FDA批准药物治疗危险地低血压

FDA批准药物治疗危险地低血压
https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm590249.htm
2017年12月21日美国食品和药品监管局今天批准Giapreza (血管紧张素angiotensin II) 注射为成年中有败血症或其他分配性休克静脉输注增加血压。
FDA的药品评价和研究中心中心血管和肾产品部主任Norman Stockbridge，M.D.，Ph.D.说：'休克，不能维持血流至生命组织，可能导致器官衰竭和死亡，'  '对危重地生病不能对可得到的治疗适当反应的低血压患者这是一个需求的治疗选择。'
血压是当心脏泵出血液时推向动脉的血管壁的一种力量。低血压是异常地低血压。休克是一种危重情况其中血压掉至如此低，使大脑，肾脏和其他生命器官不能接受足够血流至适当地功能。
在一项321例有休克和一个危重低血压患者临床试验，与用安慰剂治疗患者比较显著地更多患者对用Giapreza治疗反应。Giapreza有效地增加血压当加入至用于升高血压的常用治疗。
Giapreza可能致危险的血凝块

Generic Name: angiotensin ii
Dosage Form: angiotensin ii injection

Giapreza increases blood pressure in adults with septic or other distributive shock.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Giapreza must be administered as an intravenous infusion. Giapreza must be diluted in 0.9% sodium chloride prior to use. Dilute the contents of one vial of Giapreza in 0.9% saline to achieve a final concentration of 5,000 ng/mL or 10,000 ng/mL.

Discard vial and any unused portion of the drug product after use.

Diluted solution may be stored at room temperature or under refrigeration. Discard prepared solution after 24 hours at room temperature or under refrigeration.

The recommended starting dosage of Giapreza is 20 nanograms (ng)/kg/min via continuous intravenous infusion. Administration through a central venous line is recommended.

Monitor blood pressure response and titrate Giapreza every 5 minutes by increments of up to 15 ng/kg/min as needed to achieve or maintain target blood pressure. Do not exceed 80 ng/kg/min during the first 3 hours of treatment. Maintenance doses should not exceed 40 ng/kg/min. Doses as low as 1.25 ng/kg/min may be used.

Once the underlying shock has sufficiently improved, down-titrate every 5 to 15 minutes by increments of up to 15 ng/kg/min based on blood pressure.

Injection: 2.5 mg/mL angiotensin II and 5 mg/2 mL angiotensin II (2.5 mg/mL) in a vial.

Giapreza is a clear, aqueous solution.

None.

The safety of Giapreza was evaluated in 321 adults with septic or other distributive shock in a randomized, double-blind, placebo-controlled study, ATHOS-3. There was a higher incidence of arterial and venous thrombotic and thromboembolic events in patients who received Giapreza compared to placebo-treated patients in the ATHOS-3 study (13% vs. 5%). The major imbalance was in deep venous thromboses. Use concurrent venous thromboembolism (VTE) prophylaxis.

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.

ATHOS-3

The safety of Giapreza was evaluated in ATHOS-3 [see Warnings and Precautions(5.1)]. Patients in ATHOS-3 were receiving other vasopressors in addition to Giapreza or placebo, which were titrated to effect on mean arterial pressure (MAP).

Table 2 summarizes adverse reactions with an incidence of at least 4% among patients treated with Giapreza and with a rate of at least 1.5% higher with Giapreza than with placebo.

Concomitant use of angiotensin converting enzyme (ACE) inhibitors may increase the response to Giapreza.

Concomitant use of angiotensin II blockers (ARBs) may decrease the response to Giapreza.

Risk Summary

The published data on angiotensin II use in pregnant women are not sufficient to determine a drug-associated risk of adverse developmental outcomes. Animal reproduction studies have not been conducted with Giapreza.

All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Septic or other distributive shock is a medical emergency that can be fatal if left untreated. Delaying treatment in pregnant women with hypotension associated with septic or other distributive shock is likely to increase the risk of maternal and fetal morbidity and mortality.

Risk Summary

It is not known whether Giapreza is present in human milk. No data are available on the effects of angiotensin II on the breastfed child or the effects on milk production.

