Desmoda Drug Information

• is indicated for the management of central diabetes insipidus as antidiuretic replacement therapy for adults and pediatric patients. Limitations of Use
• DESMODA is not indicated for the treatment of nephrogenic diabetes insipidus. DESMODA is a vasopressin analog indicated for the management of central diabetes insipidus as antidiuretic replacement therapy for adults and pediatric patients. Limitations of Use
• DESMODA is not indicated for the treatment of nephrogenic diabetes insipidus.

• 2.1 Recommended Dosage for Central Diabetes Insipidus
• Instruct patients about appropriate fluid restriction during DESMODA treatment due to risk of hyponatremia [see Warnings and Precautions (5.1)].
• Individualize the dosage of DESMODA for each patient and adjust the dosage according to the diurnal pattern of response. Estimate patient response by adequate duration of sleep and water turnover.
• Recommended starting dosage of DESMODA for adults and pediatric patients is 0.05 mg orally twice daily.
• Titrate the daily dosage as needed to obtain an adequate antidiuretic response.
• Administer DESMODA on an empty stomach, at least 1 hour prior to or 2 hours after food.
• Administer DESMODA using an oral syringe provided by the pharmacy.
• Monitor response by measuring urine volume and osmolarity. Monitoring measurements of plasma osmolarity may also be useful. 2.2 Switching Patients with Central Diabetes Insipidus to DESMODA From Desmopressin Acetate Nasal Spray
• For patients with central diabetes insipidus switching to DESMODA from desmopressin acetate nasal spray, wait twelve hours after the last dose.
• Monitor patients closely during the initial dose titration period. Instruct patients about appropriate fluid restriction during DESMODA treatment due to risk of hyponatremia. (2.1)
• Recommended starting dosage for adults and pediatric patients is 0.05 mg twice. (2.1)
• Titrate the daily dosage as needed to obtain an adequate antidiuretic response. (2.1)
• Take DESMODA on an empty stomach, at least 1 hour before or 2 hours after food. (2.1)
• Monitor response by measuring urine volume and osmolarity. (2.1)
• For patients with central diabetes insipidus switching to DESMODA from desmopressin acetate nasal spray, wait twelve hours after the last dose. Monitor patients closely during the initial dose titration period. (2.2)

• The following serious adverse reactions are described below and elsewhere in the labeling:
• Hyponatremia [see Warnings and Precautions (5.1)]
• Fluid Retention [see Warnings and Precautions (5.2)]
• Hypersensitivity [see Warnings and Precautions (5.3)]
• Risk of Benzyl Alcohol Toxicity in Neonates [see Warnings and Precautions (5.4)] The following adverse reactions associated with the use of desmopressin acetate were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or 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: oxybutynin 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 In long-term clinical studies in which patients with diabetes insipidus were followed for periods up to 44 months of desmopressin acetate oral therapy, transient increases in AST (SGOT) no higher than 1.5 times the upper limit of normal were occasionally observed. Elevated AST (SGOT) returned to the normal range despite the continued use of desmopressin acetate oral therapy. Most common adverse reactions include: headache, dizziness, nausea, abdominal pain, hypertension, and diarrhea. (6) To report SUSPECTED ADVERSE REACTIONS, contact Eton Pharmaceuticals, Inc. at 1-855-224-0233 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

• 7.1 Other Drugs that may Increase Risk of Hyponatremia Concomitant administration of DESMODA 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, thiazide diuretics, NSAIDs, lamotrigine, sulfonylureas, particularly chlorpropamide, oxybutynin and carbamazepine). Monitor serum sodium more frequently in patients taking DESMODA concomitantly with these drugs and when doses of these drugs are increased [see Warnings and Precautions (5.1), Adverse Reactions (6)]. 7.2 Other Vasoconstrictors Desmopressin acetate can elevate blood pressure. Use of large doses of DESMODA with other vasoconstrictors may require a reduction of the DESMODA dosage [see Adverse Reactions (6)].
• Drugs that may Increase Risk of Hyponatremia: Requires more frequent monitoring of serum sodium. (7.1)
• Other Vasoconstrictors : Concomitant use may elevate blood pressure and require a reduction in DESMODA dosage. (7.2)

Pregnancy Risk Summary Available data on the use of desmopressin acetate during pregnancy over decades of use have not identified a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks associated with untreated central diabetes insipidus during pregnancy (see Clinical Considerations). 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 to 38 times, respectively, the maximum recommended human dose based on body surface areas (mg/m2) (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease Associated Maternal and Embryo-Fetal Risk There are risks associated with untreated central diabetes insipidus during pregnancy such as dehydration, preterm birth and oligohydramnios.

