Treprostinil (Orenitram) is an orally available vasodilator that acts on the pulmonary and systemic vasculature. It is used to treat patients with pulmonary arterial hypertension. It is especially used after IV epoprostenol.

Treprostinil Uses:

• Pulmonary arterial hypertension: 
  • Injection:
    • Treatment of pulmonary arterial hypertension (PAH) (WHO Group I) in patients with NYHA class II–IV symptoms to reduce exercise-related symptoms and to prevent clinical decline when switching from epoprostenol (IV) Inhalation:
    • Treatment of pulmonary arterial hypertension (PAH) (WHO Group I) in patients with NYHA class III symptoms to regain the ability to exercise.

Note: Coexistent bosentan or sildenafil has been used in nearly all tracked clinical trial experiences.

• Oral:
  • Treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) in individuals with WHO functional class II–III symptoms to improve capacity for exercise.

Treprostinil (Orenitram) Dose in Adults

Treprostinil (Orenitram) Dose in the treatment of pulmonary arterial hypertension (PAH):

• Inhalation:

Note: Patients' capacity to give treprostinil and take care of the breathing apparatus and related equipment should be carefully evaluated prior to treatment. To avoid treatment pauses, immediate availability to a backup inhaler, accessories, and medication is crucial.

• Initial: 18 mcg (or 3 inhalations) four times a day, every four hours; Reduce to 1 to 2 inhalations if 3 inhalations are not tolerated, then increase to 3 inhalations as tolerated.
• Maintenance: Target dose and maximum dose: 54 mcg (or 9 inhalations) four times per day; if tolerated, increase the dose by an additional 3 inhalations at intervals of around 1 to 2 weeks.

Oral:

• Initial: 0.25 mg every 12 hours or 0.125 mg every 8 hours;
• The dose can be increased in increments of 0.25 mg or 0.5 mg every 12 hours or 0.125 mg every 8 hours after every 3 to 4 days as endured to attain the best possible clinical reaction.
• If dose increments are not endured, contemplate gentler titration.
• Tolerability determines the maximum dose.
• Reduce the dose in 0.25 mg increments if the side effects become intolerable; avoid abrupt stopping. Reduce the dosage daily in increments of 0.5 mg to 1 mg after stopping.

• Conversion from injection to oral dosing:
  • Reduce the dose of parenteral treprostinil up to 30 ng/kg/minute each day while simultaneously increasing the dose of oral treprostinil up to 2 mg 3 times on a daily basis as endured.
  • To approximate an equivalent total everyday dose of oral treprostinil, use the following equation:

Treprostinil oral total day-to-day dose (mg) = Parenteral treprostinil dose (ng/kg/minute) x weight (kg) x 0.0072

• Missed doses: Take the missing dose as soon as it is practical if you forget to take a dose. Start again at a lesser dose and retitrate if two doses are missed.

Dosage adjustment:

• Start with a dose of 0.125 mg every 12 hours and increase in 0.125 mg increments every 3 to 4 days.
• Planned short-term treatment interruption:
  • A brief parenteral treprostinil infusion may be used if the patient is unable to continue oral therapy.
  • To determine the total daily dose of parenteral treprostinil (ng/kg/minute), multiply the oral total daily dose (mg) by 139 and divide by the patient's weight (kg).

SubQ (preferred) or IV infusion:

Note:

• Prior to beginning, patients should have a complete evaluation to determine their capacity to manage the infusion system outside of the hospital setting and administer treprostinil.
• To avoid treatment pauses, quick access to a backup pump, infusion sets, and medication is crucial.

New to prostacyclin therapy:

• Initial: 1.25 ng/kg/minute;
• Reduce the dose to 0.625 ng/kg/minute if systemic effects make it impossible to tolerate it.
• For the first four weeks, increase the dose in 1.25 ng/kg/minute weekly increments, and then for the remaining four weeks, increase it in 2.5 ng/kg/minute weekly increments.
• limited knowledge about doses more than 40 ng/kg/minute.

Note:

• The dosage must be gradually increased separately (symptom improvement with minimal adverse effects).
• Avert abrupt withdrawal.
• The same dose rate may be used if the infusion is restarted shortly after it has been stopped. Longer interruptions can call for retitration.
  • Transitioning from epoprostenol (see table):

Note:

• To observe the reaction (e.g., walking distance, signs/symptoms of illness development), the shift should take place in an inpatient setting.
• The transfer could take one or two days.
• In order to transition, the intravenous epoprostenol dose is lowered while the treprostinil infusion is started and increased.
• Increases in PAH symptoms should be managed during the transition by initially increasing the treprostinil dose.
• Epoprostenol dosage should be reduced in order to treat any negative effects brought on by prostacyclin.