The safety and efficacy of Giapreza in pediatric patients have not been established.

In ATHOS-3, 48% of the total patient population was aged 65 years and older. There was no significant difference in safety or efficacy between patients less than 65 and those 65 years or older when treated with Giapreza.

Overdose of Giapreza would be expected to result in hypertension, necessitating close monitoring and supportive care. Effects are expected to be brief because the half-life of angiotensin II is less than one minute.

Angiotensin II is a naturally occurring peptide hormone of the renin-angiotensin-aldosterone system (RAAS) that causes vasoconstriction and an increase in blood pressure. Giapreza is a sterile, aqueous solution of synthetic human angiotensin II for intravenous administration by infusion. Each 1 mL of Giapreza contains 2.5 mg angiotensin II equivalent to an average of 2.9 mg angiotensin II acetate, 25 mg mannitol, and Water for Injection adjusted with sodium hydroxide and/or hydrochloric acid to pH of 5.5.

The chemical name of the synthetic angiotensin II acetate is L-Aspartyl-L-arginyl-L-valyl-Ltyrosyl-L-isoleucyl-L-histidyl-L-prolyl-L-phenylalanine, acetate salt. The counter ion acetate is present in a non-stoichiometric ratio. It is a white to off-white powder, soluble in water.

The structure of angiotensin II acetate is shown below.

Molecular formula: C50H71N13O12 ∙ (C2H4O2)n; (n= number of acetate molecules; theoretical n = 3)

Average molecular weight: 1046.2 (as free base).

Angiotensin II raises blood pressure by vasoconstriction and increased aldosterone release. Direct action of angiotensin II on the vessel wall is mediated by binding to the G-protein-coupled angiotensin II receptor type 1 on vascular smooth muscle cells, which stimulates Ca2+/calmodulin-dependent phosphorylation of myosin and causes smooth muscle contraction.

For the 114 (70%) patients in the Giapreza arm who reached the target MAP at Hour 3, the median time to reach the target MAP endpoint was approximately 5 minutes. Giapreza is titrated to effect for each individual patient.

Following intravenous infusion of angiotensin II in adults with septic or other distributive shock, serum levels of angiotensin II are similar at Baseline and Hour 3 after intravenous infusion. After 3 hours of treatment, however, the serum level of angiotensin I (the angiotensin II precursor peptide) is reduced by approximately 40%.

Distribution:

No specific studies were conducted that examined the distribution of Giapreza.

Metabolism and Excretion:

No specific studies were conducted that examined the metabolism and excretion of Giapreza.

The plasma half-life of IV administered angiotensin II is less than one minute. It is metabolized by aminopeptidase A and angiotensin converting enzyme 2 to angiotensin-(2-8) [angiotensin III] and angiotensin-(1-7), respectively in plasma, erythrocytes and many of the major organs (i.e., intestine, kidney, liver and lung). Angiotensin II type 1 receptor (AT1) mediated activity of angiotensin III is approximately 40% of angiotensin II; however, aldosterone synthesis activity is similar to angiotensin II. Angiotensin-(1-7) exerts the opposite effects of angiotensin II on AT1 receptors and causes vasodilation.

Specific Populations

No formal pharmacokinetic studies were conducted with Giapreza in the following specific populations.

Renal Impairment

The clearance of angiotensin II is not dependent on renal function. Therefore, the pharmacokinetics of Giapreza are not expected to be influenced by renal impairment.

Hepatic Impairment

The clearance of angiotensin II is not dependent on hepatic function. Therefore, the pharmacokinetics of Giapreza are not expected to be influenced by hepatic impairment.

Age

The effect of age was analyzed in the 163 patients receiving Giapreza in ATHOS-3. There were no significant differences in pharmacokinetics between age groups (< 65 years / ≥ 65 years).

Male and Female Patients

The effect of sex was analyzed in the 163 patients receiving Giapreza in ATHOS-3. There were no significant differences in pharmacokinetics between male and female patients.

No genetic toxicity studies have been conducted with Giapreza. No carcinogenicity or fertility studies with Giapreza have been conducted in animals.

