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Orenitram（TREPROSTINIL DIOLAMINE）曲前列环素缓释片
2013年12月20日下午，药品生产企业联合治疗公司（ UTHR ）表示， Orenitram（曲前列环素）缓释片获FDA批准用于肺动脉高压世界卫生组织I组患者的治疗以提高其运动能力。
主要疗效研究FREEDOM-M 表明，服用Orenitram片每日两次患者比安慰剂组步行时间增加，中位增加时间为六分钟。
“此次批准标志着FDA第一次批准口服环前列腺素类似物用于治疗疾病 – 同时这也是我们获得FDA批准的第五个治疗药物 – 是对我们为医生和患者提供治疗肺动脉高压更多选择使命的有力支持，”公司总裁兼首席营运官Roger Jeffs表示。
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Drug Name(s) |
ORENITRAM |
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FDA Application No. |
(NDA) 203496 |
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Active Ingredient(s) |
TREPROSTINIL DIOLAMINE |
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Company |
UNITED THERAP |
FDA批准曲前列尼尔缓释片治疗肺动脉高压
12月20日美国FDA批准Orenitram（曲前列尼尔，treprostinil Extended-Release Tablets）缓释片用于治疗肺动脉高压（PAH ）在WHO I组患者，提高他们的运动能力。
此前FDA从未批准过一种口服前列环素类似物用于疗何疾病的治疗，并且这是FDA批准的第5个PAH药物，以为医师和患者提供比较广泛的治疗选择。
一项主要名为“FREEDOM-M”的疗效研究建立了效果证据，包括有WHO功能II-III级症状和特发性或遗传性PAH（75％）或结缔组织病（19％）相关PAH病因的患者。研究显示：接受Orenitram每日两次的患者6分钟行走距离（6MWD）比安慰剂组患者增加23米（中位数）[p=0.013]。然而，另外两项III期临床研究（FREEDOM-C和FREEDOM-C2）并没有显示出它在第16周对运动能力（6MWD）中位数有益（分别为11米[p=0.072]和10米[P=0.089]）。
在临床研究中报告的Orenitram最常见（经安慰剂校正后发生率>10％）副作用为头痛、恶心和腹泻。
Orenitram每天给药两次，与食物一起服用，但每日总剂量也可以分成三次。 Orenitram有四种剂量规格：0.125毫克，0.25毫克，1毫克和2.5毫克。当患者耐受时，Orenitram的剂量可以适当增加，以达到最佳临床应答。最大剂量是应根据耐受性来确定。
Orenitram含有与Remodulin（Treprostinil Injection，曲前列尼尔注射液。在我国注册名：瑞莫杜林）和Tyvaso®（Treprostinil Inhalation Solution，曲前列尼尔吸入溶液）具有相同的活性成分。
Orenitram最大的价值可能是取代皮下、静脉或吸入给药，但取代使用尚未作过研究
ORENITRAM (treprostinil) tablet, extended release
[United Therapeutics Corp.]
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These highlights do not include all the information needed to use ORENITRAM™ safely and effectively. See Full Prescribing Information for ORENITRAM.
ORENITRAM (treprostinil) Extended-Release Tablets for oral administration
Initial U.S. Approval: 2002
INDICATIONS AND USAGE
Orenitram is a prostacyclin vasodilator indicated for:
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Treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise capacity. The study that established effectiveness included predominately patients with WHO functional class II-III symptoms and etiologies of idiopathic or heritable PAH (75%) or PAH associated with connective tissue disease (19%). (1.1)
As the sole vasodilator, the effect on exercise is small. Orenitram has not been shown to add to other vasodilator therapy. (1.1)
DOSAGE AND ADMINISTRATION
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Give with food. Swallow tablets whole; use only intact tablets. (2.1)
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Starting dose: 0.25 mg BID. (2.1)
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Titrate by 0.25 mg or 0.5 mg BID or 0.125 mg TID, not more than every 3 to 4 days as tolerated. (2.1)
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Maximum dose is determined by tolerability. (2.1)
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Mild hepatic impairment (Child Pugh Class A): Initiate at 0.125 mg BID. Increment at 0.125 mg BID every 3 to 4 days. (2.1)
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Avoid use in patients with moderate hepatic impairment. (2.1)
DOSAGE FORMS AND STRENGTHS
Extended-Release Tablets: 0.125 mg, 0.25 mg, 1 mg and 2.5 mg. (3)
CONTRAINDICATIONS
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Severe hepatic impairment (Child Pugh Class C). (4)
WARNINGS AND PRECAUTIONS
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Do not abruptly discontinue dosing. (2.2, 5.1)
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Increased risk of bleeding, particularly in patients receiving anticoagulants. (5.2)
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Do not take Orenitram with alcohol (5.3)
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In patients with diverticulosis Orenitram tablets can become lodged in a diverticulum. (5.4)
ADVERSE REACTIONS
Most common adverse reactions (incidence >10%) reported in clinical studies with Orenitram are headache, nausea, and diarrhea. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact United Therapeutics Corp. at 1-866-458-6479 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
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Blood pressure lowering drugs (e.g., diuretics, antihypertensive agents, or vasodilators): Risk of hypotension (7.1)
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When co-administered with strong CYP2C8 inhibitors the initial dose is 0.125 mg BID with 0.125 mg BID dose increments every 3 to 4 days. (7.3)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 2/2014
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Back to Highlights and Tabs
FULL PRESCRIBING INFORMATION
1. INDICATIONS AND USAGE
1.1 Pulmonary Arterial Hypertension
Orenitram is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise capacity. The study that established effectiveness included predominately patients with WHO functional class II-III symptoms and etiologies of idiopathic or heritable PAH (75%) or PAH associated with connective tissue disease (19%).
