1) ORAL: COMMON: The most common adverse events reported (10% or greater) are headache, nausea and diarrhea. OTHER EFFECTS: Flushing, pain in the jaw and/or extremities, hypokalemia and abdominal discomfort may develop. An increased risk of bleeding due to inhibition of platelet aggregation can occur. PARENTERAL: COMMON: Injection site pain and infusion site reaction occur in most patients. Other potentially serious adverse events included vasodilatation, hypotension, and edema.
2) SUDDEN DRUG WITHDRAWAL: Abrupt discontinuation and/or a sudden reduction in dosage can result in worsening of pulmonary arterial hypertension.
3) CYP2C8 INHIBITORS: Concomitant administration of treprostinil and strong CYP2C8 inhibitors (eg, gemfibrozil) can increase exposure to treprostinil.
4) BLOOD PRESSURE LOWERING AGENTS: Coadministration of diuretics, antihypertensive agents and vasodilators can increase the risk of hypotension.
5) ALCOHOL: Concomitant administration of alcohol and treprostinil can result in the drug being released at a faster rate.

1) OVERDOSE: Limited data. Overdose effects are anticipated to be an extension of adverse clinical events following therapeutic doses. During clinical trials, the dose-limiting pharmacologic effects included hypotension, severe headache, nausea, vomiting and diarrhea.

1) Treatment is symptomatic and supportive. Monitor blood pressure frequently. Assess for coingestants (erg, diuretics, antihypertensive agents, other vasodilators) that may potentiate hypotension. Assess for coingestion of alcohol, which can cause faster release and absorption. Replace fluids (oral or IV (0.9% NaCl at 10 to 20 mL/kg) fluids) as indicated. Gastrointestinal events (ie, vomiting and diarrhea) are likely to occur. Treat with antiemetics as needed. Monitor fluid and serum electrolytes including potassium as indicated. Replace fluids (ie, oral fluids; administer intravenous fluids as needed) and electrolytes as necessary. Obtain a baseline CBC and platelet count in patients at increased risk for bleeding (eg, patients taking anticoagulants).

1) Treatment is symptomatic and supportive. Treat moderate to severe hypotension with IV fluids, dopamine or norepinephrine as necessary. Correct any significant electrolyte abnormalities in patients with severe vomiting and/or diarrhea. Treprostinil can inhibit platelet aggregation; therefore, patients with evidence of active bleeding or coagulation disorders require laboratory monitoring. Give blood or blood products, if bleeding develops.

1) PREHOSPITAL: Prehospital activated charcoal should be avoided, due to the likely development of vomiting following exposure of treprostinil.
2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain their airway.

1) Airway management is unlikely to be necessary following a mild to moderate exposure. Ensure adequate ventilation and perform endotracheal intubation in patients that develop evidence of profound hypotension, severe bleeding or shock.

1) None.

1) Treprostinil is UNLIKELY to be removed by dialysis due to the high degree of protein binding (96%).

1) HOME CRITERIA: Asymptomatic adults with an inadvertent ingestion of 1 to 2 extra doses or an adult with mild gastrointestinal symptoms can be monitored at home. A child that has inadvertently chewed or broken a tablet(s) before ingesting or is suspected of chewing a tablet(s) should be evaluated in a healthcare setting.
2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
3) ADMISSION CRITERIA: Patients with ongoing symptoms including hypotension or moderate to severe bleeding, requiring therapeutic intervention, should be admitted.
4) CONSULT CRITERIA: Consult a Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or for whom the diagnosis is unclear. Consider a hematology consult in patients that develop significant bleeding.

1) ORAL: As an extended release osmotic tablet, it slowly releases the drug at a near zero-order rate; therefore, the tablet should NOT be split, chewed, crushed or broken. Absolute oral bioavailability is approximately 17%. Absorption is affected by food. Maximum concentrations occur between approximately 4 and 6 hours. Treprostinil is highly bound to human plasma proteins (96%). It is primarily metabolized by CPY2C8 and to a lesser extent CYP2C9.

1) In patients with hypotension, consider other agents (eg, diuretics, antihypertensives, vasodilators) that may lower blood press or cause hypotension. In the event of bleeding, consider other agents (ie, anticoagulant therapy, aspirin therapy, other antiplatelet agents) or conditions that may cause an increase in bleeding tendencies.

1) WITH THERAPEUTIC USE
2) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE
2) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE
2) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE
2) WITH POISONING/EXPOSURE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) WITH THERAPEUTIC USE

1) RATS: In animal studies, no teratogenicity was noted at the highest dose of 20 mg/kg/day (about 55 times the human exposure) (Prod Info ORENITRAM(R) oral extended release tablets, 2014).
2) RABBITS: In animal studies, total fetal skeletal malformations were significantly increased with exposures of 1.5 and 3 mg/kg/day; a few external fetal and soft tissue malformations also occurred at these doses. No teratogenicity or adverse effects on maternal status were noted with doses of 0.5 mg/kg/day (about 5 times the human exposure) or on fetal viability and growth at doses of 1.5 mg/kg/day (Prod Info ORENITRAM(R) oral extended release tablets, 2014).

