include nausea, vomiting, and headache (Robson & Leung, 1998; Prod Info DDAVP(R) injection, 2006; Kallio et al, 1993).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMOSTATIC FUNCTION
    1) WITH THERAPEUTIC USE
    a) Desmopressin, a potent systemic hemostatic agent, has been used prophylactically to prevent bleeding during surgery, in particular patients with mild and moderate factor VIII or von Willebrand's factor deficiency (Saulnier et al, 1994; Cattaneo et al, 1993; Prod Info DDAVP(R) injection, 2006).
    B) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Desmopressin-induced thrombocytopenia has been reported (Castaman et al, 1996). It has been observed that some individuals with type I platelet discordant von Willebrand's disease developed a mutation which allows moderate thrombocytopenia to occur following a desmopressin infusion (Castaman et al, 1995).
    b) CASE REPORT (ADULT): Acute subdural hemorrhage secondary to profound thrombocytopenia occurred in a 48-year-old female following a total abdominal hysterectomy. The patient had a history of hypertension and chronic renal insufficiency, and was given a single preoperative dose of intravenous desmopressin (0.24 mcg/kg). Approximately 14 hours following surgery the patient became comatose. Lab values were as follows: PT 22.3/12 s; PTT 31.1/23.7 s, platelet 45,000/mm(3), fibrin degradation product 10 mcg/mL, fibrinogen 339 mg/dL, and bleeding time of over 10 minutes. Based on the patient's poor prognosis, surgery was not performed; death occurred on postoperative day 3 (Sun & Chien, 1998).
    C) THROMBOEMBOLUS
    1) WITH THERAPEUTIC USE
    a) LACK OF EVIDENCE: Cattaneo (1997) reviewed clinical trials of thrombotic complications in the literature and found that the risk of thrombosis in desmopressin-treated and placebo treated patients was 3.4 and 2.7%, respectively, which was NOT statistically significant (Cattaneo, 1997).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) WITH THERAPEUTIC USE
    a) Flushing of the skin has occurred with parenteral use of desmopressin with no apparent change in blood pressure (Prod Info DDAVP(R) injection, 2006).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) Severe allergic reactions are rare with desmopressin use. Anaphylaxis has only been reported following intravenous administration (Prod Info DDAVP(R) injection, 2006).

Reproductive

    3.20.1) SUMMARY
    A) In a retrospective chart review of 49 pregnant women receiving desmopressin for the management of diabetes insipidus, there were no safety issues that could be related to desmopressin in either the mother or infant.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Pregnancy Category - B (Prod Info DDAVP(R) tablets, desmopressin acetate, 1998).
    B) LACK OF EFFECT
    1) In a retrospective chart review of 49 pregnant women receiving desmopressin for the management of diabetes insipidus, there were no safety issues that could be related to desmopressin in either the mother or infant (Ray, 1998). The authors recommend a large database to confirm these findings.
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is not known if desmopressin is excreted in human milk (Prod Info DDAVP(R) tablets, desmopressin acetate, 1998).

Carcinogenicity

    3.21.3) HUMAN STUDIES
    A) LACK OF DATA
    1) Carcinogenicity, mutagenicity, and impairment of fertility have NOT been evaluated at the time of this review (Prod Info DDAVP(R) tablets, desmopressin acetate, 1998).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serial serum electrolytes (especially sodium), serum osmolality, urine output (volume and osmolarity), and fluid status after overdose and in patients with vomiting, headache, depressed mental status, or seizures after therapeutic use.
    B) Monitor mental status and vital signs.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor serial serum electrolytes (especially sodium), serum osmolality, urine output (volume and osmolarity), and fluid status after overdose and in patients with vomiting, headache, depressed mental status, or seizures after therapeutic use.
    2) Obtain a baseline serum sodium level and follow serial levels in symptomatic patients.
    3) Monitor platelet count, coagulation factors, and bleeding time in symptomatic patients or patients with evidence of bleeding.
    4.1.3) URINE
    A) URINALYSIS
    1) Monitor urine output closely in symptomatic patients.
    2) Analyze urine volume and osmolality following a significant exposure.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs and neurological status in all symptomatic patients.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with symptomatic hyponatremia should be admitted.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Symptomatic patients or those ingesting more than a therapeutic dose should be referred to a healthcare facility for evaluation and treatment, and monitored for at least 8 hours.

