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Treprostinil (Systemic)


VA CLASSIFICATION
Primary: CV402

Commonly used brand name(s): Remodulin.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antihypertensive (pulmonary) —

Vasodilator—

Indications

Accepted

Hypertension, pulmonary arterial (treatment)—Treprostinil is indicated for the treatment of pulmonary arterial hypertension (PAH) in patients with NYHA Class II-IV symptoms to diminish symptoms associated with exercise.{01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    412.49{01}

Mechanism of action/Effect:

The major pharmacological actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation. Studies in animals have demonstrated vasodilatory effects such as, reduction in right and left ventricular afterload and increased cardiac output and stroke volume. Other studies have shown that treprostinil causes a dose-related negative inotropic and lusitropic effect. There were no major effects on cardiac conduction.{01}

Absorption:

Treprostinil absorption is relatively rapid and complete after subcutaneous infusion, with an absolute bioavailability approximately 100%.{01}

In patients with mild (n=4) or moderate (n=5) hepatic insufficiency and portopulmonary hypertension following a subcutaneous dose of 10 ng per kg of body weight per min for 150 mins the AUC 0-∞ was increased 3-fold and 5-fold respectively.{01}

Distribution:

Volume of distribution (Vol D) approximately 14 L per 70 kg ideal body weight{01}

Protein binding:

Human plasma protein binding is approximately 91% in in vitro concentrations ranging from 330 to 10,000 mcg per L{01}

Biotransformation:

Treprostinil is metabolized by the liver however, the precise enzymes are unknown. Five metabolites have been described (HU1 through HU5) however, the biological activity and metabolic fate of these are unknown. The chemical structure of HU1 is unknown. The metabolite HU5 is the glucuronide conjugate of treprostinil. The other metabolites are formed by oxidation of the 3-hydroxyoctyl side chain (HU2) and subsequent additional oxidation (HU3) or dehydration (HU4). Study results of in vitro human hepatic cytochrome P450 demonstrates that treprostinil does not inhibit CYP-1A2, 2C9, 2C19, 2D6, 2E1, or 3A. Whether treprostinil induces these enzymes has not been studied.{01}


Half-life:

Approximately 2 to 4 hours{01}

Time to peak concentration:

Steady state concentration—approximately 10 hours{01}

Peak serum concentration:

In patients with mild (n=4) or moderate (n=5) hepatic insufficiency and portopulmonary hypertension following a subcutaneous dose of 10 ng per kg of body weight per min for 150 mins the C max was increased 2-fold and 4-fold respectively.{01}

Concentrations in patients treated with an average dose of 9.3 ng per kg of body weight per min were approximately 2 mcg per L{01}.

Trepostinil's linear pharmacokinetics can be described by a two compartment model resulting in plasma concentrations of 0.03 to 8 mcg per L with a dosage range of 1.25 to 22.5 ng per kg of body weight per min.{01}

Elimination:
    Renal—approximately 79%; dose eliminated as 4% unchanged drug and 64% identified metabolites.{01}
    Fecal—approximately 13%{01}
    Systemic clearance— approximately 30 liters per hour for a 70 kg ideal body weight patient.{01}
    Hepatic insufficiency— reduced clearance by up to 80% compared to healthy adults.{01}
{01}

Precautions to Consider

Carcinogenesis and Mutagenesis

Long-term studies to evaluate the carcinogenic potential of treprostinil have not been done. In vitro and in vivo mutagenicity studies did not demonstrate any mutagenic or clastogenic effects of treprostinil{01}.

Pregnancy/Reproduction
Fertility—
In animal studies no evidence of impaired fertility was found in male or female rats given continuous subcutaneous infusion rates of up to 450 ng per kg of body weight per min [about 59 times the recommended starting human rate of infusion (1.25 ng per kg of body weight per min) and about 8 times the average rate (9.3 ng per kg of body weight per min) achieved in clinical trials, on a ng per m2 body surface area basis]. In this study, males were dosed from 10 weeks prior to mating and through the 2-week mating period. Females were dosed from 2 weeks prior to mating until gestational day six.{01}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done.The use of treprostinil during pregnancy is only recommended if clearly needed.{01}

In animal studies continuous subcutaneous infusion of treprostinil in pregnant rats during organogenesis and late gestational development, at rates as high as 900 ng per kg of body weight per min (about 117 times the starting human rate of infusion, on a ng per m2body surface area basis and about 16 times the average rate achieved in clinical trials) resulted in no evidence of harm to fetus. In rats, continuous subcutaneous infusion of treprostinil from implantation to the end of lactation, at rates of up to 450 ng per kg of body weight per min, did not affect the growth and development of offspring. {01}

In pregnant rabbits, effects of continuous subcutaneous infusion of treprostinil during organogenesis were limited to an increased incidence of fetal skeletal variations (bilateral full rib or right rudimentary rib on lumbar 1) associated with maternal toxicity (reduction in body weight and food consumption) at an infusions rate of 150 ng per kg of body weight per min (about 41 times the starting human rate of infusion, on a ng per m 2 body surface area basis, and 5 times the average rate used in clinical trials).{01}

FDA Pregnancy Category B{01}

Breast-feeding

It is not known whether treprostinil is distributed into human breast milk or absorbed systemically after ingestion.{01}.