1) Treprostinil is classified as FDA pregnancy category C (Prod Info ORENITRAM(R) oral extended release tablets, 2014).
2) There are no data on the use of treprostinil diolamine in pregnant women. The effects, if any, on the developing fetus, labor, and delivery are unknown. Animal reproductive studies have shown adverse effects on the fetus. Due to the lack of human safety information, treprostinil diolamine should be used in pregnant women only if the drug is clearly needed (Prod Info ORENITRAM(R) oral extended release tablets, 2014).

1) RATS: In animal studies, pregnancy rates decreased from 8% (with 10 mg/kg/day doses) to 17% to 32% (with 20 and 30 mg/kg/day and 20 mg/kg/day doses, respectively), with 1 dam in each of the 20 and 30 mg/kg/day groups producing no viable fetuses. Increases in postimplantation loss occurred with exposures between 10 to 30 mg/kg/day. Mean live births significantly decreased with dose levels of 10 mg/kg/day or more. No adverse effects on maternal status or fetal viability and growth occurred with doses of 5 mg/kg/day (about 13 times the human exposure) (Prod Info ORENITRAM(R) oral extended release tablets, 2014).
2) RABBITS: In animal studies, doses of 4 mg/kg/day reduced rabbit pregnancy rates by 17%, with 2 rabbits producing no viable fetuses. Dose-dependent increases in postimplantation loss were observed. Mean fetal weights were significantly lower with exposures of 0.5 to 3 mg/kg/day, while fetal weights were reduced slightly with 4 mg/kg/day exposures (Prod Info ORENITRAM(R) oral extended release tablets, 2014).

1) It is unknown whether treprostinil diolamine is excreted in human breast milk or absorbed systemically following ingestion. The effects on the nursing infant from exposure to the drug in milk are unknown. It is also not known if treprostinil affects the quantity and composition of breast milk. Because many drugs are excreted into human milk and the potential for adverse reaction in the nursing infant exists, it is recommended to either discontinue nursing or treprostinil diolamine (Prod Info ORENITRAM(R) oral extended release tablets, 2014).

1) RATS: No effects on fertility or sperm motility were seen with doses about 10- to 18-fold the usual human exposure (Prod Info ORENITRAM(R) oral extended release tablets, 2014).

1) At the time of this review, human carcinogenicity studies have not been conducted.

1) In animal studies, the administration of treprostinil at 0, 5, 10 and 20 mg/kg/day in male and 0, 3, 7.5 and 15 mg/kg/day in female Tg.rasH2 mice daily for 26 weeks did not significantly increase the incidence of tumors. The highest dose levels used in males and females were approximately 8- and 17-fold, respectively, the human exposure at the mean dose of 3.4 mg twice daily (Prod Info ORENITRAM(R) oral extended release tablets, 2014).

A) Patients with ongoing symptoms including hypotension or moderate to severe bleeding, requiring therapeutic intervention, should be admitted.

A) Asymptomatic adults with an inadvertent ingestion of 1 to 2 extra doses or an adult with mild gastrointestinal symptoms can be monitored at home. A child that has inadvertently chewed or broken a tablet(s) before ingesting or is suspected of chewing a tablet(s) should be evaluated in a healthcare setting.

A) Consult a Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or for whom the diagnosis is unclear. Consider a hematology consult in patients that develop significant bleeding.

A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

1) Prehospital activated charcoal should be avoided, due to the likely development of vomiting following exposure.

1) CHARCOAL ADMINISTRATION
2) CHARCOAL DOSE

1) MANAGEMENT OF MILD TO MODERATE TOXICITY
2) MANAGEMENT OF SEVERE TOXICITY

1) Monitor blood pressure frequently.
2) Monitor fluid status and electrolytes including potassium, if vomiting and diarrhea are significant.
3) Monitor for clinical evidence of bleeding. Obtain a baseline CBC with differential in patients at risk for bleeding (eg, patients currently taking anticoagulants); repeat as indicated.
4) Serum treprostinil concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.

1) SUMMARY
2) DOPAMINE
3) NOREPINEPHRINE

1) Transfusion of whole blood or packed red cells may be needed in patients with moderate or severe bleeding.

1) Maximum drug concentrations occur between 4 and 6 hours following oral administration of treprostinil (Prod Info ORENITRAM(R) oral extended release tablets, 2014).