Monitoring

    A) Monitor serial serum electrolytes (especially sodium), serum osmolality, urine output (volume and osmolarity), and fluid status after overdose and in patients with vomiting, headache, depressed mental status, or seizures after therapeutic use.
    B) Monitor mental status and vital signs.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) Based on limited data, it is not known if activated charcoal would be of benefit following oral exposure of desmopressin.
    2) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor serial serum electrolytes (especially sodium), serum osmolality, urine output (volume and osmolarity), and fluid status after overdose and in patients with vomiting, headache, depressed mental status, or seizures after therapeutic use. Monitor vital signs and neurologic status.
    B) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    C) HYPONATREMIA
    1) Evaluate for hyponatremia and associated symptoms. Patients with mild symptoms can be managed with water restriction. Patents with moderate to severe symptoms should receive 0.9% sodium chloride (rarely 3% sodium chloride in patients with very severe symptoms). The goal is slow correction; the serum sodium should not increase more than 2 mEq/L/hour in any 4 hour period or more than 15 mEq/L per day. Rapid correction may cause central pontine myelinolysis. Monitor serum electrolytes, fluid intake and output, and urine electrolytes.
    D) HYPERTENSIVE EPISODE
    1) Monitor blood pressure. Transient increases in blood pressure may occur which do NOT require intervention.
    E) HYPOTENSIVE EPISODE
    1) Monitor blood pressure. Transient decreases in blood pressure may occur which do NOT require intervention.

Range Of Toxicity

Summary

    A) Unsupervised use of the nasal formulation by children and adolescents has caused hyponatremia and seizures, the exact dose used is unclear. Profound hyponatremia, water intoxication, and seizures, have been reported at therapeutic doses in children with unrestricted free water intake.
    B) THERAPEUTIC DOSE: INTRAVENOUS: 0.3 mcg/kg over 15 min. INTRAVENOUS/SUBCUTANEOUS: 2 to 4 mcg/day in 2 divided doses. INTRANASALLY: 10 to 40 mcg/day (0.1 to 0.4 mL). ORAL: 0.1 to 0.8 mg/day in divided doses.