Pediatrics

No information is available on the relationship of age to the effects of treprostinil in the pediatric population £ 16 years of age. Safety and efficacy have not been established{01}


Geriatrics


No information is available on the relationship of age to the effects of treprostinil in geriatric patients. Treprostinil was not studied in a sufficient number of patients 65 years of age and older to determine whether the elderly respond differently than younger patients {01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Anticoagulants    (treprostinil inhibits platelet aggregation, therefore, there is an increased risk of bleeding among patients maintained on anticoagulants {01})


» Antihypertensive agents, or
» Diuretics, or
» Vasodilators    (reduction in blood pressure caused by treprostinil may be exacerbated by these medications that alter blood pressure{01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypersensitivity to treprostinil or to structurally related compounds{01}
Risk-benefit should be considered when the following medical problems exist
Hepatic insufficiency, or
Portopulmonary hypertension with hepatic insufficiency     (Use in patients with portopulmonary hypertension, and mild (n=4) or moderate (n=5) hepatic insufficiency had a C max that was increased 2-fold and 4-fold, respectively, and AUC 0-∞was increased 3-fold and 5-fold, when given treprostinil at a subcutaneous dose of 10 ng per kg of body weight per min for 150 minutes. Clearance in patients with hepatic insufficiency was reduced by up to 80% compared to healthy patients. Dose reduction is recommended.{01}
Note: Treprostinil has not been studied in patients with severe hepatic insufficiency.{01}

)




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Edema (swelling)
    
infusion site reaction- including erythema, induration or rash (accumulation of blood at site of injection; dry, red, hot, or irritated skin; hardening of site of injection )
    
vasodilation ( feeling of warmth or heat; flushing or redness of skin, especially on face and neck; feeling faint, dizzy, or light-headedness)
{01}
Incidence less frequent
    
hypotension (blurred vision; confusion; dizziness, faintness, or lightheadedness when getting up from a lying or sitting position; sudden sweating; confusion; unusual tiredness or weakness ){01}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Diarrhea
    
dizziness
    
headache
    
Infusion site pain
    
jaw pain
    
nausea
    
pruritus (itching skin)
    
rash
{01}




Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
In clinical trials, fourteen patients received some level of overdose; in only two cases the excess delivery produced an event of substantial hemodynamic concern (hypotension, near-syncope).{01}

The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Diarrhea
    
flushing (feeling of warmth; redness of the face, neck, arms and occasionally, upper chest)
    
headache
    
hypotension ( blurred vision; confusion; dizziness, faintness, or lightheadedness when getting up from a lying or sitting position; sudden sweating; unusual tiredness or weakness)
    
nausea
    
vomiting
{01}

Treatment of overdose
There is no known antidote to treprostinil. Treatment is generally symptomatic and supportive. Most events were self-limiting and resolved with reduction or withholding of treprostinil{01}.

Supportive care—Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Treprostinil (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to treprostinil or to structurally related compounds
Other medications, especially anticoagulants, antihypertensive agents, diuretics, and vasodilators

Proper use of this medication

» Proper dosing
Treprostinil is administered by continuous subcutaneous infusion and should not be stopped abruptly.

Proper storage

Precautions while using this medication
Caution should be used in patients with portopulmonary hypertension and hepatic insufficiency, or in hepatic insufficiency; adjust dose appropriately


Side/adverse effects
Signs of potential side effects, especially edema, hypotension, infusion site reactions including erythema, induration or rash and vasodilation.


General Dosing Information
Treprostinil is administered by continuous subcutaneous infusion via a self-inserted subcutaneous catheter, using an infusion pump designed for subcutaneous delivery.{01}

Continuous subcutaneous infusion with treprostinil must be performed in a setting with adequate personnel and equipment for monitoring and emergency care. Trepostinil should be used only by clinicians experienced in the diagnosis and treatment of pulmonary arterial hypertension (PAH){01}

The goal of chronic dosage adjustments is to establish a dose at which PAH symptoms are improved, while minimizing excessive pharmacological effects of treprostinil. In order to avoid symptoms associated with the use of treprostinil, therapy should not be withdrawn abruptly or the infusion rate suddenly reduced. Abrupt withdrawal or sudden large reductions in dosage of treprostinil may result in worsening of PAH symptoms and should be avoided{01}

To avoid potential interruptions in drug delivery, the patient must have immediate access to a backup infusion pump and subcutaneous infusion sets.{01}

The drug dose rate must be individualized according to the patient's body weight and according to the desired rapidity and extent of pharmacodynamic effect {01}For specific information on treprostinil infusion delivery rates refer to the manufacturer's product information.

