LONDON, May 12, 2020 /PRNewswire/ -- Hikma
Pharmaceuticals PLC (Hikma, Group), the multinational
pharmaceutical company, announces the launch of Propofol Injectable
Emulsion, USP, 20 mL, 50 mL and 100 mL Vials, in the United States through its US affiliate,
Hikma Pharmaceuticals USA Inc.,
following approval of its supplemental Abbreviated New Drug
Application by the U.S. Food and Drug Administration (FDA).
Propofol Injectable Emulsion is indicated for the initiation and
maintenance of sedation and anesthesia, including for intubated,
mechanically ventilated adults in the Intensive Care Unit. It is
currently on the FDA's Drug Shortage List, following a surge in
demand due to the increase in hospitalized, ventilated patients
resulting from the COVID-19 pandemic.
In order to get needed supplies to patients as quickly as
possible, Hikma is launching with available, limited quantities of
its 20 mL and 100 mL vials, with 50 mL vials to follow shortly
thereafter. The company is working quickly to scale up
manufacturing and will continue releasing product as soon as it is
"The launch of Propofol is the latest example of Hikma's
ongoing, company-wide commitment to delivering essential medicines
to our customers and their patients during this critical time,"
said Riad Mishlawi, President of Injectables, Hikma. "We have
focused our strong US and global manufacturing capabilities on
producing medicines that are in highest demand due to the outbreak
of COVID-19 including anaesthetics, pain medicines, sedatives,
neuromuscular blocking agents, anti-infectives and other support
medications. We are grateful to the FDA for their timely approval
of our application for Propofol Injection and look forward to
delivering this needed medicine to hospitals and patients."
Hikma is the third largest US supplier of generic injectable
medicines by volume, with a growing portfolio of over 100 products.
Today one in every six injectable generic medicines used in US
hospitals is a Hikma product.
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Important Safety Information for Propofol Injectable
Propofol injectable emulsion is contraindicated in patients with
a known hypersensitivity to propofol or any of its components.
Propofol injectable emulsion is contraindicated in patients with
allergies to eggs, egg products, soybeans or soy products.
WARNINGS & PRECAUTIONS
- Use of propofol has been associated with both fatal and
life-threatening anaphylactic and anaphylactoid reactions.
- For general anesthesia or monitored anesthesia care (MAC)
sedation, propofol should be administered only by persons trained
in the administration of general anesthesia and not involved in the
conduct of the surgical/diagnostic procedure.
- For sedation of intubated, mechanically ventilated patients in
the Intensive Care Unit (ICU), propofol should be administered only
by persons skilled in the management of critically ill patients and
trained in cardiovascular resuscitation and airway management.
- Use of propofol 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.
- Abrupt discontinuation of propofol prior to weaning or for
daily evaluation of sedation levels should be avoided.
- Propofol injectable emulsion should not be coadministered
through the same IV catheter with blood or plasma because
compatibility has not been established.
- There have been reports in which failure to use aseptic
technique when handling propofol injectable emulsion 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
- 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. Propofol injectable emulsion vial is never to be
accessed more than once or used on more than one
- Pediatric Neurotoxicity: published animal studies demonstrate
that the administration of anesthetic and sedation drugs that block
NMDA receptors and/or potentiate GABA activity increase neuronal
apoptosis in the developing brain and result in long-term cognitive
deficits when used for longer than 3 hours.
- A lower induction dose and a slower maintenance rate of
administration should be used in elderly, debilitated, or ASA-PS
III or IV patients.
- Propofol use requires caution when administered to patients
with disorders of lipid metabolism such as primary
hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis.
- When propofol 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
propofol. 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). it is
recommended that lidocaine be administered prior to propofol
administration or that it be added to propofol immediately before
administration and in quantities not exceeding 20 mg lidocaine/200
- Perioperative myoclonia, rarely including convulsions and
opisthotonos, has occurred in association with propofol
- Clinical features of anaphylaxis, including angioedema,
bronchospasm, erythema, and hypotension, occur rarely following
- There have been rare reports of pulmonary edema in temporal
relationship to the administration of propofol, although a causal
relationship is unknown.
- Rarely, cases of unexplained postoperative pancreatitis
(requiring hospital admission) have been reported after anesthesia
in which propofol was one of the induction agents used. Due to a
variety of confounding factors in these cases, including
concomitant medications, a causal relationship to propofol is
- Propofol has no vagolytic activity. Reports of bradycardia,
asystole, and rarely, cardiac arrest have been associated with
propofol. 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
- Intensive Care Unit Sedation: the administration of propofol
should be initiated as a continuous infusion and changes in the
rate of administration made slowly (greater than 5 min) in order to
minimize hypotension and avoid acute overdosage.
- Failure to reduce the infusion rate in patients receiving
propofol 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
propofol infusion for ICU sedation, especially when it is used for
- Opioids and paralytic agents should be discontinued and
respiratory function optimized prior to weaning patients from
mechanical ventilation. Infusions of propofol should be adjusted to
maintain a light level of sedation prior to weaning patients from
mechanical ventilatory support.
- Since propofol injectable emulsion is formulated in an
oil-in-water emulsion, elevations in serum triglycerides may occur
when propofol is administered for extended periods of time.
Administration of propofol should be adjusted if fat is being
inadequately cleared from the body.
- The long-term administration of propofol to patients with renal
failure and/or hepatic insufficiency has not been evaluated.
