Li Meng Xin

General

Induction and maintenance of anaesthesia or sedation is generally smooth with minimal evidence of excitation. The most commonly reported ADRs are pharmacologically predictable side effects of an anaesthetic/sedative agent, such as hypotension. The nature, severity and incidence of adverse events observed in patients receiving Li Meng Xin 1% may be related to the condition of the recipients and the operative or therapeutic procedures being undertaken.

The following definitions of frequencies are used:

Very common (>1/10), common (>1/100 to <1/10), uncommon ((>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

Table of Adverse Drug Reactions

⁽¹⁾ Serious bradycardias are rare. There have been isolated reports of progression to asystole.

⁽²⁾ Occasionally, hypotension may require use of intravenous fluids and reduction of the administration rate of Li Meng Xin.

⁽³⁾ Very rare reports of rhabdomyolysis have been received where Li Meng Xin has been given at doses greater than 4 mg/kg/hr for ICU sedation.

⁽⁴⁾ May be minimised by using the larger veins of the forearm and antecubital fossa. With Li Meng Xin 1% local pain can also be minimised by the co-administration of lidocaine.

⁽⁶⁾ Brugada-type ECG - elevated ST-segment and coved T-wave in ECG.

⁽⁷⁾ Rapidly progressive cardiac failure (in some cases with fatal outcome) in adults. The cardiac failure in such cases was usually unresponsive to inotropic supportive treatment.

⁽⁸⁾ Abuse of and drug dependence on propofol, predominantly by health care professionals.

⁽⁹⁾ Not known as it cannot be estimated from the available clinical trial data.

⁽¹⁰⁾ Necrosis has been reported where tissue viability has been impaired.

Dystonia/dyskinesia have been reported.

Local

The local pain which may occur during the induction phase of Li Meng Xin 1% anaesthesia can be minimised by the co-administration of lidocaine (see "Dosage and Administration") and by the use of the larger veins of the forearm and antecubital fossa. Thrombosis and phlebitis are rare. Accidental clinical extravasation and animal studies showed minimal tissue reaction. Intra-arterial injection in animals did not induce local tissue effects.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard.

General

Adverse event information is derived from controlled clinical trials and worldwide marketing experience. In the description below, rates of the more common events represent US/Canadian clinical study results. Less frequent events are also derived from publications and marketing experience in over 8 million patients; there are insufficient data to support an accurate estimate of their incidence rates. These studies were conducted using a variety of premedicants, varying lengths of surgical/diagnostic procedures, and various other anesthetic/sedative agents. Most adverse events were mild and transient.

Anesthesia And MAC Sedation In Adults

The following estimates of adverse events for Li Meng Xin injectable emulsion include data from clinical trials in general anesthesia/MAC sedation (N=2889 adult patients). The adverse events listed below as probably causally related are those events in which the actual incidence rate in patients treated with Li Meng Xin injectable emulsion was greater than the comparator incidence rate in these trials. Therefore, incidence rates for anesthesia and MAC sedation in adults generally represent estimates of the percentage of clinical trial patients which appeared to have probable causal relationship.

The adverse experience profile from reports of 150 patients in the MAC sedation clinical trials is similar to the profile established with Li Meng Xin during anesthesia (see below). During MAC sedation clinical trials, significant respiratory events included cough, upper airway obstruction, apnea, hypoventilation, and dyspnea.

Anesthesia In Pediatric Patients

Generally the adverse experience profile from reports of 506 Li Meng Xin injectable emulsion pediatric patients from 6 days through 16 years of age in the US/Canadian anesthesia clinical trials is similar to the profile established with Li Meng Xin injectable emulsion during anesthesia in adults (see Pediatric percentages [Peds %] below). Although not reported as an adverse event in clinical trials, apnea is frequently observed in pediatric patients.

ICU Sedation In Adults

The following estimates of adverse events include data from clinical trials in ICU sedation (N=159 adult patients). Probably related incidence rates for ICU sedation were determined by individual case report form review. Probable causality was based upon an apparent dose response relationship and/or positive responses to rechallenge. In many instances the presence of concomitant disease and concomitant therapy made the causal relationship unknown. Therefore, incidence rates for ICU sedation generally represent estimates of the percentage of clinical trial patients which appeared to have a probable causal relationship.

Incidence greater than 1% - Probably Causally Related

General

Adverse event information is derived from controlled clinical trials and worldwide marketing experience. In the description below, rates of the more common events represent US/Canadian clinical study results. Less frequent events are also derived from publications and marketing experience in over 8 million patients; there are insufficient data to support an accurate estimate of their incidence rates. These studies were conducted using a variety of premedicants, varying lengths of surgical/diagnostic procedures, and various other anesthetic/sedative agents. Most adverse events were mild and transient.

Anesthesia And MAC Sedation In Adults

The following estimates of adverse events for DIPRIVAN Injectable Emulsion include data from clinical trials in general anesthesia/MAC sedation (N=2889 adult patients). The adverse events listed below as probably causally related are those events in which the actual incidence rate in patients treated with DIPRIVAN Injectable Emulsion was greater than the comparator incidence rate in these trials. Therefore, incidence rates for anesthesia and MAC sedation in adults generally represent estimates of the percentage of clinical trial patients which appeared to have probable causal relationship.

The adverse experience profile from reports of 150 patients in the MAC sedation clinical trials is similar to the profile established with DIPRIVAN Injectable Emulsion during anesthesia (see below). During MAC sedation clinical trials, significant respiratory events included cough, upper airway obstruction, apnea, hypoventilation, and dyspnea.

Anesthesia In Pediatric Patients

Generally the adverse experience profile from reports of 506 DIPRIVAN Injectable Emulsion pediatric patients from 6 days through 16 years of age in the US/Canadian anesthesia clinical trials is similar to the profile established with DIPRIVAN Injectable Emulsion during anesthesia in adults (see Pediatric percentages [Peds %] below). Although not reported as an adverse event in clinical trials, apnea is frequently observed in pediatric patients.

ICU Sedation In Adults

The following estimates of adverse events include data from clinical trials in ICU sedation (N=159 adult patients). Probably related incidence rates for ICU sedation were determined by individual case report form review. Probable causality was based upon an apparent dose response relationship and/or positive responses to rechallenge. In many instances the presence of concomitant disease and concomitant therapy made the causal relationship unknown. Therefore, incidence rates for ICU sedation generally represent estimates of the percentage of clinical trial patients which appeared to have a probable causal relationship.

Incidence greater than 1% - Probably Causally Related

Incidence less than 1% - Probably Causally Related

Incidence less than 1% - Causal Relationship Unknown

Drug Abuse And Dependence

There are reports of the abuse of propofol for recreational and other improper purposes, which have resulted in fatalities and other injuries. Instances of self-administration of DIPRIVAN Injectable Emulsion by health care professionals have also been reported, which have resulted in fatalities and other injuries. Inventories of DIPRIVAN Injectable Emulsion should be stored and managed to prevent the risk of diversion, including restriction of access and accounting procedures as appropriate to the clinical setting.