Dose should be increased for lack of improvement in, or worsening of, symptoms and it should be decreased for excessive pharmacological effects or for unacceptable infusion site symptoms. {01}.

The infusion pump minimum and maximum flow rates and reservoir capacity should be compatible with the concentration of the treprostinil solution used {01}. The infusion pump should also have the following features:    • Small, lightweight, and portable {01}
   • Adjustable infusion rates to 0.002 mL per hr{01}
   • Alarm capability for detecting occlusion/no delivery, end of infusion, low battery, programming error and motor malfunctions{01}
   • Accuracy to at least ± 6% of the programmed rate {01}
   • Positive pressure driven {01}
   • Polyvinyl chloride, polypropylene, or glass reservoir {01}


Prior to administration, parenteral drugs should be inspected visually for particulate matter and discoloration. If particulate matter or discoloration is noted, treprostinil should not be administered.{01}


Parenteral Dosage Forms

TREPROSTINIL SODIUM INJECTION

Usual Adult Dose
Pulmonary arterial hypertension{01}
Initiation: Subcutaneous injection, 1.25 ng per kg of body weight per min. Depending on clinical response, the infusion rate should be reduced to 0.625 ng per kg of body weight per min if the initial dose cannot be tolerated{01}
Note: Patients with mild or moderate hepatic insufficiency, the initial dose of treprostinil should be decreased to 0.625 ng per kg of ideal body weight per min and should be increased cautiously{01}



Maintenance: Subcutaneous injection increased in increments of no more than 1.25 ng per kg of body weight per min per week for the first four weeks and then no more than 2.5 ng per kg of body weight per min per week for the remaining duration of infusion, depending on clinical response.{01}
Note: Abrupt cessation of infusion should be avoided.{01}


   • Infusion rate formula for treprostinil 1.0 mg per mL is calculated using the following formula: Patient weight (kg) x dose (ng/kg/min) x 0.00006{01}
   • Infusion rate formula for treprostinil 2.5 mg per mL is calculated using the following formula: Patient weight (kg) x dose (ng/kg/min) x 0.000024{01}
   • Infusion rate formula for treprostinil 5.0 mg per mL is calculated using the following formula: Patient weight (kg) x dose (ng/kg/min) x 0.000012{01}
   • Infusion rate formula for treprostinil 10.0 mg per mL is calculated using the following formula: Patient weight (kg) x dose (ng/kg/min) x 0.000006{01}



Usual adult prescribing limits
There is little experience with administered doses greater than 40 ng/kg/min {01}

Usual Pediatric Dose
Safety and efficacy have not been established. Dose selection should be cautious. {01}

Usual Geriatric Dose
Dose selection should be cautious due to the greater frequency of geriatric-specific problems.{01}

Strength(s) usually available
U.S.—


1.0 mg/mL (Rx) [Remodulin ( Each ml contains 5.3 mg sodium chloride) (3.0 mg metacresol) (6.3 mg sodium citrate) (water for injection ) (sodium hydroxide and hydrochloric acid to adjust pH between 6.0 and 7.2)]


2.5 mg/mL (Rx) [Remodulin ( Each ml contains 5.3 mg sodium chloride) (3.0 mg metacresol) (6.3 mg sodium citrate) (water for injection) (sodium hydroxide and hydrochloric acid to adjust pH between 6.0 and 7.2)]


5.0 mg/mL (Rx) [Remodulin ( Each ml contains 5.3 mg sodium chloride) (3.0 mg metacresol) (6.3 mg sodium citrate) (water for injection ) (sodium hydroxide and hydrochloric acid to adjust pH between 6.0 and 7.2)]


10.0 mg/mL (Rx) [Remodulin ( Each ml contains 4.0 mg sodium chloride) (3.0 mg metacresol) (6.3 mg sodium citrate) (water for injection) (sodium hydroxide and hydrochloric acid to adjust pH between 6.0 and 7.2)]
{01}
Canada—
Not commercially available.

Packaging and storage:
Unopened vials stored at 15-25°C (59 to 77°F) are stable until the date indicated.{01}

Store at 25°C (77°F), with excursions permitted to 15-30°C (59 to 86°F). USP controlled room temperature{01}

Stability:
During use, a single syringe of treprostinil can be administered up to 72 hours at 37°C. Single vials of treprostinil should be used for no more than 14 days after the initial introduction into the vial.{01}



Developed: 09/19/02



References
  1. Product Information: Remodulin (R), treprostinil. United Therapeutics Corp., Research Triangle Park, NC, (PI revised 03/2002) reviewed 09/2002.
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