Anesthesia S / I-40

• If you have an allergy to propofol, eggs, soy products, or any other part of Anesthesia S/I-40 (propofol).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are breast-feeding. Do not breast-feed while you take this medicine.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Anesthesia S/I-40 with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Anesthesia S/I-40 or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Anesthesia S/I-40 (propofol). This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

FOR INTRAVENOUS ADMINISTRATION

Rx Only

Strict aseptic technique must always be maintained during handling. DIPRIVAN Injectable Emulsion is a single access parenteral product (single patient infusion vial) which contains 0.005% disodium edetate (EDTA) to inhibit the rate of growth of microorganisms, for up to 12 hours, in the event of accidental extrinsic contamination. However, DIPRIVAN Injectable Emulsion can still support the growth of microorganisms, as it is not an antimicrobially preserved product under USP standards. Do not use if contamination is suspected. Discard unused drug product as directed within the required time limits. There have been reports in which failure to use aseptic technique when handling DIPRIVAN Injectable Emulsion was associated with microbial contamination of the product and with fever, infection/sepsis, other lifethreatening illness, and/or death. 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 Injectable Emulsion vials are never to be accessed more than once or used on more than one person.
(See WARNINGS and DOSAGE AND ADMINISTRATION, Handling Procedures).

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 Injectable Emulsion 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 Injectable Emulsion 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 Injectable Emulsion 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 Injectable Emulsion. 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 Injectable Emulsion in quantities greater than 20 mg lidocaine/200 mg DIPRIVAN Injectable Emulsion 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 Injectable Emulsion administration or that it be added to DIPRIVAN Injectable Emulsion 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 (<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 Injectable Emulsion.

Perioperative myoclonia, rarely including convulsions and opisthotonos, has occurred in association with DIPRIVAN Injectable Emulsion administration.

Clinical features of anaphylaxis, including angioedema, bronchospasm, erythema, and hypotension, occur rarely following DIPRIVAN Injectable Emulsion administration.

There have been rare reports of pulmonary edema in temporal relationship to the administration of DIPRIVAN Injectable Emulsion, although a causal relationship is unknown.

Rarely, cases of unexplained postoperative pancreatitis (requiring hospital admission) have been reported after anesthesia in which DIPRIVAN Injectable Emulsion 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 Injectable Emulsion is unclear.

DIPRIVAN Injectable Emulsion has no vagolytic activity. Reports of bradycardia, asystole, and rarely, cardiac arrest have been associated with DIPRIVAN Injectable Emulsion. 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 Sedation

(See WARNINGS and DOSAGE AND ADMINISTRATION, Handling Procedures.) The administration of DIPRIVAN Injectable Emulsion should be initiated as a continuous infusion and changes in the rate of administration made slowly (>5 min) in order to minimize hypotension and avoid acute overdosage (see DOSAGE AND ADMINISTRATION).

Patients should be monitored for early signs of significant hypotension and/or cardiovascular depression, which may be profound. These effects are responsive to discontinuation of DIPRIVAN Injectable Emulsion, IV fluid administration, and/or vasopressor therapy. In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus administration should not be used during sedation in order to minimize undesirable cardiorespiratory depression, including hypotension, apnea, airway obstruction, and oxygen desaturation.

As with other sedative medications, there is wide interpatient variability in DIPRIVAN Injectable Emulsion dosage requirements, and these requirements may change with time.

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, especially when it is used for long durations.

Opioids and paralytic agents should be discontinued and respiratory function optimized prior to weaning patients from mechanical ventilation. Infusions of DIPRIVAN Injectable Emulsion should be adjusted to maintain a light level of sedation prior to weaning patients from mechanical ventilator support. Throughout the weaning process, this level of sedation may be maintained in the absence of respiratory depression. Because of the rapid clearance of DIPRIVAN Injectable Emulsion, abrupt discontinuation of a patient’s infusion may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation, making weaning from mechanical ventilation difficult. It is therefore recommended that administration of DIPRIVAN Injectable Emulsion be continued in order to maintain a light level of sedation throughout the weaning process until 10 to15 minutes prior to extubation, at which time the infusion can be discontinued.

Since DIPRIVAN Injectable Emulsion is formulated in an oil-in-water emulsion, elevations in serum triglycerides may occur when DIPRIVAN Injectable Emulsion is administered for extended periods of time. Patients at risk of hyperlipidemia should be monitored for increases in serum triglycerides or serum turbidity. Administration of DIPRIVAN Injectable Emulsion should be adjusted if fat is being inadequately cleared from the body. A reduction in the quantity of concurrently administered lipids is indicated to compensate for the amount of lipid infused as part of the DIPRIVAN Injectable Emulsion formulation; 1 mL of DIPRIVAN Injectable Emulsion contains approximately 0.1 g of fat (1.1 kcal).