偶発的な過剰摂取は心肺機能低下を引き起こす可能性があります。. 呼吸抑制は、酸素による人工換気によって治療されるべきです。. 心血管うつ病は、患者の頭を下げ、重症の場合は血漿エキスパンダーとプレッサー剤を使用する必要があります。.

過剰摂取が発生した場合は、Li Meng Xin注射可能なエマルジョン投与を直ちに中止する必要があります。. 過剰摂取は心肺機能低下を引き起こす可能性があります。. 呼吸抑制は、酸素による人工換気によって治療されるべきです。. 心血管うつ病は、患者の足を上げ、静脈内液の流量を増やし、プレッサー剤や抗コリン剤を投与することにより、患者の再配置を必要とする場合があります。.

過剰摂取が発生した場合は、DIPRIVAN注射可能な乳 ⁇ 液の投与を直ちに中止する必要があります。. 過剰摂取は心肺機能低下を引き起こす可能性があります。. 呼吸抑制は、酸素による人工換気によって治療されるべきです。. 心血管うつ病は、患者の足を上げ、静脈内液の流量を増やし、プレッサー剤や抗コリン剤を投与することにより、患者の再配置を必要とする場合があります。.

Pharmacotherapeutic group: Other general anaesthetics

ATC code: N01AX10

Mechanism of action

Propofol (2, 6-diisopropylphenol) is a short-acting general anaesthetic agent with a rapid onset of action of approximately 30 seconds. Recovery from anaesthesia is usually rapid. The mechanism of action, like all general anaesthetics, is poorly understood. However, propofol is thought to produce its sedative/anaesthetic effects by the positive modulation of the inhibitory function of the neurotransmitter GABA through the ligand-gated GABA_A receptors.

Pharmacodynamic properties

In general, falls in mean arterial blood pressure and slight changes in heart rate are observed when Li Meng Xin 1% is administered for induction and maintenance of anaesthesia. However, the haemodynamic parameters normally remain relatively stable during maintenance and the incidence of untoward haemodynamic changes is low.

Although ventilatory depression can occur following administration of Li Meng Xin 1%, any effects are qualitatively similar to those of other intravenous anaesthetic agents and are readily manageable in clinical practice.

Li Meng Xin 1% reduces cerebral blood flow, intracranial pressure and cerebral metabolism. The reduction in intracranial pressure is greater in patients with an elevated baseline intracranial pressure.

Clinical efficacy and safety

Recovery from anaesthesia is usually rapid and clear headed with a low incidence of headache and post-operative nausea and vomiting.

In general, there is less post-operative nausea and vomiting following anaesthesia with Li Meng Xin 1% than following anaesthesia with inhalational agents. There is evidence that this may be related to a reduced emetic potential of propofol.

Li Meng Xin 1%, at the concentrations likely to occur clinically, does not inhibit the synthesis of adrenocortical hormones.

Paediatric population

Limited studies on the duration of propofol based anaesthesia in children indicate safety and efficacy is unchanged up to duration of 4 hours. Literature evidence of use in children documents use for prolonged procedures without changes in safety or efficacy.

Pharmacodynamic properties of Li Meng Xin are dependent upon the therapeutic blood Li Meng Xin concentrations. Steady-state Li Meng Xin blood concentrations are generally proportional to infusion rates. Undesirable side effects such as cardiorespiratory depression are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in infusion rates. An adequate interval (3 to 5 minutes) must be allowed between dosage adjustments in order to assess clinical effects.

The hemodynamic effects of Li Meng Xin injectable emulsion during induction of anesthesia vary. If spontaneous ventilation is maintained, the major cardiovascular effect is arterial hypotension (sometimes greater than a 30% decrease) with little or no change in heart rate and no appreciable decrease in cardiac output. If ventilation is assisted or controlled (positive pressure ventilation), there is an increase in the incidence and the degree of depression of cardiac output. Addition of an opioid, used as a premedicant, further decreases cardiac output and respiratory drive.

If anesthesia is continued by infusion of Li Meng Xin injectable emulsion, the stimulation of endotracheal intubation and surgery may return arterial pressure towards normal. However, cardiac output may remain depressed. Comparative clinical studies have shown that the hemodynamic effects of Li Meng Xin injectable emulsion during induction of anesthesia are generally more pronounced than with other intravenous (I.V.) induction agents.

Induction of anesthesia with Li Meng Xin injectable emulsion is frequently associated with apnea in both adults and pediatric patients. In adult patients who received Li Meng Xin injectable emulsion (2 to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30 to 60 seconds in 24% of patients, and more than 60 seconds in 12% of patients. In pediatric patients from birth through 16 years of age assessable for apnea who received bolus doses of Li Meng Xin injectable emulsion (1 to 3.6 mg/kg), apnea lasted less than 30 seconds in 12% of patients, 30 to 60 seconds in 10% of patients, and more than 60 seconds in 5% of patients.

During maintenance of general anesthesia, Li Meng Xin injectable emulsion causes a decrease in spontaneous minute ventilation usually associated with an increase in carbon dioxide tension which may be marked depending upon the rate of administration and concurrent use of other medications (e.g., opioids, sedatives, etc.).

During monitored anesthesia care (MAC) sedation, attention must be given to the cardiorespiratory effects of Li Meng Xin injectable emulsion. Hypotension, oxyhemoglobin desaturation, apnea, and airway obstruction can occur, especially following a rapid bolus of Li Meng Xin injectable emulsion. During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus administration in order to minimize undesirable cardiorespiratory effects. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).

Clinical and preclinical studies suggest that Li Meng Xin injectable emulsion is rarely associated with elevation of plasma histamine levels.

Preliminary findings in patients with normal intraocular pressure indicate that Li Meng Xin injectable emulsion produces a decrease in intraocular pressure which may be associated with a concomitant decrease in systemic vascular resistance.

Clinical studies indicate that Li Meng Xin injectable emulsion when used in combination with hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. Li Meng Xin injectable emulsion does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension (see Clinical Trials - Neuroanesthesia).

Clinical studies indicate that Li Meng Xin injectable emulsion does not suppress the adrenal response to ACTH.

Animal studies and limited experience in susceptible patients have not indicated any propensity of Li Meng Xin injectable emulsion to induce malignant hyperthermia.

Hemosiderin deposits have been observed in the livers of dogs receiving Li Meng Xin injectable emulsion containing 0.005% disodium edetate over a four-week period; the clinical significance of this is unknown.

