Remodulin

The following adverse reactions are discussed elsewhere in labeling: Infections associated with intravenous administration [see WARNINGS AND PRECAUTIONS].

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Patients receiving Remodulin as a subcutaneous infusion reported a wide range of adverse events, many potentially related to the underlying disease (dyspnea, fatigue, chest pain, right ventricular heart failure, and pallor). During clinical trials with subcutaneous infusion of Remodulin, infusion site pain and reaction were the most common adverse events among those treated with Remodulin. Infusion site reaction was defined as any local adverse event other than pain or bleeding/bruising at the infusion site and included symptoms such as erythema, induration or rash. Infusion site reactions were sometimes severe and could lead to discontinuation of treatment.

Table 3: Percentages of subjects reporting subcutaneous infusion site adverse events

Other adverse events included diarrhea, jaw pain, edema, vasodilatation and nausea, and these are generally considered to be related to the pharmacologic effects of Remodulin, whether administered subcutaneously or intravenously.

Table 4 lists adverse reactions defined by a rate of at least 3% more frequent in patients treated with subcutaneous Remodulin than with placebo in controlled trials in PAH.

Table 4: Adverse Reactions in Controlled 12-Week Studies of Subcutaneous Remodulin and at least 3% more frequent than on Placebo.

Reported adverse reactions (at least 3% more frequent on drug than on placebo) are included except those too general to be informative, and those not plausibly attributable to the use of the drug, because they were associated with the condition being treated or are very common in the treated population.

While hypotension occurred in both groups, the event was experienced twice as frequently in the Remodulin group as compared to the placebo group (4% in Remodulin treatment group verses 2% in placebo-controlled group). As a potent vasodilator, hypotension is possible with the administration of Remodulin.

The safety of Remodulin was also studied in a long-term, open-label extension study in which 860 patients were dosed for a mean duration of 1.6 years, with a maximum exposure of 4.6 years. Twenty-nine (29%) percent achieved a dose of at least 40 ng/kg/min (max: 290 ng/kg/min). The safety profile during this chronic dosing study was similar to that observed in the 12-week placebo controlled study except for the following suspected adverse drug reactions (occurring in at least 3% of patients): anorexia, vomiting, infusion site infection, asthenia, and abdominal pain.

In controlled studies of Remodulin administered subcutaneously, there were no reports of infection related to the drug delivery system. There were 187 infusion system complications reported in 28% of patients (23% Remodulin, 33% placebo); 173 (93%) were pump related and 14 (7%) related to the infusion set. Eight of these patients (4 Remodulin, 4 Placebo) reported non-serious adverse events resulting from infusion system complications. Adverse events resulting from problems with the delivery systems were typically related to either symptoms of excess Remodulin (e.g., nausea) or return of PAH symptoms (e.g., dyspnea). These events were generally resolved by correcting the delivery system pump or infusion set problem such as replacing the syringe or battery, reprogramming the pump, or straightening a crimped infusion line. Adverse events resulting from problems with the delivery system did not lead to clinical instability or rapid deterioration. In addition to these adverse events due to the drug delivery system during subcutaneous administration, the following adverse events may be attributable to the IV mode of infusion including arm swelling, paresthesias, hematoma and pain [see WARNINGS AND PRECAUTIONS].

Post-Marketing Experience

In addition to adverse reactions reported from clinical trials, the following events have been identified during post-approval use of Remodulin. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The following events have been chosen for inclusion because of a combination of their seriousness, frequency of reporting, and potential connection to Remodulin. These events are thrombophlebitis associated with peripheral intravenous infusion, thrombocytopenia bone pain, pruritus and dizziness. In addition, generalized rashes, sometimes macular or papular in nature, and cellulitis have been infrequently reported.