EDTA is a strong chelator of trace metals including zinc. Although with DIPRIVAN Injectable Emulsion there are no reports of decreased zinc levels or zinc deficiency-related adverse events, DIPRIVAN Injectable Emulsion should not be infused for longer than 5 days without providing a drug holiday to safely replace estimated or measured urine zinc losses.

In clinical trials mean urinary zinc loss was approximately 2.5 to 3 mg/day in adult patients and 1.5 to 2 mg/day in pediatric patients.

In patients who are predisposed to zinc deficiency, such as those with burns, diarrhea, and/or major sepsis, the need for supplemental zinc should be considered during prolonged therapy with DIPRIVAN Injectable Emulsion.

At high doses (2 to 3 grams per day), EDTA has been reported, on rare occasions, to be toxic to the renal tubules. Studies to date in patients with normal or impaired renal function have not shown any alteration in renal function with DIPRIVAN Injectable Emulsion containing 0.005% disodium edetate. In patients at risk for renal impairment, urinalysis and urine sediment should be checked before initiation of sedation and then be monitored on alternate days during sedation.

The long-term administration of DIPRIVAN Injectable Emulsion to patients with renal failure and/or hepatic insufficiency has not been evaluated.

When DIPRIVAN Injectable Emulsion is used in patients with increased intracranial pressure or impaired cerebral circulation, significant decreases in mean arterial pressure should be avoided  because of the resultant decreases in cerebral perfusion pressure. To avoid significant hypotension and decreases in cerebral perfusion pressure, an infusion or slow bolus of approximately 20 mg every 10 seconds should be utilized instead of rapid, more frequent, and/or larger boluses of DIPRIVAN Injectable Emulsion. Slower induction, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 to 2 mg/kg). When increased ICP is suspected, hyperventilation and hypocarbia should accompany the administration of DIPRIVAN Injectable Emulsion (see DOSAGE AND ADMINISTRATION).

Slower rates of administration should be utilized in premedicated patients, geriatric patients, patients with recent fluid shifts, and patients who are hemodynamically unstable. Fluid deficits should be corrected prior to administration of DIPRIVAN Injectable Emulsion. In those patients where additional fluid therapy may be contraindicated, other measures, e.g., elevation of lower extremities, or use of pressor agents, may be useful to offset the hypotension which is associated with the induction of anesthesia with DIPRIVAN Injectable Emulsion.

Information for Patients

Patients should be advised that performance of activities requiring mental alertness, such as operating a motor vehicle, or hazardous machinery or signing legal documents may be impaired for some time after general anesthesia or sedation.

Drug Interactions

The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (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 Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output.

During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion 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, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion.

DIPRIVAN Injectable Emulsion 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).

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. In pediatric patients, administration of fentanyl concomitantly with DIPRIVAN Injectable Emulsion may result in serious bradycardia.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of propofol.

Propofol was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538. Propofol was not mutagenic in either the gene mutation/gene conversion test using Saccharomyces cerevisiae, or in vitro cytogenetic studies in Chinese hamsters. In the in vivo mouse micronucleus assay with Chinese Hamsters propofol administration did not produce chromosome aberrations.

Female Wistar rats were administered either 0, 10, or 15 mg/kg/day propofol intravenously from 2 weeks before pregnancy to day 7 of gestation did not show impaired fertility. Male fertility in rats was not affected in a dominant lethal study at intravenous doses up to 15 mg/kg/day for 5 days.

Pregnancy

Pregnancy Category B

Reproduction studies have been performed in rats and rabbits at intravenous doses of 15 mg/kg/day (approximately equivalent to the recommended human induction dose on a mg/m2 basis) and have revealed no evidence of impaired fertility or harm to the fetus due to propofol. Propofol, however, has been shown to cause maternal deaths in rats and rabbits and decreased pup survival during the lactating period in dams treated with 15 mg/kg/day (approximately equivalent to the recommended human induction dose on a mg/m2 basis). The pharmacological activity (anesthesia) of the drug on the mother is probably responsible for the adverse effects seen in the offspring. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human responses, DIPRIVAN Injectable Emulsion should be used during pregnancy only if clearly needed.

Labor and Delivery

DIPRIVAN Injectable Emulsion is not recommended for obstetrics, including cesarean section deliveries. DIPRIVAN Injectable Emulsion crosses the placenta, and as with other general anesthetic agents, the administration of DIPRIVAN Injectable Emulsion may be associated with neonatal depression.

Nursing Mothers

DIPRIVAN Injectable Emulsion is not recommended for use in nursing mothers because DIPRIVAN Injectable Emulsion has been reported to be excreted in human milk and the effects of oral absorption of small amounts of propofol are not known.

Pediatric Use

The safety and effectiveness of DIPRIVAN Injectable Emulsion have been established for induction of anesthesia in pediatric patients aged 3 years and older and for the maintenance of anesthesia aged 2 months and older.

DIPRIVAN Injectable Emulsion is not recommended for the induction of anesthesia in patients younger than 3 years of age and for the maintenance of anesthesia in patients younger than 2 months of age as safety and effectiveness have not been established.