Pharmacodynamic properties of propofol are dependent upon the therapeutic blood propofol concentrations. Steady-state propofol blood concentrations are generally proportional to infusion rates. Undesirable side effects, such as cardiorespiratory depression, are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in infusion rates. An adequate interval (3 to 5 minutes) must be allowed between dose adjustments in order to assess clinical effects.

The hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of anesthesia vary. If spontaneous ventilation is maintained, the major cardiovascular effect is arterial hypotension (sometimes greater than a 30% decrease) with little or no change in heart rate and no appreciable decrease in cardiac output. If ventilation is assisted or controlled (positive pressure ventilation), there is an increase in the incidence and the degree of depression of cardiac output. Addition of an opioid, used as a premedicant, further decreases cardiac output and respiratory drive.

If anesthesia is continued by infusion of DIPRIVAN Injectable Emulsion, the stimulation of endotracheal intubation and surgery may return arterial pressure towards normal. However, cardiac output may remain depressed. Comparative clinical studies have shown that the hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of anesthesia are generally more pronounced than with other intravenous (IV) induction agents.

Induction of anesthesia with DIPRIVAN Injectable Emulsion is frequently associated with apnea in both adults and pediatric patients. In adult patients who received DIPRIVAN Injectable Emulsion (2 to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30 to 60 seconds in 24% of patients, and more than 60 seconds in 12% of patients. In pediatric patients from birth through 16 years of age assessable for apnea who received bolus doses of DIPRIVAN Injectable Emulsion (1 to 3.6 mg/kg), apnea lasted less than 30 seconds in 12% of patients, 30 to 60 seconds in 10% of patients, and more than 60 seconds in 5% of patients.

During maintenance of general anesthesia, DIPRIVAN Injectable Emulsion causes a decrease in spontaneous minute ventilation usually associated with an increase in carbon dioxide tension which may be marked depending upon the rate of administration and concurrent use of other medications (e.g., opioids, sedatives, etc.).

During monitored anesthesia care (MAC) sedation, attention must be given to the cardiorespiratory effects of DIPRIVAN Injectable Emulsion. Hypotension, oxyhemoglobin desaturation, apnea, and airway obstruction can occur, especially following a rapid bolus of DIPRIVAN Injectable Emulsion. During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus administration in order to minimize undesirable cardiorespiratory effects. In the elderly, debilitated, or ASAPS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).

Clinical and preclinical studies suggest that DIPRIVAN Injectable Emulsion is rarely associated with elevation of plasma histamine levels.

Preliminary findings in patients with normal intraocular pressure indicate that DIPRIVAN Injectable Emulsion produces a decrease in intraocular pressure which may be associated with a concomitant decrease in systemic vascular resistance.

Clinical studies indicate that DIPRIVAN Injectable Emulsion when used in combination with hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. DIPRIVAN Injectable Emulsion does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension (see Clinical Trials, Neuroanesthesia).

Clinical studies indicate that DIPRIVAN Injectable Emulsion does not suppress the adrenal response to ACTH.

Animal studies and limited experience in susceptible patients have not indicated any propensity of DIPRIVAN Injectable Emulsion to induce malignant hyperthermia.

Hemosiderin deposits have been observed in the livers of dogs receiving DIPRIVAN Injectable Emulsion containing 0.005% disodium edetate over a four-week period; the clinical significance of this is unknown.

吸収。

Li Meng Xin 1%を使用して麻酔を維持すると、血中濃度が所定の投与率の定常状態値に ⁇ 近的に近づきます。.

分布。

プロポフォールは広範囲に分布し、体から急速に除去されます(総体クリアランス1.5〜2リットル/分)。.

除去。

ボーラス投与後または注入終了後のプロポフォール濃度の低下は、非常に急速に分布する3コンパートメントオープンモデルで説明できます。 (半減期2〜4分。) 迅速な排除。 (半減期30〜60分。) そして遅い最終段階。, ⁇ 流不良の組織からのプロポフォールの再配布の代表。.

クリアランスは、主に血流に依存する肝臓で代謝プロセスによって発生し、尿中に排 ⁇ されるプロポフォールとそれに対応するキノールの不活性な抱合体を形成します。.

3 mg / kgを静脈内投与した後、プロポフォールクリアランス/ kg体重は次のように年齢とともに増加しました:クリアランスの中央値は、1か月未満の新生児(n = 25)(20 ml / kg / min)で、年長児と比較してかなり低かった(n = 36、年齢範囲は4か月〜7年)。. さらに、新生児では個人間のばらつきがかなりありました(範囲3.7〜78 ml / kg / min)。. 大きな変動を示すこの限られた試験データのため、この年齢層に対して推奨用量を与えることはできません。.

3 mg / kgボーラス1回投与後の高齢の子供のプロポフォールクリアランスの中央値は、37.5 ml / min / kg(4-24か月)(n = 8)、38.7 ml / min / kg(11-43か月)(n = 6)、48 ml / min / kg(1〜3年)(n = 12 kg / n.

直線性。

薬物動態は、Li Meng Xin 1%の推奨注入率範囲にわたって直線的です。.

小児患者では、長期注入後の突然の中止により、手足の紅潮、興奮、震え、過敏症を引き起こす可能性があります。. 徐脈の発生率の増加(5%)、興奮(4%)、および震え(9%)も観察されています。.

この製品の成分であるベンジルアルコールは、特に小児患者において、深刻な有害事象と死亡と関連しています。. 「あえぎ症候群」(中枢神経系のうつ病、代謝性アシドーシス、あえぎ呼吸、血と尿に含まれる高レベルのベンジルアルコールとその代謝物によって特徴付けられる)は、ベンジルアルコール投与量> 99 mg / kg /日に関連しています新生児および低出生体重新生児。. 追加の症状には、 ⁇ 進的な神経学的悪化、発作、頭蓋内出血、血液異常、皮膚の破壊、肝不全および腎不全、低血圧、徐脈、心血管虚脱などがあります。.

この製品の通常の治療用量は、「あえぎ症候群」に関連して報告された量よりも大幅に低いベンジルアルコールの量を提供しますが、毒性が発生する可能性のあるベンジルアルコールの最小量は不明です。. 早産および低産体重の乳児、ならびに高用量を受けている患者は、毒性を発現する可能性が高くなります。. これとベンジルアルコールを含む他の薬を投与する開業医は、すべてのソースからのベンジルアルコールの毎日の代謝負荷の合計を考慮する必要があります。.

老人用。

Li Meng Xinの誘導線量要件に対する年齢の影響は、16歳から80歳までの各10年間に約30人の患者を抱える211人の非治療患者を対象とした非盲検研究で評価されました。. 麻酔を誘発するための平均線量は、54歳までの患者と55歳以上の患者について計算されました。. 54歳までの患者に麻酔を誘発する平均用量は1.99 mg / kgであり、54歳以上の患者では1.66 mg / kgでした。. その後の臨床試験では、60歳以上の被験者の投与要件が低いことが示されています。.