Therapeutic Dose

    7.2.1) ADULT
    A) DISEASE STATE
    1) CENTRAL CRANIAL DIABETES INSIPIDUS -
    a) IV/SUBQ
    1) 0.5 mL (2 mcg) to 1 mL (4 mcg) IV or SubQ daily, in two divided doses (Prod Info desmopressin acetate intravenous injection, subcutaneous injection, 2013).
    b) NASAL SPRAY
    1) 0.1 mL (10 mcg) to 0.4 mL (40 mcg) daily, as a single dose or divided into two or three doses (Prod Info desmopressin acetate nasal spray, 2013)
    c) ORAL TABLET
    1) Initial dose, 0.05 mg twice daily; adjustments should be made in the range of 0.1 to 1.2 mg divided into 2 or 3 daily doses (Prod Info desmopressin acetate oral tablets, 2014)
    d) RHINAL TUBE
    1) 0.1 mL to 0.4 mL daily, as a single dose or divided into two or three doses (Prod Info DDAVP(R) Rhinal Tube intranasal solution, 2011)
    2) HEMOPHILIA A AND VON WILLEBRAND DISEASE
    a) IV
    1) 4 mcg/mL infused over 15 to 30 minutes at a dose of 0.3 mcg/kg body weight; 50 mL of diluent for adults weighing more than 10 kg (Prod Info desmopressin acetate intravenous injection, subcutaneous injection, 2013)
    3) NOCTURNAL ENURESIS
    a) ORAL TABLET
    1) Initial dose, 0.2 mg at bedtime; MAX: 0.6 mg (Prod Info desmopressin acetate oral tablets, 2014)
    7.2.2) PEDIATRIC
    A) DISEASE STATE
    1) CENTRAL CRANIAL DIABETES INSIPIDUS
    a) IV/SUBQ
    1) 11 YEARS OR YOUNGER: Safety and efficacy in the pediatric population 11 years or younger have not been established (Prod Info desmopressin acetate intravenous injection, subcutaneous injection, 2013)
    2) 12 YEARS AND OLDER: 0.5 mL (2 mcg) to 1 mL (4 mcg) IV or SubQ daily, usually in 2 divided doses (Prod Info desmopressin acetate intravenous injection, subcutaneous injection, 2013)
    b) NASAL SPRAY
    1) 3 MONTHS TO 12 YEARS: 0.05 mL (5 mcg) to 0.3 mL (30 mcg) daily, as a single dose or in 2 divided doses; however, the nasal spray pump can only deliver doses of 0.1 mL or in multiples of 0.1 mL. Doses less than 0.1 mL should be administered using the rhinal delivery system . Do NOT use the nasal spray pump in pediatric patients requiring doses less than 0.1 mL (Prod Info desmopressin acetate nasal spray, 2013)
    c) ORAL TABLET
    1) 4 TO 17 YEARS: Initial dose, 0.05 mg twice daily; adjustments should be made in the range of 0.1 to 1.2 mg administered 2 or 3 times daily (Prod Info desmopressin acetate oral tablets, 2014)
    2) RHINAL TUBE
    a) 3 MONTHS TO 12 YEARS: 0.05 mL to 0.3 mL daily, as a single dose or in 2 divided doses (Prod Info DDAVP(R) Rhinal Tube intranasal solution, 2011)
    3) HEMOPHILIA A AND VON WILLEBRAND DISEASE
    a) IV
    1) 2 MONTHS OR YOUNGER: IV Desmopressin should not be used in the infant population 2 months or younger for the treatment of either hemophilia A or von Willebrand's disease (Prod Info desmopressin acetate intravenous injection, subcutaneous injection, 2013)
    2) 3 MONTHS TO 17 YEARS: 4 mcg/mL infused over 15 to 30 minutes at a dose of 0.3 mcg/kg body weight. WEIGHT MORE THAN 10 KG: 50 mL of diluent; WEIGHT 10 KG OR LESS: 10 mL of diluent (Prod Info desmopressin acetate intravenous injection, subcutaneous injection, 2013)
    4) NOCTURNAL ENURESIS
    a) ORAL TABLET
    1) 6 TO 17 YEARS: 0.2 mg at bedtime; MAX: 0.6 mg (Prod Info desmopressin acetate oral tablets, 2014)

Maximum Tolerated Exposure

    A) INADVERTENT OVERUSE
    1) CASE REPORT - A 15-year-old boy who was allowed to use desmopressin unsupervised, and drank excessive amounts of water, presented with coma and seizures secondary to water intoxication. Toxicity persisted for 36 hours after presentation, and was presumed secondary to inadvertent desmopressin overdose from overzealous use (Segal-Kuperschmit et al, 1997).
    2) CASE REPORT - A 6-year-old girl developed seizures and coma secondary to water intoxication after unsupervised use of desmopressin. It was felt this developed secondary to inadvertent excessive dosing (Apakama & Bleetman, 1999).
    B) GENERAL/SUMMARY
    1) ANIMAL DATA - Oral doses up to 0.2 mg/kg/day have been administered to dogs and rats for 6 months without any significant drug-related toxicities reported (Prod Info DDAVP(R) tablets, desmopressin acetate, 1996). An intravenous dose of 2 mg/kg in mice demonstrated no effect.

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Desmopressin is a synthetic hemostatic agent. It is an analogue of the natural pituitary hormone 8-arginine vasopressin (ADH), an antidiuretic hormone which affects renal water conservation (Prod Info desmopressin acetate oral tablets, 2014).

Physicochemical

Ph

    A) NASAL SPRAY - It has an adjusted pH of 4.0 (Prod Info DDAVP(R), 1994).

Molecular Weight

    A) TABLET - 1183.34 (Prod Info DDAVP(R) tablets, desmopressin acetate, 1996).
    B) NASAL SPRAY - 1183.2 (Prod Info DDAVP(R), 1994).

References

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