In pediatric patients, administration of fentanyl concomitantly with DIPRIVAN Injectable Emulsion may result in serious bradycardia (see PRECAUTIONS, General).

DIPRIVAN Injectable Emulsion is not indicated for use in pediatric patients for ICU sedation or for MAC sedation for surgical, nonsurgical or diagnostic procedures as safety and effectiveness have not been established.

There have been anecdotal reports of serious adverse events and death in pediatric patients with upper respiratory tract infections receiving DIPRIVAN Injectable Emulsion for ICU sedation.

In one multicenter clinical trial of ICU sedation in critically ill pediatric patients that excluded patients with upper respiratory tract infections, the incidence of mortality observed in patients who received DIPRIVAN Injectable Emulsion (n=222) was 9%, while that for patients who received standard sedative agents (n=105) was 4%. While causality has not been established, DIPRIVAN Injectable Emulsion is not indicated for sedation in pediatric patients until further studies have been performed to document its safety in that population (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Pediatric Patients and DOSAGE AND ADMINISTRATION).

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).

• Use as part of your daily cleansing routine
• May be covered with a sterile bandage

Since this medication is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

Propofol can cause severe drowsiness or dizziness, which may last for several hours. You will need someone to drive you home after your surgery or procedure. Do not drive yourself or do anything that requires you to be awake and alert for at least 24 hours after you have been treated with propofol.

Applies to propofol: intravenous emulsion

Cardiovascular

Very common (10% or more): Hypotension (up to 75%)
Common (1% to 10%): Hypertension, bradycardia
Uncommon (0.1% to 1%): Arrhythmias, tachycardia, extrasystole
Rare (0.01% to 0.1%): Pulmonary edema, asystole, syncope, perioperative arrhythmias, cardiac arrest
Very rare (less than 0.01%): Cardiac failure, pulmonary edema
Frequency not reported: Cardiac arrhythmia[Ref]

Dermatologic

Very common (10% or more): Pruritus (up to 28%)
Common (1% to 10%): Transient flush, rash[Ref]

Gastrointestinal

Common (1% to 10%): Nausea, vomiting
Very rare (less than 0.01%): Pancreatitis, abdominal cramps[Ref]

Genitourinary

Rare (Less than 0.1%): Discoloration of the urine following prolonged use[Ref]

Hepatic

Frequency not reported: Hepatomegaly[Ref]

Hypersensitivity

Rare (0.01% to 0.1%): Anaphylaxis, in some cases with angioedema, bronchospasm, erythema, and hypotension (these reactions have been reported to respond to adrenaline)[Ref]

Local

Common (1% to 10%): Pain during injection (burning, tingling/slinging)
Very rare (less than 0.01%): Tissue necrosis following accidental extravascular administration[Ref]

Metabolic

Very rare (less than 0.01%): Metabolic acidosis, hyperkalemia, hyperlipidemia[Ref]

Musculoskeletal

Very rare (less than 0.01%): Rhabdomyolysis (when administered at doses greater than 4 mg/kg/hour for ICU sedation)[Ref]

Nervous system

Very common (10% or more): Paresthesia (up to 74%), excitation phenomena such as involuntary movements, twitches, tremors, hypertonus, hiccup
Common (1% to 10%): Headache, shivering
Rare (0.01% to 0.1%): Convulsions and seizures of the epileptic type
Very rare (less than 0.01%): Postoperative unconsciousness
Frequency not reported: Involuntary movements[Ref]

Paresthesias (including burning, tingling, stinging) and/or pruritus, usually manifested in the perineal region, were the most frequently recorded adverse reactions in clinical trials. Paresthesias and pruritus generally occurred within 5 minutes after administration of the initial dose and were generally transient and mild to moderate in intensity. The pharmacologic basis of these sensory phenomena is unknown. No pretreatments, including the use of nonsteroidal anti-inflammatory drugs, opioids, or lidocaine, are known to have an effect on or to reduce the incidence of these sensations.[Ref]

Respiratory

Very common (10% or more): Hypoxemia (up to 11%)
Common (1% to 10%): Procedural pain (bronchoscopy), transient apnea, cough
Very rare (less than 0.01%): Pulmonary edema, hiccough[Ref]

Renal

Very rare (less than 0.01%): Renal failure[Ref]

Hematologic

Common (1% to 10%): Thrombosis, phlebitis[Ref]

Some side effects of propofol may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Data not available

This drug should be used during pregnancy only if the benefit outweighs the risk; some manufacturers consider this drug to be contraindicated in pregnancy. AU TGA pregnancy category: C US FDA pregnancy category: B

-Animal studies have shown some evidence of delayed ossification or abnormal cranial ossification with an increase in the incidence of subcutaneous hematomas. There are no adequate and well-controlled studies in pregnant women. -This drug should not be used for obstetric anesthesia because it crosses the placenta and may be associated with neonatal depression. AU TGA pregnancy category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details. US FDA pregnancy category B: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.