高齢患者では、誘導線量を減らし、投与の維持速度を遅くする必要があります。. この患者グループでは、低血圧、無呼吸、気道閉塞、および/または酸素の脱飽和などの望ましくない心肺機能低下を最小限に抑えるために、急速な(単一または反復)ボーラス投与を使用しないでください。. すべての投与量は、患者の状態と反応に応じて滴定する必要があります。. (見る。 投与量と投与。 -。 高齢者、衰弱またはASA-PS IIIまたはIV患者。 と。 臨床薬理学。 -。 老年医学。.)

過剰摂取。

過剰摂取が発生した場合は、Li Meng Xin注射可能なエマルジョン投与を直ちに中止する必要があります。. 過剰摂取は心肺機能低下を引き起こす可能性があります。. 呼吸抑制は、酸素による人工換気によって治療されるべきです。. 心血管うつ病は、患者の足を上げ、静脈内液の流量を増やし、プレッサー剤や抗コリン剤を投与することにより、患者の再配置を必要とする場合があります。.

禁 ⁇ 。

Li Meng Xin注射可能なエマルジョンは、Li Meng Xin注射可能なエマルジョンまたはそのコンポーネントのいずれかに対する過敏症が知られている患者には禁 ⁇ です。.

Li Meng Xin注射可能な乳剤は、卵、卵製品、大豆または大豆製品に対するアレルギーのある患者には禁 ⁇ です。.

臨床薬理学。

一般的な。

Li Meng Xinは、麻酔または鎮静の誘導および維持に使用するための静脈内鎮静催眠剤です。. Li Meng Xinの治療用量の静脈内注射は、通常、注射の開始から40秒以内(1つの腕脳循環の時間)に、最小限の興奮で催眠術を誘発します。. 他の急速に行動する静脈内麻酔薬と同様に、血液脳平衡のハーフタイムは約1〜3分で、麻酔の誘導率を占めます。.

薬力学。

Li Meng Xinの薬力学的特性は、治療用血中Li Meng Xin濃度に依存します。. 定常状態のLi Meng Xin血中濃度は、一般的に注入率に比例します。. 心肺機能低下などの望ましくない副作用は、ボーラス投与または注入速度の急速な増加に起因する高血中濃度で発生する可能性があります。. 臨床効果を評価するために、投与量調整の間に適切な間隔(3〜5分)を許可する必要があります。.

麻酔導入時のLi Meng Xin注射可能な乳 ⁇ 液の血行力学的効果はさまざまです。. 自然換気が維持されている場合、主要な心血管効果は、心拍数の変化がほとんどないかまったくなく、心拍出量が大幅に減少しない動脈低血圧(30%減少する場合があります)です。. 換気が補助または制御されている場合(正圧換気)、心臓出力の発生率と抑制の度合いが増加します。. プレメディカントとして使用されるオピオイドを追加すると、心臓の出力と呼吸ドライブがさらに減少します。.

Li Meng Xin注射可能なエマルジョンの注入によって麻酔が継続される場合、気管内挿管および手術の刺激により、動脈圧が正常に戻る可能性があります。. ただし、心臓の出力は低下したままになる場合があります。. 比較臨床試験では、麻酔導入時のLi Meng Xin注射可能な乳 ⁇ 液の血行力学的効果は、他の静脈内(I.V.)誘導剤よりも一般的に顕著であることが示されています。.

Li Meng Xin注射可能な乳 ⁇ 液による麻酔の誘導は、成人および小児患者の両方で無呼吸と頻繁に関連しています。. Li Meng Xin注射可能な乳 ⁇ 液(2〜2.5 mg / kg)を受けた成人患者では、無呼吸は患者の7%で30秒未満、患者の24%で30〜60秒、12%で60秒以上続きました。患者。. ⁇ Meng Xin注射可能な乳 ⁇ 液をボーラス投与された無呼吸について評価可能な、誕生から16歳までの小児患者。 (1〜3.6 mg / kg。) 無呼吸は患者の12%で30秒未満続きました。, 患者の10%で30〜60秒。, 患者の5%で60秒以上。.

全身麻酔の維持中、Li Meng Xin注射可能な乳 ⁇ 液は、通常、二酸化炭素張力の増加に関連する自然分換気の減少を引き起こします。これは、投与率と他の薬物の同時使用に応じてマークされる場合があります(例:.、オピオイド、鎮静剤など.)。.

監視された麻酔ケア(MAC)鎮静中、Li Meng Xin注射可能な乳 ⁇ 液の心肺効果に注意を払う必要があります。. 低血圧、オキシヘモグロビン脱飽和、無呼吸、気道閉塞が発生する可能性があり、特にLi Meng Xin注射可能なエマルジョンの急速なボーラス投与後に発生します。. MAC鎮静の開始中、遅い注入または遅い注射技術が迅速なボーラス投与よりも好ましいです。. MAC鎮静の維持中、望ましくない心肺効果を最小限に抑えるために、間欠的ボーラス投与よりも可変速注入が望ましいです。. 高齢者、衰弱、またはASA-PS IIIまたはIV患者では、MAC鎮静には急速(単一または反復)ボーラス投与を使用しないでください(参照)。 警告。).

臨床および前臨床試験では、Li Meng Xin注射可能なエマルジョンが血漿ヒスタミンレベルの上昇と関連することはめったにないことが示唆されています。.

正常な眼圧の患者の予備調査結果は、Li Meng Xin注射可能なエマルジョンが眼圧の低下を引き起こし、全身血管抵抗の付随する低下に関連している可能性があることを示しています。.

臨床研究では、低炭症と組み合わせて使用 すると、Li Meng Xin注射可能なエマルジョンが脳血管抵抗を高め、脳血流、脳代謝酸素消費量、および頭蓋内圧を低下させることが示されています。. Li Meng Xin注射可能なエマルジョンは、動脈二酸化炭素張力の変化に対する脳血管反応性に影響を与えません(参照)。 臨床試験。 -。 神経麻酔。).

臨床試験では、Li Meng Xin注射可能なエマルションはACTHに対する副腎反応を抑制しないことが示されています。

動物実験および感受性の高い患者での限られた経験は、悪性高体温を誘発するLi Meng Xin注射可能な乳 ⁇ 液の傾向を示していません。.

ヘモシデリン沈着物は、4週間にわたって0.005%エデト酸二ナトリウムを含むLi Meng Xin注射エマルジョンを受けている犬の肝臓で観察されています。これの臨床的意義は不明です。.

薬物動態。

Li Meng Xinの薬物動態は、血漿、急速平衡組織、およびゆっくり平衡化組織を表すコンパートメントを備えた3コンパートメント線形モデルによってよく説明されています。.