When used as the sole vasodilator, the effect of Orenitram on exercise is about 10% of the deficit, and the effect, if any, on a background of another vasodilator is probably less than this. Orenitram is probably most useful to replace subcutaneous, intravenous, or inhaled treprostinil, but this use has not been studied.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosing
Orenitram is supplied as extended release tablets. Individualize dosing of Orenitram according to clinical response.
The recommended starting dose of Orenitram is 0.25 mg twice daily (BID) with food, taken approximately 12 hours apart. Increase the dose as tolerated to achieve optimal clinical response. The recommended increment is 0.25 or 0.5 mg BID every 3-4 days. If 0.25 mg BID dose increments are not tolerated consider titrating slower. The total daily dose can be divided and given three times daily with food (TID; approximately 8 hours apart), titrating by increments of 0.125 mg TID.
The maximum dose is determined by tolerability. The mean dose in a controlled clinical trial at 12 weeks was 3.4 mg BID. Maximum doses studied were 12 mg BID in the 12-week blinded study and up to 21 mg BID in an open-label long-term study.
If intolerable pharmacologic effects occur, decrease the dose in increments of 0.25 mg. Avoid abrupt discontinuation [see Warnings and Precautions (5.1)].
Concomitant administration with CYP2C8 inhibitors: When co-administered with strong CYP2C8 inhibitors (e.g., gemfibrozil) the initial dose is 0.125 mg BID with 0.125 mg BID dose increments every 3 to 4 days.
Take Orenitram with food. Swallow Orenitram intact; use only intact tablets.
2.2 Interruptions and Discontinuation
If a dose of medication is missed, take the missed dose as soon as possible, with food. If a patient misses two or more doses, restart at a lower dose and re-titrate.
In the event of a planned short-term treatment interruption for patients unable to take oral medications, consider a temporary infusion of subcutaneous or intravenous treprostinil. To calculate the total daily dose (mg) of treprostinil for the parenteral route divide the oral total daily dose by 5.
When discontinuing Orenitram, reduce the dose in steps of 0.5 to 1 mg per day [see Warnings and Precautions (5.1)].
3 DOSAGE FORMS AND STRENGTHS
Orenitram (treprostinil extended-release) is available in the following four strengths:
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- 0.125 mg [White tablet imprinted with UT 0.125]
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- 0.25 mg [Green tablet imprinted with UT 0.25]
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- 1 mg [Yellow tablet imprinted with UT 1]
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- 2.5 mg [Pink tablet imprinted with UT 2.5]
5 WARNINGS AND PRECAUTIONS
5.1 Worsening PAH Symptoms upon Abrupt Withdrawal
Abrupt discontinuation or sudden large reductions in dosage of Orenitram may result in worsening of PAH symptoms.
5.2 Risk of Bleeding
Orenitram inhibits platelet aggregation and increases the risk of bleeding.
5.3 Increased Exposure with Alcohol
Do not take Orenitram with alcohol as release of treprostinil from the tablet may occur at a faster rate than intended.
5.4 Use in Patients with Blind-end Pouches
The tablet shell does not dissolve. In patients with diverticulosis, Orenitram tablets can lodge in a diverticulum.
6 ADVERSE REACTIONS
6.1 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 clinical practice.