Transitioning From IV Epoprostenol to SubQ (Preferred) or IV Treprostinil

Use in Children:

Not indicated.   

Pregnancy Risk Factor C (oral)

• Some animal reproduction studies have shown harmful effects.
• It is important to avoid pregnancy for women with pulmonary arterial hypertension (PAH).

Use during breastfeeding:

• It is unknown if breast milk contains treprostinil.
• According to the manufacturer of the oral drug, it is recommended that you decide whether or not to breastfeed.

Dose in Kidney Disease:

• Inhalation:
  • The manufacturer's labelling does not mention dosage modifications (it has not been studied). Titrate gradually and use with caution.
• IV infusion, SubQ infusion:
  • No dosage adjustment needed; titrate gradually.
• Oral:
  • No dosage adjustment needed.

Hemodialysis:

• Treprostinil is not removed by dialysis.

Treprostinil Dose in Liver disease:

Inhalation:

• There are no dosage modifications given in the manufacturer’s labeling. However, hepatic impairment increases systemic exposure to treprostinil. Use vigilantly and slowly titrate.

SubQ infusion, IV infusion:

• Mild to moderate impairment:
  • Initial: 0.625 ng/kg/minute (ideal body weight).
  • Use vigilantly and slowly titrate.
• Severe impairment:
  • There are no dosage adjustments provided in the manufacturer’s labeling (it has not been studied). Use vigilantly and slowly titrate.

Oral:

• Mild impairment (Child-Pugh class A):
  • Initial: 0.125 mg every 12 hours; increase in increments of 0.125 mg every 12 hours every 3 to 4 days.
• Moderate impairment (Child-Pugh class B):
  • Avoid use.
• Severe impairment (Child-Pugh class C):
  • Use is contraindicated by the manufacturer.

Common Side Effects of Treprostinil (Orenitram):

• Cardiovascular:
  • Flushing
  • Vasodilatation
• Central Nervous System:
  • Infusion-Site Pain
  • Headache
• Dermatologic:
  • Skin Rash
• Gastrointestinal:
  • Diarrhea
  • Nausea
• Local:
  • Infusion Site Reaction
• Neuromuscular & Skeletal:
  • Limb Pain
  • Jaw Pain
• Respiratory:
  • Cough
  • Pharyngolaryngeal Pain
  • Throat Irritation

Less Common Side Effects Of Treprostinil (Orenitram):

• Cardiovascular:
  • Edema
  • Syncope
  • Hypotension
• Endocrine & Metabolic:
  • Hypokalemia
• Gastrointestinal:
  • Abdominal Distress

Frequency of side effects not defined:

• Central Nervous System:
  • Pain
  • Paresthesia
• Gastrointestinal:
  • Sore Throat.
• Hematologic & Oncologic:
  • Bleeding Tendency Disorder
  • Decreased Platelet Aggregation
  • Hematoma
• Neuromuscular & Skeletal:
  • Swelling Of Extremities (Arm)
• Respiratory:
  • Epistaxis (Long-Term Therapy)
  • Hemoptysis (Long-Term Therapy)
  • Nasal Discomfort (Long-Term Therapy)
  • Pneumonia (Long-Term Therapy)
  • Wheezing (Long-Term Therapy)

Contraindications to Treprostinil (Orenitram):

Injection/inhalation:

• No contraindications 

Oral:

• Severe hepatic impairment (Child Pug class C).

Canadian labeling: Additional contraindications not in US labeling

• Sensitivity to treprostinil and any other element of the formulation

There is not much evidence of cross-reactivity between prostaglandins and allergenic prostaglandins. Cross-sensitivity is possible due to similarities in chemical structure or pharmacologic effects.

Warnings and precautions

• Bleeding
  • Inhibiting platelet aggregation and raising the risk of bleeding may result from this.
• Hypotension
  • It may cause hypotension symptoms. Patients with low blood pressure should be careful.
• Rebound pulmonary hypertension
  • Sudden withdrawal or large dose reductions can exacerbate symptoms of PAH.
  • The same dose rate may be used if a SubQ IV or IV infusion is reintroduced within a few hours after discontinuation. Retitration may be necessary for longer-term interruptions. Treatment interruptions must be avoided, regardless of which route was used (inhalation IV, oral, or SubQ).
  • It is crucial to have quick access to medication, a backup inhaler, or pump/infusion settings to avoid treatment hiccups.
• Hepatic impairment
  • Use with caution in patients with hepatic impairment.
    • SubQ/Question
      • Reduce the dose and urge patients with mild to moderate hepatic impairment to do so. It may be necessary to titrate slowly in patients with severe hepatic impairment.
    • Oral:
      • It may be suggested that patients with mild hepatic impairment lower their dose.
        People who are mildly impaired should not be used, and patients who are severely impaired shouldn't be.
• Respiratory disease
  • Inhalation: Inhalation is not safe and efficient in patients suffering from underlying respiratory diseases (e.g. asthma, COPD).
  • The success of treatment for acute lung infections needs to be constantly checked for signs of aggravation.