I.V.ボーラス投与では、血漿と脳の間に急速な平衡があり、麻酔の急速な発症を説明しています。. 血漿レベルは、分布と代謝クリアランスの両方の結果として、最初は急速に低下します。. Li Meng Xinのボーラスに続いて、分布はこの減少の約半分を占めます。.

ただし、分布は時間とともに一定ではありませんが、体組織が血漿と平衡化して飽和するにつれて減少します。. 平衡化が発生する速度は、注入の速度と持続時間の関数です。. 平衡化が発生すると、組織と血漿の間でLi Meng Xinの正味の移動がなくなります。.

約1時間麻酔を維持した後、またはICUで1日間鎮静した後、推奨用量のLi Meng Xin注射可能なエマルジョンを中止すると、血中Li Meng Xin濃度が急速に低下し、急速に覚 ⁇ します。. より長い注入(ICU鎮静の10日間)は、Li Meng Xinの重要な組織貯蔵の蓄積をもたらし、循環するLi Meng Xinの減少が遅くなり、覚 ⁇ までの時間が増加します。.

最小有効治療濃度のみを達成するためにLi Meng Xin注射可能なエマルジョン投与量を毎日滴定することにより、長期投与後でも10〜15分以内に急速な覚 ⁇ が発生する可能性があります。. ただし、必要以上の注入レベルが長期間維持されている場合、脂肪と筋肉から血漿へのLi Meng Xinの再分布は、有意でゆっくりとした回復になる可能性があります。.

以下の図は、ICU鎮静を提供するためにさまざまな期間の注入後の血漿リーメンシンレベルの低下を示しています。.

短時間の注入後のLi Meng Xin血漿レベルの低下に対する分布の大きな寄与(約50%)は、非常に長い注入後、一定の注入を維持するために、注入速度の半分だけ注入速度を下げることが適切であることを意味します血漿レベル。. したがって、Li Meng Xin注射可能なエマルジョンを長期間投与されている患者の注入速度を低下させることができないと、薬物の血中濃度が過度に高くなる可能性があります。. したがって、ICU鎮静のためのLi Meng Xin注射可能なエマルジョン注入の使用中、臨床反応への滴定と鎮静レベルの毎日の評価は重要です。.

大人。

Li Meng Xinクリアランスは23〜50 mL / kg / minの範囲です(70 kgの成人では1.6〜3.4 L / min)。. それは主に腎臓から排 ⁇ される不活性代謝物への肝抱合によって排除されます。. グルクロニド抱合体は、投与量の約50%を占めます。. Li Meng Xinは、健康な成人の分布量が60 L / kgに近い定常状態の分布量(10日間の注入)を持っています。. 性別による薬物動態の違いは観察されていません。. 10日間の注入後のLi Meng Xinの最終半減期は1〜3日です。.

老年医学。

患者の年齢が上がるにつれて、定義された麻酔エンドポイント(用量要件)を達成するために必要なLi Meng Xinの用量が減少します。. これは、EEGバースト抑制によって測定されるように、薬力学や脳感受性の加齢に伴う変化ではないようです。. 患者の年齢が上がると、薬物動態の変化により、特定のI.V.ボーラス投与量では、より高いピーク血漿濃度が発生し、これは減量要件を説明できます。. 高齢者におけるこれらのより高いピーク血漿濃度は、低血圧、無呼吸、気道閉塞、および/または動脈酸素脱飽和を含む心肺効果に患者を素因にする可能性があります。. より高い血漿レベルは、分布の体積と部門間のクリアランスの加齢に伴う減少を反映しています。. したがって、高齢患者の鎮静および麻酔の開始と維持には、低用量が推奨されます。. (見る。 投与量と投与。.)

小児科。

Li Meng Xinの薬物動態は、約1〜2時間Li Meng Xin注射可能な乳 ⁇ 液を投与された3〜12歳の子供を対象に研究されました。. これらの子供で観察されたLi Meng Xinの分布とクリアランスは大人に似ていました。.

臓器不全。

Li Meng Xinの薬物動態は、正常な肝機能および腎機能を持つ成人と比較して、慢性肝硬変または慢性腎機能障害のある人では異ならないようです。. Li Meng Xinの薬物動態に対する急性肝不全または腎不全の影響は研究されていません。.

臨床試験。

麻酔および監視麻酔ケア(MAC)鎮静。

小児麻酔。

Li Meng Xin注射可能な乳 ⁇ 液は、心臓外科患者を含む臨床試験で研究されました。. ほとんどの患者は3歳以上でした。. 患者の大多数は健康なASA-PS IまたはII患者でした。. これらの研究における投与量の範囲を表1および2に示します。.

表1:麻酔の小児科。

表2:麻酔の小児科的メンテナンス。

神経麻酔。

Li Meng Xin注射可能な乳 ⁇ 液は、2つの臨床試験で上膜腫瘍の開頭術を受けている患者で研究されました。. 平均病変サイズ(前/後x側)は、1回の試行でそれぞれ31 mm x 32 mm、もう1回の試行で55 mm x 42 mmでした。. 麻酔は、1.4 mg / kgの中央値Li Meng Xin用量(範囲:0.9〜6.9 mg / kg)で誘発され、中央値維持Li Meng Xin用量146 mcg / kg / min(範囲:68〜425 mcg / kg / min)。. Li Meng Xinメンテナンス注入の持続時間の中央値は285分(範囲:48〜622分)でした。.

Li Meng Xin注射可能なエマルジョンは、脳脊髄液圧(CSFP)への影響を評価するために、制御された臨床試験で注入によって投与されました。. 平均動脈圧は25分間で比較的一定に維持され、ベースラインからの変化は-4%±17%(平均±SD)でした。. CSFPの変化は-46%±14%でした。. CSFPは頭蓋内圧(ICP)の間接的な ⁇ 度であるため、Li Meng Xin注射可能なエマルジョンは、注入または低炭 ⁇ と低速ボーラスによって投与された場合、動脈圧の変化に関係なくICPを低下させることができます。.

集中治療室(ICU)鎮静。

成人患者。

ICU患者を対象とした臨床試験で、Li Meng Xin注射可能なエマルジョンをベンゾジアゼピンおよびオピオイドと比較しました。. これらのうち、302はLi Meng Xin注射可能なエマルジョンを受け取り、ICU鎮静の全体的な安全データベースを構成しています。.