In a 12-week placebo-controlled monotherapy study (Study 1; WHO Group 1; functional class II-III), the most commonly reported adverse reactions that occurred in patients receiving Orenitram included: headache, nausea, and diarrhea. Table 1 lists the adverse reactions that occurred at a rate on Orenitram at least 5% higher than on placebo.
Orenitram patients in Table 1 for Study 1 (N = 151) had access to 0.25 mg tablets at randomization. Approximately 91% of such patients experienced an adverse reaction, but only 4% discontinued therapy for an adverse reaction (compared to 3% receiving placebo). The overall discontinuation rate for any reason was 17% for active and 14% for placebo.
Table 1: Adverse Reactions with Rates at Least 5% Higher on Orenitram Monotherapy than on Placebo
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Reaction |
Orenitram
N=151 |
Placebo
N=77 |
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Headache |
63% |
19% |
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Diarrhea |
30% |
16% |
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Nausea |
30% |
18% |
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Flushing |
15% |
6% |
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Pain in jaw |
11% |
4% |
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Pain in extremity |
14% |
8% |
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Hypokalemia |
9% |
3% |
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Abdominal discomfort |
6% |
0% |
Orenitram was studied in a long-term, open-label extension study in which 824 patients were dosed for a mean duration of approximately 2 years. About 70% of patients continued treatment with Orenitram for at least a year. The mean dose was 4.2 mg BID at one year. The adverse reactions were similar to those observed in the placebo-controlled trials.
7 DRUG INTERACTIONS
7.1 Antihypertensive Agents or Other Vasodilators
Concomitant administration of Orenitram with diuretics, antihypertensive agents or other vasodilators increases the risk of symptomatic hypotension.
7.2 Anticoagulants
Treprostinil inhibits platelet aggregation; there is increased risk of bleeding, particularly among patients receiving anticoagulants.
7.3 Effect of CYP2C8 Inhibitors
Co-administration of Orenitram and the CYP2C8 enzyme inhibitor gemfibrozil in healthy adult volunteers increases exposure to treprostinil. Reduce the starting dose of Orenitram to 0.125 mg BID and use 0.125 mg BID increments every 3 to 4 days [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C.
Animal reproductive studies with treprostinil diolamine have shown an adverse effect on the fetus. There are no adequate and well-controlled studies in humans.
In rats, treatment with treprostinil diolamine had no effect on reproductive performance or sperm motility at doses up to 10 mg/kg/day. The exposures at this dose level are about 10- (male) to 18- (female) fold the usual human exposure at the mean dose of 3.4 mg BID.
In pregnant rats, reversible, dose-dependent decreases in body weight gain and food consumption were observed during the first four days of dosing in animals administered 10, 20 and 30 mg/kg/day treprostinil diolamine. In a dose range-finding study, there was a 17% decrease in the pregnancy rate in the animals administered 20 and 30 mg/kg/day. One dam in each of the 20 and 30 mg/kg/day had litters with no viable fetuses. In the definitive study (0, 5, 10 and 20 mg/kg/day), there were four treatment-related deaths, and a 32% decrease in the pregnancy rate for rats administered 20 mg/kg/day. There was an 8% decrease in the pregnancy rate in the animals administered 10 mg/kg/day. Across both studies, an increase in post-implantation loss was observed in animals administered 10 to 30 mg/kg/day, and a significant decrease in the mean number of live births was seen at dose levels ≥10 mg/kg/day. The no observed adverse effect level was 5 mg/kg/day (maternal, fetal viability and growth), and 20 mg/kg/day (teratogenicity), the highest dose tested in the definitive study. The exposures at 5 and 20 mg/kg/day doses represent 13 and 55 times, respectively, the human exposure.
For F1 progeny, a decreased copulation index was observed at the 5 and 10 mg/kg/day treprostinil diolamine dose levels in rats. The no observed effect levels for physical development, reflex development, exploratory behavior, learning and memory, and sexual maturation was 10 mg/kg/day. The no observed effect level for F1 progeny general development (based on body weight) was 10 mg/kg/day for females and ≤ 2.5 mg/kg/day for males; the no observed effect level for F1 reproductive performance was 2.5 mg/kg/day or 6 times the human exposure.