Read the entire FDA prescribing information for Remodulin (Treprostinil Sodium)

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• diuretics such as
  • acetazolamide (Diamox)
  • amiloride (Midamor)
  • bumetanide (Bumex)
  • chlorothiazide (Diuril)
  • chlorthalidone (Thalitone)
  • ethacrynic acid (Edecrin)
  • furosemide (Lasix)
  • hydrochlorothiazide (Microzide, HCTZ)
  • metolazone (Zaroxolyn)
  • torsemide (Demadex)
  • triamterene (Dyrenium, Dyazide, Maxzide)
• angiotensin-converting enzyme (ACE) blockers such as
  • benazepril (Lotensin, Lotensin HCT)
  • captopril (Capoten, Capozide)
  • enalapril (Vasotec, Vaseretic)
  • fosinopril (Monopril, Monopril HCT)
  • lisinopril (Prinivil, Prinzide, Zestril, Zestoretic)
  • moexipril (Univasc, Uniretic)
  • quinapril (Accupril, Accuretic, Quinaretic)
  • ramipril (Altace)
  • trandolapril (Mavik, Tarka)
• angiotensin receptor II blockers such as
  • azilsartan (Edarbi)
  • candesartan (Atacand)
  • irbesartan (Avapro)
  • losartan (Cozaar)
  • olmesartan (Benicar)
  • telmisartan (Micardis, Twynsta)
  • valsartan (Diovan)
• beta blockers such as
  • metoprolol (Toprol XL, Lopressor)
  • carvedilol (Coreg)
  • bisoprolol (Zebeta)
  • betaxolol (Kerlone)
  • nebivolol (Bystolic)
  • propranolol (Inderal)
• calcium channel blockers such as
• nifedipine (Adalat, Nifedical, Procardia)
• amlodipine (Norvasc)
• verapamil (Calan, Isoptin, Covera, Verelan)
• diltiazem (Cardizem)
• vasodilators such as
  • doxazosin (Cardura)
  • prazosin (Minipress)
  • terazosin (Hytrin)
  • clonidine (Catapres)
  • hydralazine (Bidil, Hydra-Zide)
  • minoxidil

• medications that affect your platelets such as clopidogrel (Plavix), aspirin, prasugrel (Effient), ticagrelor (Brilinta), ticlopidine (Ticlid), abciximab (ReoPro), eptifibatide (Integrilin), tirofiban (Aggrastat), and cilostazol (Pletal)
• anticoagulant (blood thinner) medications such as warfarin (Coumadin, Jantoven), heparin, enoxaparin (Lovenox), fondaparinux (Arixtra), rivaroxaban (Xarelto), and apixaban (Eliquis) 
• alcohol

This is not a complete list of all drug interactions. Ask your doctor or pharmacist for more information.

Before receiving Remodulin, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to Remodulin or to any of the inactive ingredients
• have liver problems
• have kidney problems
• have diverticulosis
• have low blood pressure or high blood pressure
• have had a stroke
• have stomach ulcers
• are pregnant or are breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of treprostinil injection in children 16 years of age and younger. Safety and efficacy have not been established.

Geriatric

Appropriate studies have not been performed on the relationship of age to the effects of treprostinil injection in the geriatric population. However, elderly patients are more likely to have age-related liver, kidney, or heart problems, which may require an adjustment in the dose for patients receiving treprostinil.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Defibrotide