すべての臨床試験において、すべてのLi Meng Xin注射可能なエマルジョン患者の平均注入維持率は27±21 mcg / kg / minでした。. 適切な鎮静を維持するために必要な維持注入速度は、2.8 mcg / kg / minから130 mcg / kg / minの範囲でした。. 55歳以上の患者(約20 mcg / kg / min)の注入率は、55歳未満の患者(約38 mcg / kg / min)と比較して低かった。. 鎮痛要件の減少の報告がありますが、ほとんどの患者はICU鎮静の維持中に鎮痛のためのオピオイドを受けました。. これらの研究では、鎮痛のために必要に応じてモルヒネまたはフェンタニルを使用しました。. 一部の患者は、ベンゾジアゼピンおよび/または神経筋遮断薬も投与されました。. 鎮静の長期維持中に、一部のICU患者は神経機能または呼吸機能の評価のために24時間に1回または2回覚 ⁇ されました。.

Li Meng Xin注射可能なエマルジョンをベンゾジアゼピン注入またはボーラスと比較した医学および術後のICU研究では、適切な鎮静、平均動脈圧、または検査所見の維持に明らかな違いはありませんでした。. コンパレータと同様に、Li Meng Xin注射可能なエマルションは、副腎皮質刺激ホルモン(ACTH)の課題に対する責任を維持しながら、鎮静中の血中コルチゾールを減少させました。. 発表された文献の症例報告は一般に、ポルフィリンまたは悪性高体温の病歴のある患者では、Li Meng Xin注射可能な乳 ⁇ 液が安全に使用されたことを反映しています。.

19歳から43歳までの血行力学的に安定した頭部外傷患者では、Li Meng Xin注射可能なエマルジョンまたはモルヒネで適切な鎮静が維持されました。. 治療群間で、鎮静、頭蓋内圧、脳 ⁇ 流圧、または神経学的回復の妥当性に明らかな違いはありませんでした。. 脳 ⁇ 流ICUの重度の頭部損傷患者の文献レポートでは、利尿薬の有無にかかわらず、Li Meng Xin注射可能な乳 ⁇ 液注入と過換気により、脳 ⁇ 流圧力を維持しながら頭蓋内圧が制御されました。. 一部の患者では、ボーラス投与により血圧が低下し、脳 ⁇ 流圧力が低下しました。.

Li Meng Xin注射可能な乳 ⁇ 液は、標準的な抗けいれん療法に反射するてんかん重積に有効であることが判明しました。. これらの患者、ならびにARDS /呼吸不全および破傷風患者の場合、鎮静維持投与量は一般に他の重症患者集団の投与量よりも高かった。.

小児患者。

Li Meng Xinと標準鎮静剤(SSA)の安全性と有効性を評価する単一の無作為化対照臨床試験が、327人の小児ICU患者に対して実施されました。. 患者は無作為化され、Li Meng Xin 2%(113人の患者)、Li Meng Xin 1%(109人の患者)、またはSSA(例:.、ロラゼパム、抱水クロラール、フェンタニル、ケタミン、モルヒネ、またはフェノバルビタール)。. Li Meng Xin療法は、5.5 mg / kg / hrの注入速度で開始され、必要に応じて鎮静を標準化されたレベルに維持するために滴定されました。. 研究の結果は、SSAと比較してLi Meng Xinで治療された患者の死亡数の増加を示しました。. 試験中または28日間のフォローアップ期間内に死亡した25人の患者のうち、Li Meng Xin 2%治療グループで12人(11%)、Li Meng Xin 1%治療で9人(8%)グループ、および4%はSSA治療グループ(4%)でした。. グループ間の死亡率の違いは統計的に有意ではありませんでした。. 死亡のレビューでは、基礎疾患の状態との相関関係、薬物との相関関係、または死因の決定的なパターンを明らかにできませんでした。.

Cardiac Anesthesia

Li Meng Xin injectable emulsion was evaluated in clinical trials involving patients undergoing coronary artery bypass graft (CABG).

In post-CABG (coronary artery bypass graft) patients, the maintenance rate of Li Meng Xin administration was usually low (median 11 mcg/kg/min) due to the intraoperative administration of high opioid doses. Patients receiving Li Meng Xin injectable emulsion required 35% less nitroprusside than midazolam patients. During initiation of sedation in post-CABG patients, a 15% to 20% decrease in blood pressure was seen in the first 60 minutes. It was not possible to determine cardiovascular effects in patients with severely compromised ventricular function.

In pediatric patients, abrupt discontinuation of DIPRIVAN Injectable Emulsion following prolonged infusion may result in flushing of the hands and feet, agitation, tremulousness and hyperirritability. Increased incidences of bradycardia (5%), agitation (4%), and jitteriness (9%) have also been observed.

Geriatric Use

The effect of age on induction dose requirements for propofol was assessed in an open-label study involving 211 unpremedicated patients with approximately 30 patients in each decade between the ages of 16 and 80. The average dose to induce anesthesia was calculated for patients up to 54 years of age and for patients 55 years of age or older. The average dose to induce anesthesia in patients up to 54 years of age was 1.99 mg/kg and in patients above 54 it was 1.66 mg/kg. Subsequent clinical studies have demonstrated lower dosing requirements for subjects greater than 60 years of age.

A lower induction dose and a slower maintenance rate of administration of DIPRIVAN Injectable Emulsion should be used in elderly patients. In this group of patients, rapid (single or repeated) bolus administration should not be used in order to minimize undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation. All dosing should be titrated according to patient condition and response (see DOSAGE AND ADMINISTRATION, Elderly, Debilitated or ASA-PS III or IV Patients and CLINICAL PHARMACOLOGY, Geriatrics).

OVERDOSE

If overdosage occurs, DIPRIVAN Injectable Emulsion administration should be discontinued immediately. Overdosage is likely to cause cardiorespiratory depression. Respiratory depression should be treated by artificial ventilation with oxygen. Cardiovascular depression may require repositioning of the patient by raising the patient's legs, increasing the flow rate of intravenous fluids, and administering pressor agents and/or anticholinergic agents.

CONTRAINDICATIONS

DIPRIVAN Injectable Emulsion is contraindicated in patients with a known hypersensitivity to propofol or any of DIPRIVAN Injectable Emulsion components.

DIPRIVAN Injectable Emulsion is contraindicated in patients with allergies to eggs, egg products, soybeans or soy products.

CLINICAL PHARMACOLOGY

General

DIPRIVAN Injectable Emulsion is an intravenous sedative-hypnotic agent for use in the induction and maintenance of anesthesia or sedation. Intravenous injection of a therapeutic dose of propofol induces hypnosis, with minimal excitation, usually within 40 seconds from the start of injection (the time for one arm-brain circulation). As with other rapidly acting intravenous anesthetic agents, the half-time of the blood-brain equilibration is approximately 1 to 3 minutes, accounting for the rate of induction of anesthesia. The mechanism of action, like all general anesthetics, is poorly understood. However, propofol is thought to produce its sedative/anesthetic effects by the positive modulation of the inhibitory function of the neurotransmitter GABA through the ligand-gated GABAa receptors.

