Diprivan

INDICATIONS AND USAGE: DIPRIVAN is an IV general anesthetic and sedation drug that can be used as described in the table below. Table 3. Indications for DIPRIVAN Indication Approved Patient Population Initiation and maintenance of Monitored Anesthesia Care (MAC) sedation Adults only Combined sedation and regional anesthesia Adults only (see PRECAUTIONS ) Induction of General Anesthesia Patients greater than or equal to 3 years of age Maintenance of General Anesthesia Patients greater than or equal to 2 months of age Intensive Care Unit (ICU) sedation of intubated, mechanically ventilated patients Adults only Safety, effectiveness and dosing guidelines for DIPRIVAN have not been established for MAC Sedation in the pediatric population; therefore, it is not recommended for this use (see PRECAUTIONS , Pediatric Use ). DIPRIVAN is not recommended for induction of anesthesia below the age of 3 years or for maintenance of anesthesia below the age of 2 months because its safety and effectiveness have not been established in those populations. In the Intensive Care Unit (ICU), DIPRIVAN can be administered to intubated, mechanically ventilated adult patients to provide continuous sedation and control of stress responses only by persons skilled in the medical management of critically ill patients and trained in cardiovascular resuscitation and airway management. DIPRIVAN is not indicated for use in Pediatric ICU sedation since the safety of this regimen has not been established (see PRECAUTIONS , Pediatric Use ). DIPRIVAN is not recommended for obstetrics, including Cesarean section deliveries. DIPRIVAN crosses the placenta, and as with other general anesthetic agents, the administration of DIPRIVAN may be associated with neonatal depression (see PRECAUTIONS ). DIPRIVAN is not recommended for use in nursing mothers because propofol has been reported to be excreted in human milk, and the effects of oral absorption of small amounts of propofol are not known (see PRECAUTIONS ).

DOSAGE AND ADMINISTRATION: Propofol blood concentrations at steady-state are generally proportional to infusion rates, especially in individual patients. Undesirable effects such as cardiorespiratory depression are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in the infusion rate. An adequate interval (3 minutes to 5 minutes) must be allowed between dose adjustments to allow for and assess the clinical effects. Shake well before use. Do not use if there is evidence of excessive creaming or aggregation, if large droplets are visible, or if there are other forms of phase separation indicating that the stability of the product has been compromised. Slight creaming, which should disappear after shaking, may be visible upon prolonged standing. When administering DIPRIVAN by infusion, syringe or volumetric pumps are recommended to provide controlled infusion rates. When infusing DIPRIVAN to patients undergoing magnetic resonance imaging, metered control devices may be utilized if mechanical pumps are impractical. Changes in vital signs indicating a stress response to surgical stimulation or the emergence from anesthesia may be controlled by the administration of 25 mg (2.5 mL) to 50 mg (5 mL) incremental boluses and/or by increasing the infusion rate of DIPRIVAN. For minor surgical procedures (e.g., body surface) nitrous oxide (60% to 70%) can be combined with a variable rate DIPRIVAN infusion to provide satisfactory anesthesia. With more stimulating surgical procedures (e.g., intra-abdominal), or if supplementation with nitrous oxide is not provided, administration rate(s) of DIPRIVAN and/or opioids should be increased in order to provide adequate anesthesia. Infusion rates should always be titrated downward in the absence of clinical signs of light anesthesia until a mild response to surgical stimulation is obtained in order to avoid administration of DIPRIVAN at rates higher than are clinically necessary. Generally, rates of 50 mcg/kg/min to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times. Other drugs that cause CNS depression (e.g., sedatives, anesthetics, and opioids) can increase CNS depression induced by propofol. Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary propofol injection maintenance infusion rate and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication. Induction of General Anesthesia Adult Patients Most adult patients under 55 years of age and classified as ASA-PS I or II require 2 mg/kg to 2.5 mg/kg of DIPRIVAN for induction when unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids. For induction, DIPRIVAN should be titrated (approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the onset of anesthesia. As with other general anesthetics, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN. Elderly, Debilitated, or ASA-PS III or IV Patients It is important to be familiar and experienced with the intravenous use of DIPRIVAN before treating elderly, debilitated, or ASA-PS III or IV patients. Due to the reduced clearance and higher blood concentrations, most of these patients require approximately 1 mg/kg to 1.5 mg/kg (approximately 20 mg every 10 seconds) of DIPRIVAN for induction of anesthesia according to their condition and responses. A rapid bolus should not be used, as this will increase the likelihood of undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation (see DOSAGE AND ADMINISTRATION ). Pediatric Patients Most patients aged 3 years through 16 years and classified ASA-PS I or II require 2.5 mg/kg to 3.5 mg/kg of DIPRIVAN for induction when unpremedicated or when lightly preme …