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Aceclofenac
• Acemetacin
• Alipogene Tiparvovec
• Alteplase, Recombinant
• Amtolmetin Guacil
• Anagrelide
• Apixaban
• Ardeparin
• Argatroban
• Aspirin
• Bemiparin
• Betrixaban
• Bivalirudin
• Bromfenac
• Bufexamac
• Celecoxib
• Certoparin
• Choline Salicylate
• Citalopram
• Clonixin
• Dabigatran Etexilate
• Dalteparin
• Danaparoid
• Desirudin
• Dexibuprofen
• Dexketoprofen
• Diclofenac
• Diflunisal
• Dipyridamole
• Dipyrone
• Droxicam
• Edoxaban
• Enoxaparin
• Eptifibatide
• Escitalopram
• Etodolac
• Etofenamate
• Etoricoxib
• Felbinac
• Fenoprofen
• Fepradinol
• Feprazone
• Floctafenine
• Flufenamic Acid
• Fluoxetine
• Flurbiprofen
• Fluvoxamine
• Fondaparinux
• Heparin
• Ibuprofen
• Indomethacin
• Ketoprofen
• Ketorolac
• Lepirudin
• Levomilnacipran
• Lornoxicam
• Loxoprofen
• Lumiracoxib
• Meclofenamate
• Mefenamic Acid
• Meloxicam
• Morniflumate
• Nabumetone
• Nadroparin
• Naproxen
• Nepafenac
• Niflumic Acid
• Nimesulide
• Nimesulide Beta Cyclodextrin
• Oxaprozin
• Oxyphenbutazone
• Parecoxib
• Parnaparin
• Paroxetine
• Phenindione
• Phenprocoumon
• Phenylbutazone
• Piketoprofen
• Piracetam
• Piroxicam
• Pixantrone
• Proglumetacin
• Propyphenazone
• Proquazone
• Protein C
• Reviparin
• Rivaroxaban
• Rofecoxib
• Salicylic Acid
• Salsalate
• Sertraline
• Sodium Salicylate
• Sulindac
• Tenoxicam
• Tiaprofenic Acid
• Tinzaparin
• Tolfenamic Acid
• Tolmetin
• Valdecoxib
• Vilazodone
• Vortioxetine
• Warfarin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

• It is used to treat high blood pressure in the lungs.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Follow how to take Remodulin as you have been told by your doctor. Do not use more than you were told to use.
• It is given into the vein or the fatty part of the skin nonstop.
• Your doctor may teach you how to give this medicine.
• Follow how to use carefully.
• Wash your hands before and after use.
• You may need to mix Remodulin with another fluid before you use it. If you do, be sure you know the right kind of fluid to use. Talk with the doctor or pharmacist if you are not sure.
• Do not use if the solution is cloudy, leaking, or has particles.
• Do not use if solution changes color.
• Throw away needles in a needle/sharp disposal box. Do not reuse needles or other items. When the box is full, follow all local rules for getting rid of it. Talk with a doctor or pharmacist if you have any questions.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

• Store unopened vials at room temperature.
• Protect from light.
• Store in a dry place. Do not store in a bathroom.
• After opening or mixing Remodulin with fluids, be sure you know how to store this medicine and how long the drug is good for.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

General

Remodulin can be administered without further dilution for subcutaneous administration, or diluted for intravenous infusion with Sterile Diluent for Remodulin or similar approved high-pH glycine diluent (e.g. Sterile Diluent for Flolan or Sterile Diluent for Epoprostenol Sodium), Sterile Water for Injection, or 0.9% Sodium Chloride Injection prior to administration. See Table 1 below for storage and administration time limits for the different diluents.

Initial Dose for Patients New to Prostacyclin Infusion Therapy

Remodulin is indicated for subcutaneous (SC) or intravenous (IV) use only as a continuous infusion. Remodulin is preferably infused subcutaneously, but can be administered by a central intravenous line if the subcutaneous route is not tolerated, because of severe site pain or reaction. The infusion rate is initiated at 1.25 ng/kg/min. If this initial dose cannot be tolerated because of systemic effects, reduce the infusion rate to 0.625 ng/kg/min.

Dosage Adjustments

The goal of chronic dosage adjustments is to establish a dose at which PAH symptoms are improved, while minimizing excessive pharmacologic effects of Remodulin (headache, nausea, emesis, restlessness, anxiety and infusion site pain or reaction).

The infusion rate should be increased in increments of 1.25 ng/kg/min per week for the first four weeks of treatment and then 2.5 ng/kg/min per week for the remaining duration of infusion, depending on clinical response. Dosage adjustments may be undertaken more often if tolerated. Avoid abrupt cessation of infusion [see Warnings and Precautions (5.4)]. Restarting a Remodulin infusion within a few hours after an interruption can be done using the same dose rate. Interruptions for longer periods may require the dose of Remodulin to be re-titrated.