Pharmacodynamics

Pharmacodynamic properties of propofol are dependent upon the therapeutic blood propofol concentrations. Steady-state propofol blood concentrations are generally proportional to infusion rates. Undesirable side effects, such as cardiorespiratory depression, are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in infusion rates. An adequate interval (3 to 5 minutes) must be allowed between dose adjustments in order to assess clinical effects.

The hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of anesthesia vary. If spontaneous ventilation is maintained, the major cardiovascular effect is arterial hypotension (sometimes greater than a 30% decrease) with little or no change in heart rate and no appreciable decrease in cardiac output. If ventilation is assisted or controlled (positive pressure ventilation), there is an increase in the incidence and the degree of depression of cardiac output. Addition of an opioid, used as a premedicant, further decreases cardiac output and respiratory drive.

If anesthesia is continued by infusion of DIPRIVAN Injectable Emulsion, the stimulation of endotracheal intubation and surgery may return arterial pressure towards normal. However, cardiac output may remain depressed. Comparative clinical studies have shown that the hemodynamic effects of DIPRIVAN Injectable Emulsion during induction of anesthesia are generally more pronounced than with other intravenous (IV) induction agents.

Induction of anesthesia with DIPRIVAN Injectable Emulsion is frequently associated with apnea in both adults and pediatric patients. In adult patients who received DIPRIVAN Injectable Emulsion (2 to 2.5 mg/kg), apnea lasted less than 30 seconds in 7% of patients, 30 to 60 seconds in 24% of patients, and more than 60 seconds in 12% of patients. In pediatric patients from birth through 16 years of age assessable for apnea who received bolus doses of DIPRIVAN Injectable Emulsion (1 to 3.6 mg/kg), apnea lasted less than 30 seconds in 12% of patients, 30 to 60 seconds in 10% of patients, and more than 60 seconds in 5% of patients.

During maintenance of general anesthesia, DIPRIVAN Injectable Emulsion causes a decrease in spontaneous minute ventilation usually associated with an increase in carbon dioxide tension which may be marked depending upon the rate of administration and concurrent use of other medications (e.g., opioids, sedatives, etc.).

During monitored anesthesia care (MAC) sedation, attention must be given to the cardiorespiratory effects of DIPRIVAN Injectable Emulsion. Hypotension, oxyhemoglobin desaturation, apnea, and airway obstruction can occur, especially following a rapid bolus of DIPRIVAN Injectable Emulsion. During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus administration in order to minimize undesirable cardiorespiratory effects. In the elderly, debilitated, or ASAPS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).

Clinical and preclinical studies suggest that DIPRIVAN Injectable Emulsion is rarely associated with elevation of plasma histamine levels.

Preliminary findings in patients with normal intraocular pressure indicate that DIPRIVAN Injectable Emulsion produces a decrease in intraocular pressure which may be associated with a concomitant decrease in systemic vascular resistance.

Clinical studies indicate that DIPRIVAN Injectable Emulsion when used in combination with hypocarbia increases cerebrovascular resistance and decreases cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure. DIPRIVAN Injectable Emulsion does not affect cerebrovascular reactivity to changes in arterial carbon dioxide tension (see Clinical Trials, Neuroanesthesia).

Clinical studies indicate that DIPRIVAN Injectable Emulsion does not suppress the adrenal response to ACTH.

Animal studies and limited experience in susceptible patients have not indicated any propensity of DIPRIVAN Injectable Emulsion to induce malignant hyperthermia.

Hemosiderin deposits have been observed in the livers of dogs receiving DIPRIVAN Injectable Emulsion containing 0.005% disodium edetate over a four-week period; the clinical significance of this is unknown.

Pharmacokinetics

The pharmacokinetics of propofol are well described by a three compartment linear model with compartments representing the plasma, rapidly equilibrating tissues, and slowly equilibrating tissues.

Following an IV bolus dose, there is rapid equilibration between the plasma and the brain, accounting for the rapid onset of anesthesia. Plasma levels initially decline rapidly as a result of both distribution and metabolic clearance. Distribution accounts for about half of this decline following a bolus of propofol. However, distribution is not constant over time, but decreases as body tissues equilibrate with plasma and become saturated. The rate at which equilibration occurs is a function of the rate and duration of the infusion. When equilibration occurs there is no longer a net transfer of propofol between tissues and plasma.

Discontinuation of the recommended doses of DIPRIVAN Injectable Emulsion after the maintenance of anesthesia for approximately one hour, or for sedation in the ICU for one day, results in a prompt decrease in blood propofol concentrations and rapid awakening. Longer infusions (10 days of ICU sedation) result in accumulation of significant tissue stores of propofol, such that the reduction in circulating propofol is slowed and the time to awakening is increased.

By daily titration of DIPRIVAN Injectable Emulsion dosage to achieve only the minimum effective therapeutic concentration, rapid awakening within 10 to 15 minutes can occur even after long-term administration. If, however, higher than necessary infusion levels have been maintained for a long time, propofol redistribution from fat and muscle to the plasma can be significant and slow recovery.

The figure below illustrates the fall of plasma propofol levels following infusions of various durations to provide ICU sedation.

The large contribution of distribution (about 50%) to the fall of propofol plasma levels following brief infusions means that after very long infusions a reduction in the infusion rate is appropriate by as much as half the initial infusion rate in order to maintain a constant plasma level. Therefore, failure to reduce the infusion rate in patients receiving DIPRIVAN Injectable Emulsion for extended periods may result in excessively high blood concentrations of the drug. Thus, titration to clinical response and daily evaluation of sedation levels are important during use of DIPRIVAN Injectable Emulsion infusion for ICU sedation.

Adults

Propofol clearance ranges from 23 to 50 mL/kg/min (1.6 to 3.4 L/min in 70 kg adults). It is chiefly eliminated by hepatic conjugation to inactive metabolites which are excreted by the kidney. A glucuronide conjugate accounts for about 50% of the administered dose. Propofol has a steady-state volume of distribution (10-day infusion) approaching 60 L/kg in healthy adults. A difference in pharmacokinetics due to gender has not been observed. The terminal half-life of propofol after a 10-day infusion is 1 to 3 days.

Geriatrics

With increasing patient age, the dose of propofol needed to achieve a defined anesthetic end point (dose-requirement) decreases. This does not appear to be an age-related change in pharmacodynamics or brain sensitivity, as measured by EEG burst suppression. With increasing patient age, pharmacokinetic changes are such that, for a given IV bolus dose, higher peak plasma concentrations occur, which can explain the decreased dose requirement. These higher peak plasma concentrations in the elderly can predispose patients to cardiorespiratory effects including hypotension, apnea, airway obstruction, and/or arterial oxygen desaturation. The higher plasma levels reflect an age-related decrease in volume of distribution and intercompartmental clearance. Lower doses are therefore recommended for initiation and maintenance of sedation and anesthesia in elderly patients (see DOSAGE AND ADMINISTRATION).