Pregnant patients with diabetes insipidus should be monitored for electrolyte imbalance, maternal hypotension, and low amniotic fluid levels. Data Animal Data In a developmental toxicity study in rats, desmopressin acetate was administered intravenously at doses of 9.68, 48.4, or 241 mcg/kg/day during the period of organogenesis (gestations days 7 to 17). Laparohysterectomy for fetal examinations were conducted on gestation day 20 for twenty females in each group; the remaining 10 females were allowed to litter in order to determine any postnatal effects that might be attributable to pre-natal treatment. No effects were seen on maternal and fetal survival, growth and morphology or post-natal offspring survival, growth, development, behavior and reproductive performance up to 241 mcg/kg/day (4 times a 0.6 mg dose received by a 60 kg patient based on body surface area). In an embryo-fetal development study and a pre- and postnatal development study in rabbits, desmopressin acetate was administered subcutaneously at doses of 2, 20 or 200 mcg/kg/day (embryo-fetal development) and 0.1, 1 or 10 mcg/kg/day (pre- and postnatal development) during the period of organogenesis (gestation days 6 to 18). No effects on maternal and fetal survival or morphology were observed in both studies at doses of up to 200 mcg/kg/day (6.5 times a 0.6 mg dose received by a 60 kg patient based on body surface area) nor were there effects in the pre- and postnatal development study on parturition, postnatal survival, growth, development or behavior, up to the highest dose tested of 10 mcg/kg/day (0.3 times a 0.6 mg dose received by a 60 kg patient, based on body surface area).

Pediatric Use Desmopressin acetate is indicated for the management of central diabetes insipidus as antidiuretic replacement therapy in pediatric patients. Use in pediatric patients requires careful fluid intake restriction to prevent possible water intoxication with hyponatremia. In younger pediatric patients, the dose must be individually adjusted to prevent an excessive decrease in plasma osmolality leading to hyponatremia and possible convulsions.

Fluid restriction should be discussed with the patient and/or guardian. DESMODA contains benzoic acid, a metabolite of benzyl alcohol. Serious adverse reactions, including fatal reactions, of new onset or worsening metabolic acidosis that progressed to neurotoxicity, and in some cases gasping syndrome, have been reported in low-birth weight neonates and preterm neonates who received benzyl alcohol-containing drugs intravenously (DESMODA is not approved for intravenous use ). Gasping syndrome is a life-threatening condition in neonates caused by benzyl alcohol toxicity that is characterized by new onset or worsening metabolic acidosis with gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and kidney failure, hypotension, bradycardia, and gasping respirations followed by death.

In reported cases, benzyl alcohol in amounts of 99 to 234 mg/kg/day produced blood BA levels of 6.6 to 14.9 mg/dL, but the minimum amount of benzyl alcohol at which gasping syndrome may occur in neonates is not known. The rate at which benzyl alcohol is metabolized to benzoic acid cannot be reliably predicted, and the relationship between systemic levels of benzoic acid and toxicity is not well-characterized. DESMODA contains 2.74 mg of benzoic acid per mL.

• is contraindicated in patients with:
• Hyponatremia or a history of hyponatremia [see Warnings and Precautions (5.1)].
• Hypersensitivity to desmopressin acetate or any of the inactive ingredients of DESMODA.Reactions have included anaphylaxis [see Warnings and Precautions (5.3)].
• Moderate to severe renal impairment (defined as creatinine clearance (CLcr) less than 50 mL/min)[see Use in Specific Populations (8.6)].
• Hypersensitivity to desmopressin acetate or any of the inactive ingredients of DESMODA. (4)
• Patients with moderate to severe renal impairment defined as creatinine clearance below 50 mL/min. (4)
• Patients with hyponatremia or a history of hyponatremia. (4)

Signs of overdose may include confusion, drowsiness, continuing headache, problems with passing urine and rapid weight gain due to fluid retention. In case of overdosage, reduce the dosage, decrease the frequency of administration, or discontinue the DESMODA. There is no known specific antidote for desmopressin acetate. The patient should be observed and treated with appropriate symptomatic therapy.