Patients with Hepatic Insufficiency

In patients with mild or moderate hepatic insufficiency, decrease the initial dose of Remodulin to 0.625 ng/kg/min ideal body weight. Remodulin has not been studied in patients with severe hepatic insufficiency [see Warnings and Precautions (5.3), Use In Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Administration

Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit. If either particulate matter or discoloration is noted, do not use.

Subcutaneous Infusion

Remodulin is administered subcutaneously by continuous infusion without further dilution, via a subcutaneous catheter, using an infusion pump designed for subcutaneous drug delivery. To avoid potential interruptions in drug delivery, the patient must have immediate access to a backup infusion pump and subcutaneous infusion sets. The ambulatory infusion pump used to administer Remodulin should: (1) be small and lightweight, (2) be adjustable to approximately 0.002 mL/hr, (3) have occlusion/no delivery, low battery, programming error and motor malfunction alarms, (4) have delivery accuracy of ±6% or better and (5) be positive pressure driven. The reservoir should be made of polyvinyl chloride, polypropylene or glass.

Remodulin is administered subcutaneously by continuous infusion at a calculated subcutaneous infusion rate (mL/hr) based on a patient's dose (ng/kg/min), weight (kg), and the vial strength (mg/mL) of Remodulin being used. During use, a single reservoir (syringe) of undiluted Remodulin can be administered up to 72 hours at 37°C. The subcutaneous infusion rate is calculated using the following formula:

Example calculations for Subcutaneous Infusion are as follows:

Intravenous Infusion

Diluted Remodulin is administered intravenously by continuous infusion via a surgically placed indwelling central venous catheter using an infusion pump designed for intravenous drug delivery. If clinically necessary, a temporary peripheral intravenous cannula, preferably placed in a large vein, may be used for short term administration of Remodulin. Use of a peripheral intravenous infusion for more than a few hours may be associated with an increased risk of thrombophlebitis. To avoid potential interruptions in drug delivery, the patient must have immediate access to a backup infusion pump and infusion sets. The ambulatory infusion pump used to administer Remodulin should: (1) be small and lightweight, (2) have occlusion/no delivery, low battery, programming error and motor malfunction alarms, (3) have delivery accuracy of ±6% or better of the hourly dose, and (4) be positive pressure driven. The reservoir should be made of polyvinyl chloride, polypropylene or glass.

Infusion sets with an in-line 0.22 or 0.2 micron pore size filter should be used.

Diluted Remodulin has been shown to be stable at ambient temperature when stored for up to 14 days using high-pH glycine diluent at concentrations as low as 0.004 mg/mL (4,000 ng/mL).

Select the intravenous infusion rate to allow for a desired infusion period length of up to 48 hours between system changeovers. Typical intravenous infusion system reservoirs have volumes of 50 or 100 mL. With this selected intravenous infusion rate (mL/hr) and the patient's dose (ng/kg/min) and weight (kg), the diluted intravenous Remodulin concentration (mg/mL) can be calculated using the following formula:

Step 1

The volume of Remodulin Injection needed to make the required diluted intravenous Remodulin concentration for the given reservoir size can then be calculated using the following formula:

Step 2

The calculated volume of Remodulin Injection is then added to the reservoir along with the sufficient volume of diluent to achieve the desired total volume in the reservoir.

Example calculations for Intravenous Infusion are as follows:

Patients Requiring Transition from Flolan

Transition from Flolan to Remodulin is accomplished by initiating the infusion of Remodulin and increasing it, while simultaneously reducing the dose of intravenous Flolan. The transition to Remodulin should take place in a hospital with constant observation of response (e.g., walk distance and signs and symptoms of disease progression). Initiate Remodulin at a recommended dose of 10% of the current Flolan dose, and then escalate as the Flolan dose is decreased (see Table 2 for recommended dose titrations).

Patients are individually titrated to a dose that allows transition from Flolan therapy to Remodulin while balancing prostacyclin-limiting adverse events. Increases in the patient's symptoms of PAH should be first treated with increases in the dose of Remodulin. Side effects normally associated with prostacyclin and prostacyclin analogs are to be first treated by decreasing the dose of Flolan.