Treprostinil: Drug Interaction

Monitoring parameters:

• activity tolerance
• BP
• Fatigue
• dyspnea

How to administer Treprostinil (Orenitram)?

Avoid treatment disruptions or quick large dosage reductions with the use of inhalation, IV, or SubQ formulations. To avoid treatment pauses, immediate availability to medication, a backup inhaler, or pump and infusion sets is essential.

Inhalation:

• Don't combine any medications.
• exclusively for use with the Tyvaso Inhalation System.
• Transfer the complete contents of one container into the medicine compartment before the first therapy session of each day; one container contains enough medication for each of the four treatment sessions in a single day.
• The device should be covered and stored upright with the remaining medication inside between each session.
• The medicine chamber and any lingering medicines must be thrown away at the end of each day.
• Avoid getting the solution in your eyes or on your skin, and wash your hands after handling.

IV infusion:

• When SubQ infusion is not tolerated or when the benefits outweigh the possible dangers of an indwelling central venous catheter, IV usage is advised.
• Prior to usage, the solution must be diluted in a high-pH glycine diluent such as Flolan sterile diluent, SWFI, NS, Remodulin sterile diluent, or a similar authorised diluent. The medication must then be delivered continuously via an external infusion pump and an indwelling central catheter.
• The ambulatory infusion pump needs to be compact and light, include warnings for low battery, programming error, motor malfunction, and occlusion/no delivery, be positive pressure driven, and have an accuracy of 6% of the programmed rate.
• Glass, polypropylene, or polyvinyl chloride should be used for the reservoir.
• To prevent treatment pauses, instant access to a backup infusion pump and infusion sets should be possible.
• Until the central line is established, the peripheral infusion may be used temporarily.
• For both central and peripheral administration, infusion sets with an in-line 0.22- or 0.2-micron filter must be utilised.
• Refer to the pump manufacturer's manual for directions on setup, programming, implantation, and refilling if switching from the usage of an external infusion pump to an implanted IV infusion pump (such as the Implantable System for Remodulin).

Oral:

• provide together with a meal that has at least 250 calories and 30 to 50 percent fat. Use only entire, undamaged tablets; do not chew, split, or crush them.

SubQ infusion (preferred):

• Utilizing an appropriately constructed infusion pump, administer undiluted through a continuous SubQ infusion.
• The ambulant infusion pump should be compact and light, able to change infusion rates in steps of 0.002 mL/hour, equipped with warnings for occlusion/no delivery, low battery, programming error, and motor breakdown, and powered by positive pressure.
• Glass, polypropylene, or polyvinyl chloride should be used for the reservoir.
• Immediate access to a backup infusion pump and subcutaneous infusion sets must be available to avoid treatment interruptions. Proactively manage infusion-site reactions based on individual patient needs and by combining multiple strategies, including improved dosing strategies (eg, more rapid dose escalation), appropriate spot selection, fewer frequent infusion site changes (eg, every 2 to 5 weeks), and analgesic care (pharmacologic and nonpharmacologic) when aching occurs.
• Replace infusion site when patient experiences continued site pain, itching, erythema, drainage, or bleeding; decreased site pain and need for site changes or discontinuation due to site pain may be reduced in patients who are managed proactively in this manner.

Mechanism of action of Treprostinil (Orenitram):

The pulmonary and systemic arterial blood arteries are both vasodilated by treprostinil. Additionally, it prevents platelet buildup.

Absorption:

• • Oral:
    • Affected by food; AUC increased 49% after a high-fat, high calorie meal. This was in comparison to fasting conditions.
    • Meals ranging in calories from 250 to 500 do not affect the relative bioavailability of 1 mg after oral administration.

• SubQ:
  • Rapidly and fully

Protein binding:

• 91% to 96%

Metabolism:

• Hepatic (primarily by CYP2C8); forms 5 inactive metabolites (HU1-HU5)

Bioavailability:

• Inhalation: 64% to 72% (dose-dependent);
• SubQ: 100%; Oral: ~17%

Half-life elimination: Terminal:

• About 4 hours

Time to peak: Oral:

• 4 to 6 hours

Excretion:

• Urine (79%; 4% as unchanged drug, 64% as metabolites); feces (13%)
• Oral: urine (0.19% as unchanged drug); feces (1.13% as unchanged drug)

International Brand Names of Treprostinil:

• Orenitram
• Remodulin
• Tyvaso
• Tyvaso Refill Tyvaso Starter
• Treprost

Treprostinil Brand Names in Pakistan:

No Brands Available in Pakistan.