A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Remodulin Side Effects, and Drug Interactions - Treprostinil sodium
Remodulin Side Effects, and Drug Interactions - Treprostinil sodium
SIDE EFFECTS
Patients receiving Remodulin 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
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 2. Percentages of subjects reporting infusion site adverse
events
| |
Reaction
|
Pain
|
|
Placebo
|
Remodulin
|
Placebo
|
Remodulin
|
|
Severe
|
1
|
38
|
2
|
39
|
|
Requiring narcotics*
|
NA**
|
NA**
|
1
|
32
|
|
Leading to discontinuation
|
0
|
3
|
0
|
7
|
* based on prescriptions for narcotics, not actual use
**medications used to treat infusion site pain were not distinguished
from those used to treat site reactions
Other adverse events included diarrhea, jaw pain, edema, vasodilatation
and nausea.
Adverse Events During Chronic Dosing: Table 3 lists adverse
events that occurred at a rate of at least 3% and were more frequent in patients
treated with Remodulin than with placebo in controlled trials in PAH.
Table 3: Adverse Events in Controlled Studies of Patients with
PAH, Occurring with at Least 3% Incidence and More Common on Remodulin than
on Placebo.
|
Adverse Event
|
Remodulin (N=236) Percent of Patients
|
Placebo (N=233) Percent of Patients
|
|
Infusion Site Pain
|
85
|
27
|
|
Infusion Site Reaction
|
83
|
27
|
|
Headache
|
27
|
23
|
|
Diarrhea
|
25
|
16
|
|
Nausea
|
22
|
18
|
|
Rash
|
14
|
11
|
|
Jaw Pain
|
13
|
5
|
|
Vasodilatation
|
11
|
5
|
|
Dizziness
|
9
|
8
|
|
Edema
|
9
|
3
|
|
Pruritus
|
8
|
6
|
|
Hypotension
|
4
|
2
|
Reported adverse events (at least 3%) 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.
Adverse Events Attributable to the Drug Delivery System in
PAH Controlled Trials
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. Most delivery system complications were easily managed
(e.g., replace syringe or battery, reprogram pump, straighten crimped infusion
line). 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. Adverse events resulting from problems
with the delivery system did not lead to clinical instability or rapid deterioration.
DRUG INTERACTIONS
Reduction in blood pressure caused by Remodulin may be exacerbated
by drugs that by themselves alter blood pressure, such as diuretics, antihypertensive
agents, or vasodilators. Since Remodulin inhibits platelet aggregation, there
is also a potential for increased risk of bleeding, particularly among patients
maintained on anticoagulants. During clinical trials, Remodulin was used concurrently
with anticoagulants, diuretics, cardiac glycosides, calcium channel blockers,
analgesics, antipyretics, nonsteroidal anti-inflammatories, opioids, corticosteroids,
and other medications.
Effect of Other Drugs on Remodulin
In vitro studies: Remodulin did not significantly affect the
plasma protein binding of normally observed concentrations of digoxin or warfarin.
In vivo studies: Acetaminophen - Analgesic doses of acetaminophen,
1000 mg every 6 hours for seven doses, did not affect the pharmacokinetics of
Remodulin, at a subcutaneous infusion rate of 15 ng/kg/min.
Remodulin has not been studied in conjunction with FlolanÒ
(epoprostenol sodium) or TracleerÔ (bosentan).
Effect of Remodulin on Other Drugs
In vivo studies: Warfarin - Remodulin does not affect the pharmacokinetics
or pharmacodymamics of warfarin. The pharmacokinetics of R- and S- warfarin
and the INR in healthy subjects given a single 25 mg dose of warfarin were unaffected
by continuous subcutaneous Remodulin at an infusion rate of 10 ng/kg/min.
Hepatic and Renal Impairment
Caution should be used in patients with hepatic or renal impairment
(see SPECIAL POPULATIONS).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies have not been performed to evaluate the carcinogenic
potential of treprostinil. In vitro and in vivo mutagenicity studies did not
demonstrate any mutagenic or clastogenic effects of treprostinil. Treprostinil
sodium did not affect fertility or mating performance of male or female rats
given continuous subcutaneous infusion at rates of up to 450 ng treprostinil/kg/min
[about 59 times the recommended starting human rate of infusion (1.25 ng/kg/min)
and about 8 times the average rate (9.3 ng/kg/min) achieved in clinical trials,
on a ng/m2 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 6.
Pregnancy
Pregnancy Category B - In pregnant rats, continuous subcutaneous
infusion of treprostinil sodium during the period of organogenesis and late
gestational development, at rates as high as 900 ng treprostinil/kg/min (about
117 times the starting human rate of infusion, on a ng/m2 basis and
about 16 times the average rate achieved in clinical trials), resulted in no
evidence of harm to the fetus. 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 infusion rate of 150 ng treprostinil/kg/min (about 41 times
the starting human rate of infusion, on a ng/m2 basis, and 5 times
the average rate used in clinical trials). In rats, continuous subcutaneous
infusion of treprostinil from implantation to the end of lactation, at rates
of up to 450 ng treprostinil/kg/min, did not affect the growth and development
of offspring. Because animal reproduction studies are not always predictive
of human response, Remodulin should be used during pregnancy only if clearly
needed.
Labor and delivery
No treprostinil sodium treatment-related effects on labor and
delivery were seen in animal studies. The effect of treprostinil sodium on labor
and delivery in humans is unknown.
Nursing mothers
It is not known whether treprostinil is excreted in human milk
or absorbed systemically after ingestion. Because many drugs are excreted in
human milk, caution should be exercised when Remodulin is administered to nursing
women.
Pediatric use
Safety and effectiveness in pediatric patients have not been
established. Clinical studies of Remodulin did not include sufficient numbers
of patients aged <16 years to determine whether they respond differently
from older patients. In general, dose selection should be cautious.
Geriatric use
Clinical studies of Remodulin did not include sufficient numbers
of patients aged 65 and over to determine whether they respond differently from
younger patients. In general, dose selection for an elderly patient should be
cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy.
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