Risk of Catheter-Related Bloodstream Infection

Chronic intravenous infusions of Remodulin are delivered using an indwelling central venous catheter. This route is associated with the risk of blood stream infections (BSIs) and sepsis, which may be fatal. Therefore, continuous subcutaneous infusion (undiluted) is the preferred mode of administration.

In an open-label study of IV treprostinil (n=47), there were seven catheter-related line infections during approximately 35 patient years, or about 1 BSI event per 5 years of use. A CDC survey of seven sites that used IV treprostinil for the treatment of PAH found approximately 1 BSI (defined as any positive blood culture) event per 3 years of use. Administration of IV Remodulin with a high pH glycine diluent has been associated with a lower incidence of BSIs when compared to neutral diluents (sterile water, 0.9% sodium chloride) when used along with catheter care guidelines.

Worsening PAH upon Abrupt Withdrawal or Sudden Large Dose Reduction

Avoid abrupt withdrawal or sudden large reductions in dosage of Remodulin, which may result in worsening of PAH symptoms.

Patients with Hepatic or Renal Insufficiency

Titrate slowly in patients with hepatic or renal insufficiency, because such patients will likely be exposed to greater systemic concentrations relative to patients with normal hepatic or renal function [see Dosage and Administration (2.4, 2.5), Use In Specific Populations (8.6, 8.7), and Clinical Pharmacology (12.3)].

Effect of Other Drugs on Treprostinil

Co-administration of a cytochrome P450 (CYP) 2C8 enzyme inhibitor (e.g., gemfibrozil) increases exposure (both Cmax and AUC) to treprostinil. Co-administration of a CYP2C8 enzyme inducer (e.g., rifampin) decreases exposure to treprostinil [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)].

Remodulin is supplied in 20-mL multidose vials as sterile solutions in water for injection, individually packaged in cartons. Unopened vials of Remodulin are stable until the date indicated when stored at 25°C (77°F), with excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. A single vial of Remodulin should be used for no more than 30 days after the initial introduction into the vial.

Remodulin Injection is supplied as:

Sterile Diluent for Remodulin is supplied separately as:

50 mL vial, carton of 1 (NDC 66302-150-50).

Patients receiving Remodulin should be given the following information: Remodulin is infused continuously through a subcutaneous or surgically placed indwelling central venous catheter, via an infusion pump. Patients receiving intravenous infusion should use an infusion set with an in-line filter. Therapy with Remodulin will be needed for prolonged periods, possibly years, and the patient's ability to accept and care for a catheter and to use an infusion pump should be carefully considered. In order to reduce the risk of infection, aseptic technique must be used in the preparation and administration of Remodulin. Additionally, patients should be aware that subsequent disease management may require the initiation of an alternative intravenous prostacyclin therapy, Flolan® (epoprostenol sodium).

©Copyright 2014 United Therapeutics Corp. All rights reserved.

Remodulin manufactured for:

United Therapeutics Corp.
Research Triangle Park, NC 27709

PRINCIPAL DISPLAY PANEL - 1 mg/mL Vial Carton

Remodulin®
(treprostinil) Injection

20 mg/20 mL
(1 mg/mL)

For Subcutaneous or
Intravenous Infusion Only.

20 mL multidose vial

United
Therapeutics
CORPORATION

PRINCIPAL DISPLAY PANEL - 2.5 mg/mL Vial Carton

Remodulin®
(treprostinil) Injection

50 mg/20 mL
(2.5 mg/mL)

For Subcutaneous or
Intravenous Infusion Only.

20 mL multidose vial

United
Therapeutics
CORPORATION

Remodulin®
(treprostinil) Injection

100 mg/20 mL
(5 mg/mL)

For Subcutaneous or
Intravenous Infusion Only.

20 mL multidose vial

United
Therapeutics
CORPORATION

PRINCIPAL DISPLAY PANEL - 10 mg/mL Vial Carton

Remodulin®
(treprostinil) Injection

200 mg/20 mL
(10 mg/mL)

For Subcutaneous or
Intravenous Infusion Only.

20 mL multidose vial

United
Therapeutics
CORPORATION