3 DOSAGE FORMS AND STRENGTHS DIPRIVAN ® (propofol) injectable emulsion, USP is available in single-dose vials as follows: 100 mg of propofol per 10 mL of an oil-in-water emulsion (10 mg per mL), 10 mL vial 200 mg of propofol per 20 mL of an oil-in-water emulsion (10 mg per mL), 20 mL vial 500 mg of propofol per 50 mL of an oil-in-water emulsion (10 mg per mL), 50 mL vial 1,000 mg of propofol per 100 mL of an oil-in-water emulsion (10 mg per mL), 100 mL vial Injectable emulsion: 100 mg per 10 mL (10 mg/mL), 200 mg per 20 mL (10 mg/mL), 500 mg per 50 mL (10 mg/mL), and 1,000 mg per 100 mL (10 mg/mL) single-dose vials ( 3 )

4 CONTRAINDICATIONS DIPRIVAN is contraindicated in patients with a known hypersensitivity to propofol or any of DIPRIVAN components. DIPRIVAN is contraindicated in patients with a history of anaphylaxis to eggs, egg products, soybeans or soy products. Known hypersensitivity to propofol, egg or soybean. ( 4 )

ADVERSE REACTIONS: To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 include data from clinical trials in general anesthesia/MAC sedation (N=2,889 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 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 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 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 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 Anesthesia/MAC Sedation ICU Sedation Cardiovascular: Bradycardia Bradycardia Decreased Cardiac Output Hypotension 26% Arrhythmia [Peds: 1.2%] Tachycardia Nodal [Peds: 1.6%] Hypotension* [Peds: 17%](see also CLINICAL PHARMACOLOGY ) Hypertension [Peds: 8%] Central Nervous System: Movement* [Peds: 17%] Injection Site: Burning/Stinging or Pain, 17.6% [Peds:10%] Metabolic/Nutritional: Hyperlipemia* Respiratory: Apnea (see also CLINICAL PHARMACOLOGY ) Respiratory Acidosis During Weaning* Skin and Appendages: Rash [Peds: 5%] Pruritus [Peds: 2%] Events without an * or % had an incidence of 1% to 3% *Incidence of events 3% to 10% Incidence less than 1% - Probably Causally Related Anesthesia MAC Sedation ICU Sedation Body as a Whole: Anaphylaxis/Anaphylactoid Reaction Perinatal Disorder Tachycardia Bigeminy Bradycardia Premature Ventricular Contractions Hemorrhage ECG Abnormal Arrhythmia Atrial Fever Extremities Pain Anticholinergic Syndrome Cardiovascular: Premature Atrial Contractions Syncope Central Nervous System: Hypertonia/Dystonia, Paresthesia Agitation Digestive: Hypersalivation Nausea Hemic/Lymphatic: Leukocytosis Injection Site: Phlebitis Pr …

7 DRUG INTERACTIONS Opioids and Sedatives The induction dose requirements of DIPRIVAN may be reduced in patients with intramuscular or intravenous premedication, particularly with opioids (e.g., morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (e.g., benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. In pediatric patients, administration of fentanyl concomitantly with DIPRIVAN may result in serious bradycardia. Analgesic Agents During maintenance of anesthesia or sedation, the rate of DIPRIVAN administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (e.g., nitrous oxide or opioids). The concurrent administration of potent inhalational agents (e.g., isoflurane, sevoflurane, desflurane, enflurane, and halothane) during maintenance with DIPRIVAN are routinely used. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN. Valproate The concomitant use of valproate and propofol may lead to increased blood levels of propofol. Reduce the dose of propofol when co-administering with valproate. Monitor patients closely for signs of increased sedation or cardiorespiratory depression. Common Neuromuscular Blocking Agents DIPRIVAN does not cause a clinically significant change in onset, intensity or duration of action of the commonly used neuromuscular blocking agents (e.g., succinylcholine and nondepolarizing muscle relaxants). Common Drugs Used as Premedication or Drugs Used During Anesthesia or Sedation No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed in adults. Opioids, Sedatives or Other Analgesic Agents : May increase the anesthetic/sedative and cardiorespiratory effects. ( 7 ) Valproate : May lead to increased blood levels of propofol. ( 7 )