In pregnant rabbits, the primary maternal adverse effects were gastrointestinal disturbance; dose-dependent decreases in mean body weight, body weight gain, and food consumption were observed. During the post-dose phase, the effect was reversed. In a dose range-finding study, there was a 17% decrease in the pregnancy rate for animals administered 4 mg/kg/day. A dose-dependent increase in post-implantation loss was observed. Two dams administered 4 mg/kg/day had litters with no viable fetuses; the mean fetal weight was slightly decreased in animals administered 4 mg/kg/day. In the definitive study, mean fetal weights were significantly decreased in animals administered 0.5 to 3 mg/kg/day of treprostinil diolamine. At doses of 1.5 and 3 mg/kg/day, external fetal and soft tissue malformations were observed in a few fetuses, and the total fetal skeletal malformations were significantly increased. The no observed adverse effect level was less than 0.5 mg/kg/day (maternal), 1.5 mg/kg/day (fetal viability and growth), and 0.5 mg/kg/day (teratogenicity). The 0.5 mg/kg/day dose represents about 5 times the human exposure.
8.2 Labor and Delivery
The effect of Orenitram on labor and delivery in humans is unknown. No treprostinil treatment-related effects on labor and delivery were seen in animal studies.
8.3 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, choose Orenitram or breastfeeding.
8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
8.5 Geriatric Use
Clinical studies of Orenitram did not include sufficient numbers of patients aged 65 years 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 or cardiac function, and of concomitant disease or other drug therapy.
8.7 Patients with Renal Impairment
No dose adjustments are required in patients with renal impairment. Orenitram is not removed by dialysis [see Clinical Pharmacology (12.3)].
10 OVERDOSAGE
Signs and symptoms of overdose with Orenitram during clinical trials reflect its dose-limiting pharmacologic effects and include severe headache, nausea, vomiting, diarrhea, and hypotension. Treat supportively.
11 DESCRIPTION
Orenitram is an extended release osmotic tablet for oral administration. Orenitram is formulated as the diolamine salt of treprostinil, a tricyclic benzindene analogue of prostacyclin. The chemical name is Acetic acid, 2-[[(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-1H-benz[f]inden-5-yl]oxy]-, complexed with 2,2'-iminobis[ethanol] (1:1). The molecular formula is C23H34O5.C4H11NO2, the molecular weight is 495.65, and it has the following structural formula:
Orenitram tablets are formulated in four strengths, which contain 0.125 mg of treprostinil (equivalent to 0.159 mg treprostinil diolamine), 0.25 mg of treprostinil (equivalent to 0.317 mg treprostinil diolamine), 1 mg of treprostinil (equivalent to 1.27 mg treprostinil diolamine), or 2.5 mg of treprostinil (equivalent to 3.17 mg treprostinil diolamine). The formulations also contain xylitol, maltodextrin, sodium lauryl sulfate, magnesium stearate, cellulose acetate, triethyl citrate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc. In addition tablets may contain colorants FD&C Blue #2, iron oxide yellow, and iron oxide red. The imprinting ink contains shellac glaze, ethanol, isopropyl alcohol USP, iron oxide black, n-butyl alcohol, propylene glycol, and ammonium hydroxide.
Orenitram is designed to release treprostinil at a near zero-order rate using an osmotic tablet technology. The tablet core is coated with a semi-permeable membrane and has a laser-drilled aperture through the membrane. Upon contact with water (e.g., after ingestion), the core tablet absorbs water through the semi-permeable membrane. The water dissolves the water-soluble treprostinil diolamine and the water-soluble osmotic excipients, which creates hydrostatic pressure within the membrane, eventually forcing the drug out through the tablet at a controlled rate.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The major pharmacologic actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds, inhibition of platelet aggregation, and inhibition of smooth muscle cell proliferation.
12.2 Pharmacodynamics
In a clinical trial of 240 healthy adult volunteers, single doses of inhaled treprostinil 54 µg (the target clinical dose) and 84 µg (supratherapeutic inhalation dose) prolonged the corrected QTc interval by approximately 10 msec. The QTc effect dissipated rapidly as the concentration of treprostinil decreased. Orenitram has not been eva luated in a thorough QTc study.
12.3 Pharmacokinetics
In patients with PAH, pharmacokinetics of treprostinil is dose-proportional for systemic exposure (AUC0-t) over the dose range of 0.5 and 15 mg BID. Upon repeat administration with a BID regimen, the accumulation in the systemic exposures to treprostinil is minimal and results in a peak-to-trough ratio of approximately 7. However, a TID regimen will reduce the peak-to-trough fluctuations to approximately 2.5 for the same total daily dose.
Absorption
The absolute oral bioavailability of Orenitram is approximately 17%. Maximum treprostinil concentrations occur between approximately 4 and 6 hours following Orenitram administration.
The absorption of Orenitram is affected by food. The AUCinf of treprostinil was increased by 49% and the Cmax was increased by an average of 13% when Orenitram was administered foll |
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