No animal toxicology studies were conducted with Giapreza.

In a cardiovascular safety pharmacology study in normotensive dogs, Giapreza doses of 150, 450, and 1800 ng/kg (5, 15 and 60 ng/kg/min) were infused intravenously for 30 minutes each. At ≥ 450 ng/kg, Giapreza caused significantly elevated MAP and systemic vascular resistance, as expected. The 1800 ng/kg dose also caused increased heart rate, increased systemic vascular resistance, increased left ventricular systolic and end-diastolic pressures, and PR interval prolongation. Giapreza did not significantly alter respiratory rate or cause electrocardiographic changes in QRS duration or QTc.

The Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) trial was a double-blind study in which 321 adults with septic or other distributive shock who remained hypotensive despite fluid and vasopressor therapy were randomized 1:1 to Giapreza or placebo. Doses of Giapreza or placebo were titrated to a target mean arterial pressure (MAP) of ≥ 75 mmHg during the first 3 hours of treatment while doses of other vasopressors were maintained. From Hour 3 to Hour 48, Giapreza or placebo were titrated to maintain MAP between 65 and 70 mmHg while reducing doses of other vasopressors. The primary endpoint was the percentage of subjects who achieved either a MAP ≥ 75 mmHg or a ≥ 10 mmHg increase in MAP without an increase in baseline vasopressor therapy at 3 hours.

91% of subjects had septic shock; the remaining subjects had other forms of distributive shock such as neurogenic shock. At the time of study drug administration, 97% of subjects were receiving norepinephrine, 67% vasopressin, 15% phenylephrine, 13% epinephrine, and 2% dopamine. 83% of subjects had received two or more vasopressors and 47% three or more vasopressors prior to study drug administration. 61% of subjects were male, 80% were White, 10% were Black, and 10% were other races. The median age of subjects was 64 years (range: 22-89 years). Patients requiring high doses of steroids, patients with a history of asthma or bronchospasm, and patients with Raynaud's syndrome were not included.

The primary endpoint was achieved by 70% of patients randomized to Giapreza compared to 23% of placebo subjects; p < 0.0001 (a treatment effect of 47%). Figure 1 shows the results in all patients and in selected subgroups.

Figure 1: ATHOS-3: Primary Endpoint – Overall Result and Results in Selected Subgroups

NE Equiv = norepinephrine equivalent dose: the sum of all vasopressors doses with each vasopressor dose converted to the clinically equivalent norepinephrine dose

Note: The figure above presents effects in various subgroups, all of which are baseline characteristics. The 95% confidence limits that are shown do not take into account the number of comparisons made, and may not reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

In the Giapreza-treated group, the median time to reach the target MAP endpoint was 5 minutes. The effect on MAP was sustained for at least the first three hours of treatment. The median dose of Giapreza was 10 ng/kg/min at 30 minutes. Of the 114 responders at Hour 3, only 2 (1.8%) received more than 80 ng/kg/min.

Patients were not necessarily on maximum doses of other vasopressors at the time of randomization. The effect of Giapreza when added to maximum doses of other vasopressors is unknown.

Mortality through Day 28 was 46% on Giapreza and 54% on placebo (hazard ratio 0.78; 95% confidence interval 0.57 – 1.07).

Giapreza (angiotensin II) Injection is a clear, aqueous solution for administration by intravenous infusion supplied as a single dose vial in two strengths:

· 2.5 mg/mL vial: NDC 68547-501-02: A carton of one 1 mL single dose vial containing 2.5 mg angiotensin II (as a sterile liquid).

· 5 mg/2 mL vial: NDC 68547-002-05: A carton of one 2 mL single dose vial containing 5 mg (2.5 mg/mL) angiotensin II (as a sterile liquid).

. Storage and Handling

· Giapreza vials should be stored in the refrigerator (36-46°F, 2-8°C).

· Discard prepared diluted solution after 24 hours at room temperature or under refrigeration.

Manufactured for:

La Jolla Pharmaceutical Company
San Diego, CA 92121

Revised: 02/2018

La Jolla Pharmaceutical Company