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Data from randomized controlled trials, cohort studies and case series over several decades with propofol use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Most of the reported exposures to propofol describe propofol exposure at the time of cesarean delivery. There are reports of neonatal depression in infants exposed to propofol during delivery (see Clinical Considerations ). In animal reproduction studies, decreased pup survival concurrent with increased maternal mortality was observed with intravenous administration of propofol to pregnant rats either prior to mating and during early gestation or during late gestation and early lactation at exposures less than the human induction dose of 2.5 mg/kg. In pregnant rats administered 15 mg/kg/day intravenous propofol (equivalent to the human induction dose) from two weeks prior to mating to early in gestation (Gestation Day 7), offspring that were allowed to mate had increased postimplantation losses. The pharmacological activity (anesthesia) of the drug on the mother is probably responsible for the adverse effects seen in the offspring. Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours. There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans [see Data , Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.4 )]). The clinical significance of these nonclinical findings is not known, and the benefits of appropriate anesthesia in pregnant women who require procedures should be balanced with the potential risks suggested by the nonclinical data. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Clinical Considerations Fetal/neonatal Adverse Reactions DIPRIVAN crosses the placenta and may be associated with neonatal depression. Monitor neonates for hypotonia and sedation following maternal exposure to propofol. Data Animal Data Pregnant rats were administered propofol intravenously at 0, 5, 10, and 15 mg/kg/day (0.3, 0.65, and 1 times the human induction dose of 2.5 mg/kg based on body surface area) during organogenesis (Gestational Days 6–15). Propofol did not cause adverse effects to the fetus at exposures up to 1 times the human induction dose despite evidence of maternal toxicity (decreased weight gain in all groups). Pregnant rabbits were administered propofol intravenously at 0, 5, 10, and 15 mg/kg/day (0.65, 1.3, 2 times the human induction dose of 2.5 mg/kg based on body surface area comparison) during organogenesis (Gestation Days 6–18). Propofol treatment decreased total numbers of corpora lutea in all treatment groups but did not cause fetal malformations at any dose despite maternal toxicity (one maternal death from anesthesia-related respiratory depression in the high dose group). Pregnant rats were administered propofol intravenously at 0, 10, and 15 mg/kg/day (0.65 and 1 times the human induction dose of 2.5 mg/kg based on body surface area) from late gestation through lactation (Gestation Day 16 to Lactation Day 22). Decreased pup survival was noted at all doses in the presence of maternal toxicity (deaths from anesthesia- induced respiratory depression). This study did not evaluate neurobehavioral function including learning and memory in the pups. Pregnant rats were administe …

12.1 Mechanism of Action 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 GABA A receptors.

11 DESCRIPTION DIPRIVAN ® (propofol) injectable emulsion, USP is an anesthetic available as a sterile, nonpyrogenic white or almost white homogeneous emulsion for intravenous administration. The structural formula is: Chemical name: 2,6 diisopropylphenol Molecular formula: C 12 H 18 O Molecular weight: 178.27 Propofol is slightly soluble in water. The pKa is 11. The octanol/water partition coefficient for propofol is 6761:1 at a pH of 6 to 8.5. Each mL of DIPRIVAN ® (Propofol) injectable emulsion, USP contains 10 mg of propofol, 100 mg of soybean oil (100 mg/mL), 22.5 mg of glycerol (22.5 mg/mL), 12 mg of purified egg phospholipids (12 mg/mL), 0.055 mg of disodium edetate anhydrous (equivalent to 0.055 mg of disodium edetate) (0.05 mg/mL) as microbial inhibitor, and sodium hydroxide to adjust pH, in water for injection. DIPRIVAN is isotonic and has a pH of 7 to 8.5. dipri-struc-01.jpg

10 OVERDOSAGE 10.1 Symptoms Overdosage is likely to cause cardiorespiratory depression. 10.2 Treatment If overdosage occurs, DIPRIVAN administration should be discontinued immediately. 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.

HOW SUPPLIED: DIPRIVAN (propofol) Injectable Emulsion, USP Vials Product Code Each Unit of Sale Strength RF260929 NDC 65219-800-01 20 mL ready-to-use single-dose vial for single patient use only. NDC 65219-800-10 Packages of ten. This product contains an RFID. 200 mg per 20 mL (10 mg per mL) 260929 NDC 63323-269-22 20 mL ready-to-use single-dose vial for single patient use only. NDC 63323-269-29 Packages of ten. 200 mg per 20 mL (10 mg per mL) 260950 NDC 63323-269-30 50 mL ready-to-use single-dose vial for single patient use only. NDC 63323-269-50 Packages of twenty. 500 mg per 50 mL (10 mg per mL) 260965 NDC 63323-269-35 100 mL ready-to-use single-dose vial for single patient use only. NDC 63323-269-65 Packages of ten. 1,000 mg per 100 mL (10 mg per mL) Propofol undergoes oxidative degradation, in the presence of oxygen, and is therefore packaged under nitrogen to eliminate this degradation path. Store between 4° to 25°C (40° to 77°F). Do not freeze. Shake well before use. All trademarks are the property of Fresenius Kabi USA, LLC.