Pediatrics

The pharmacokinetics of propofol were studied in children between 3 and 12 years of age who received DIPRIVAN Injectable Emulsion for periods of approximately 1 to 2 hours. The observed distribution and clearance of propofol in these children were similar to adults.

Organ Failure

The pharmacokinetics of propofol do not appear to be different in people with chronic hepatic cirrhosis or chronic renal impairment compared to adults with normal hepatic and renal function. The effects of acute hepatic or renal failure on the pharmacokinetics of propofol have not been studied.

Clinical Trials

Anesthesia and Monitored Anesthesia Care (MAC) Sedation

Pediatric Anesthesia

DIPRIVAN Injectable Emulsion was studied in clinical trials which included cardiac surgical patients. Most patients were 3 years of age or older. The majority of the patients were healthy ASA-PS I or II patients. The range of doses in these studies are described in Tables 1 and 2.

TABLE 1: PEDIATRIC INDUCTION OF ANESTHESIA

TABLE 2: PEDIATRIC MAINTENANCE OF ANESTHESIA

Neuroanesthesia

DIPRIVAN Injectable Emulsion was studied in patients undergoing craniotomy for supratentorial tumors in two clinical trials. The mean lesion size (anterior/posterior x lateral) was 31 mm x 32 mm in one trial and 55 mm x 42 mm in the other trial respectively. Anesthesia was induced with a median DIPRIVAN dose of 1.4 mg/kg (range: 0.9 to 6.9 mg/kg) and maintained with a median maintenance DIPRIVAN dose of 146 mcg/kg/min (range: 68 to 425 mcg/kg/min). The median duration of the DIPRIVAN Injectable Emulsion maintenance infusion was 285 minutes (range: 48 to 622 minutes).

DIPRIVAN Injectable Emulsion was administered by infusion in a controlled clinical trial to evaluate its effect on cerebrospinal fluid pressure (CSFP). The mean arterial pressure was maintained relatively constant over 25 minutes with a change from baseline of -4% ± 17% (mean ± SD). The change in CSFP was -46% ± 14%. As CSFP is an indirect measure of intracranial pressure (ICP), DIPRIVAN Injectable Emulsion, when given by infusion or slow bolus in combination with hypocarbia, is capable of decreasing ICP independent of changes in arterial pressure.

Intensive Care Unit (ICU) Sedation

Adult Patients

DIPRIVAN Injectable Emulsion was compared to benzodiazepines and opioids in clinical trials involving ICU patients. Of these, 302 received DIPRIVAN Injectable Emulsion and comprise the overall safety database for ICU sedation.

Across all clinical studies, the mean infusion maintenance rate for all DIPRIVAN Injectable Emulsion patients was 27 ± 21 mcg/kg/min. The maintenance infusion rates required to maintain adequate sedation ranged from 2.8 mcg/kg/min to 130 mcg/kg/min. The infusion rate was lower in patients over 55 years of age (approximately 20 mcg/kg/min) compared to patients under 55 years of age (approximately 38 mcg/kg/min). Although there are reports of reduced analgesic requirements, most patients received opioids for analgesia during maintenance of ICU sedation. In these studies, morphine or fentanyl was used as needed for analgesia. Some patients also received benzodiazepines and/or neuromuscular blocking agents. During long-term maintenance of sedation, some ICU patients were awakened once or twice every 24 hours for assessment of neurologic or respiratory function.

In Medical and Postsurgical ICU studies comparing DIPRIVAN Injectable Emulsion to benzodiazepine infusion or bolus, there were no apparent differences in maintenance of adequate sedation, mean arterial pressure, or laboratory findings. Like the comparators, DIPRIVAN Injectable Emulsion reduced blood cortisol during sedation while maintaining responsivity to challenges with adrenocorticotropic hormone (ACTH). Case reports from the published literature generally reflect that DIPRIVAN Injectable Emulsion has been used safely in patients with a history of porphyria or malignant hyperthermia.

In hemodynamically stable head trauma patients ranging in age from 19 to 43 years, adequate sedation was maintained with DIPRIVAN Injectable Emulsion or morphine. There were no apparent differences in adequacy of sedation, intracranial pressure, cerebral perfusion pressure, or neurologic recovery between the treatment groups. In literature reports of severely head injured patients in Neurosurgical ICUs, DIPRIVAN Injectable Emulsion infusion and hyperventilation, both with and without diuretics, controlled intracranial pressure while maintaining cerebral perfusion pressure. In some patients, bolus doses resulted in decreased blood pressure and compromised cerebral perfusion pressure.

DIPRIVAN Injectable Emulsion was found to be effective in status epilepticus which was refractory to the standard anticonvulsant therapies. For these patients, as well as for ARDS/respiratory failure and tetanus patients, sedation maintenance dosages were generally higher than those for other critically ill patient populations.

Pediatric Patients

A single, randomized, controlled, clinical trial that evaluated the safety and effectiveness of DIPRIVAN Injectable Emulsion versus standard sedative agents (SSA) was conducted on 327 pediatric ICU patients. Patients were randomized to receive either DIPRIVAN Injectable Emulsion 2%, (113 patients), DIPRIVAN Injectable Emulsion 1%, (109 patients), or an SSA (eg, lorazepam, chloral hydrate, fentanyl, ketamine, morphine, or phenobarbital). DIPRIVAN Injectable Emulsion therapy was initiated at an infusion rate of 5.5 mg/kg/hr and titrated as needed to maintain sedation at a standardized level. The results of the study showed an increase in the number of deaths in patients treated with DIPRIVAN Injectable Emulsion as compared to SSAs. Of the 25 patients who died during the trial or within the 28-day followup period: 12 (11% were) in the DIPRIVAN Injectable Emulsion 2% treatment group, 9 (8% were) in the DIPRIVAN Injectable Emulsion 1% treatment group, and 4% were (4%) in the SSA treatment group. The differences in mortality rate between the groups were not statistically significant. Review of the deaths failed to reveal a correlation with underlying disease status or a correlation to the drug or a definitive pattern to the causes of death.

Cardiac Anesthesia

DIPRIVAN Injectable Emulsion was evaluated in clinical trials involving patients undergoing coronary artery bypass graft (CABG).

In post-CABG (coronary artery bypass graft) patients, the maintenance rate of propofol administration was usually low (median 11 mcg/kg/min) due to the intraoperative administration of high opioid doses. Patients receiving DIPRIVAN Injectable Emulsion required 35% less nitroprusside than midazolam patients. During initiation of sedation in post-CABG patients, a 15% to 20% decrease in blood pressure was seen in the first 60 minutes. It was not possible to determine cardiovascular effects in patients with severely compromised ventricular function.