Diprivan PROPOFOL 10 mg/mL Injection, Emulsion — NDC 65219-800-10 (Billing 65219-0800-10)

WARNINGS: Use of DIPRIVAN has been associated with both fatal and life-threatening anaphylactic and anaphylactoid reactions. For general anesthesia or monitored anesthesia care (MAC) sedation, DIPRIVAN should be administered only by persons trained in the administration of general anesthesia and not involved in the conduct of the surgical/diagnostic procedure. Sedated patients should be continuously monitored, and facilities for maintenance of a patent airway, providing artificial ventilation, administering supplemental oxygen, and instituting cardiovascular resuscitation must be immediately available.

Patients should be continuously monitored for early signs of hypotension, apnea, airway obstruction, and/or oxygen desaturation. These cardiorespiratory effects are more likely to occur following rapid bolus administration, especially in the elderly, debilitated, or ASA-PS III or IV patients. For sedation of intubated, mechanically ventilated patients in the Intensive Care Unit (ICU), DIPRIVAN should be administered only by persons skilled in the management of critically ill patients and trained in cardiovascular resuscitation and airway management.

Use of DIPRIVAN infusions for both adult and pediatric ICU sedation has been associated with a constellation of metabolic derangements and organ system failures, referred to as Propofol Infusion Syndrome, that have resulted in death. The syndrome is characterized by severe metabolic acidosis, hyperkalemia, lipemia, rhabdomyolysis, hepatomegaly, renal failure, ECG changes* and/or cardiac failure. The following appear to be major risk factors for the development of these events: decreased oxygen delivery to tissues; serious neurological injury and/or sepsis; high dosages of one or more of the following pharmacological agents: vasoconstrictors, steroids, inotropes and/or prolonged, high-dose infusions of propofol (greater than 5 mg/kg/h for greater than 48h).

The syndrome has also been reported following large-dose, short-term infusions during surgical anesthesia. In the setting of prolonged need for sedation, increasing propofol dose requirements to maintain a constant level of sedation, or onset of metabolic acidosis during administration of a propofol infusion, consideration should be given to using alternative means of sedation. *Coved ST segment elevation (similar to ECG changes of the Brugada syndrome). Abrupt discontinuation of DIPRIVAN prior to weaning or for daily evaluation of sedation levels should be avoided.

This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation. Infusions of DIPRIVAN should be adjusted to maintain a light level of sedation through the weaning process or evaluation of sedation level (see PRECAUTIONS ). DIPRIVAN should not be coadministered through the same IV catheter with blood or plasma because compatibility has not been established.

In vitro tests have shown that aggregates of the globular component of the emulsion vehicle have occurred with blood/plasma/serum from humans and animals. The clinical significance of these findings is not known. There have been reports in which failure to use aseptic technique when handling DIPRIVAN was associated with microbial contamination of the product and with fever, infection, sepsis, other life-threatening illness, and death.

Do not use if contamination is suspected. Discard unused drug product as directed within the required time limits (see DOSAGE AND ADMINISTRATION , Handling Procedures ). There have been reports, in the literature and other public sources, of the transmission of bloodborne pathogens (such as Hepatitis B, Hepatitis C, and HIV) from unsafe injection practices, and use of propofol vials intended for single use on multiple persons.

DIPRIVAN vial is never to be accessed more than once or used on more than one person. Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block N… [Excerpted — this section continues on DailyMed.]

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… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS: General Adult and Pediatric Patients A lower induction dose and a slower maintenance rate of administration should be used in elderly, debilitated, or ASA-PS III or IV patients (see DOSAGE AND ADMINISTRATION ). Patients should be continuously monitored for early signs of hypotension and/or bradycardia. Apnea requiring ventilatory support often occurs during induction and may persist for more than 60 seconds.

DIPRIVAN use requires caution when administered to patients with disorders of lipid metabolism such as primary hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis. Very rarely the use of DIPRIVAN may be associated with the development of a period of postoperative unconsciousness which may be accompanied by an increase in muscle tone. This may or may not be preceded by a brief period of wakefulness.

Recovery is spontaneous. When DIPRIVAN is administered to an epileptic patient, there is a risk of seizure during the recovery phase. Attention should be paid to minimize pain on administration of DIPRIVAN.

Transient local pain can be minimized if the larger veins of the forearm or antecubital fossa are used. Pain during intravenous injection may also be reduced by prior injection of IV lidocaine (1 mL of a 1% solution). Pain on injection occurred frequently in pediatric patients (45%) when a small vein of the hand was utilized without lidocaine pretreatment.

With lidocaine pretreatment or when antecubital veins were utilized, pain was minimal (incidence less than 10%) and well-tolerated. There have been reports in the literature indicating that the addition of lidocaine to DIPRIVAN in quantities greater than 20 mg lidocaine/200 mg DIPRIVAN results in instability of the emulsion which is associated with increases in globule sizes over time and (in rat studies) a reduction in anesthetic potency. Therefore, it is recommended that lidocaine be administered prior to DIPRIVAN administration or that it be added to DIPRIVAN immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg DIPRIVAN.

Venous sequelae, i.e., phlebitis or thrombosis, have been reported rarely (less than 1%). In two clinical studies using dedicated intravenous catheters, no instances of venous sequelae were observed up to 14 days following induction. Intra-arterial injection in animals did not induce local tissue effects.

Accidental intra-arterial injection has been reported in patients, and, other than pain, there were no major sequelae. Intentional injection into subcutaneous or perivascular tissues of animals caused minimal tissue reaction. During the post-marketing period, there have been rare reports of local pain, swelling, blisters, and/or tissue necrosis following accidental extravasation of DIPRIVAN.

Perioperative myoclonia, rarely including convulsions and opisthotonos, has occurred in association with DIPRIVAN administration. Clinical features of anaphylaxis, including angioedema, bronchospasm, erythema, and hypotension, occur rarely following DIPRIVAN administration. There have been rare reports of pulmonary edema in temporal relationship to the administration of DIPRIVAN, although a causal relationship is unknown.

Rarely, cases of unexplained postoperative pancreatitis (requiring hospital admission) have been reported after anesthesia in which DIPRIVAN was one of the induction agents used. Due to a variety of confounding factors in these cases, including concomitant medications, a causal relationship to DIPRIVAN is unclear. DIPRIVAN has no vagolytic activity.

Reports of bradycardia, asystole, and rarely, cardiac arrest have been associated with DIPRIVAN. Pediatric patients are susceptible to this effect, particularly when fentanyl is given concomitantly. The intravenous administration of anticholinergic agents (e.g., atropine or glycopyrrolate) should be considered to modify potential increases in vagal tone due to concomitant agents (e.g., succinylcholine) or surgical stimuli.

Intensive Care Unit Se… [Excerpted — this section continues on DailyMed.]

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 by health care professionals have also been reported, which have resulted in fatalities and other injuries. Inventories of DIPRIVAN should be stored and managed to prevent the risk of diversion, including restriction of access and accounting procedures as appropriate to the clinical setting.