- Neurosurgical Anesthesia: when propofol 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
- Cardiac Anesthesia: 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 propofol.
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.
- Studies conducted in young animals and children suggest
repeated or prolonged use of general anesthetic or sedation drugs
in children younger than 3 years may have negative effects on their
The following adverse reactions have been reported at incidences
greater than 1% probably causally related: Cardiovascular
(bradycardia, arrhythmia, tachycardia nodal, hypotension,
hypertension, decreased cardiac output), Central Nervous System
(movement), Injection Site (burning/stinging or pain),
Metabolic/Nutritional (hyperlipemia), Respiratory (apnea,
respiratory acidosis during weaning), and Skin and Appendages
The following adverse reactions have been reported at incidences
less than 1% probably causally related: 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, pruritus), Metabolic (hypomagnesemia),
Musculoskeletal (myalgia), Nervous (dizziness, agitation, chills,
somnolence, delirium), Respiratory (wheezing, cough, laryngospasm,
hypoxia, decreased lung function), Skin and Appendages (flushing,
pruritus), Special Senses (amblyopia, vision abnormal), and
Urogenital (cloudy urine, green urine).
The following adverse reactions have been reported at incidences
less than 1% causal relationship unknown: Body as a Whole
(asthenia, awareness, chest pain, extremities pain, fever,
increased drug effect, neck rigidity/stiffness, trunk pain, fever,
sepsis, whole body weakness) Cardiovascular (arrhythmia, atrial
fibrillation, atrioventricular heart block, bigeminy, bleeding,
bundle branch block, cardiac arrest, ECG abnormal, edema,
extrasystole, heart block, hypertension, myocardial infarction,
myocardial ischemia, premature ventricular contractions, ST segment
depression, supraventricular tachycardia, tachycardia, ventricular
fibrillation, right heart failure, ventricular tachycardia),
Central Nervous System (abnormal dreams, agitation, amorous
behavior, anxiety, bucking/jerking/thrashing,
chills/shivering/clonic/myoclonic movement, combativeness,
confusion, delirium, depression, dizziness, emotional lability,
euphoria, fatigue, hallucinations, headache, hypotonia, hysteria,
insomnia, moaning, neuropathy, opisthotonos, rigidity, seizures,
somnolence, tremor, twitching, intracranial hypertension, thinking
abnormal), Digestive (cramping, diarrhea, dry mouth, enlarged
parotid, nausea, swallowing, vomiting, ileus, liver function
abnormal), Hematologic/Lymphatic (coagulation disorder,
leukocytosis), Injection Site (hives/itching, phlebitis,
redness/discoloration), Metabolic/Nutritional (hyperkalemia,
hyperlipemia, BUN increased, creatinine increased, dehydration,
hyperglycemia, metabolic acidosis, osmolality increased),
Respiratory (bronchospasm, burning in throat, cough, dyspnea,
hiccough, hyperventilation, hypoventilation, hypoxia, laryngospasm,
pharyngitis, sneezing, tachypnea, upper airway obstruction), Skin
and Appendages (conjunctival hyperemia, diaphoresis, urticaria,
rash), Special Senses (diplopia, ear pain, eye pain, nystagmus,
taste perversion, tinnitus), and Urogenital (oliguria, urine
retention, kidney failure).
The induction dose requirements of propofol 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
propofol and may also result in more pronounced decreases in
systolic, diastolic, and mean arterial pressures and cardiac
During maintenance of anesthesia or sedation, the rate of
propofol 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
propofol has not been extensively evaluated. These inhalational
agents can also be expected to increase the anesthetic or sedative
and cardiorespiratory effects of propofol.
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.
Propofol 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 propofol may result in serious
USE IN SPECIFIC POPULATIONS
There are no adequate
and well-controlled studies in pregnant women.
Labor and delivery
Propofol is not recommended for
obstetrics, including cesarean section deliveries. Propofol crosses
the placenta, and as with other general anesthetic agents, the
administration of propofol may be associated with neonatal
Propofol 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.
The safety and effectiveness of propofol
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. Propofol 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 propofol may result in serious bradycardia.
Propofol 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 propofol for ICU sedation.
Published juvenile animal studies demonstrate that the
administration of anesthetic and sedation drugs, such as propofol,
that either block NMDA receptors or potentiate the activity of GABA
during the period of rapid brain growth or synaptogenesis, results
in widespread neuronal and oligodendrocyte cell loss in the
developing brain and alterations in synaptic morphology and
Benzyl alcohol, a component of this product, has been associated
with serious adverse events and death, particularly in pediatric
patients. Although normal therapeutic doses of this product deliver
amounts of benzyl alcohol that are substantially lower than those
reported in association with the "gasping syndrome", the minimum
amount of benzyl alcohol at which toxicity may occur is not known.
Practitioners administering this and other medications containing
benzyl alcohol should consider the combined daily metabolic load of
benzyl alcohol from all sources.
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 propofol 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. All dosing should be titrated
according to patient condition and response.
DOSAGE AND ADMINISTRATION
Refer to package insert for dosage and administration
instructions for induction of general anesthesia, maintenance of
anesthesia, and monitored anesthesia care (MAC) sedation. Also
refer to package insert for a summary of dosage guidelines table.
Dosages and rates of administration in this table should be
individualized and titrated to clinical response.
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
When administering propofol by infusion, syringe or volumetric
pumps are recommended to provide controlled infusion rates. When
infusing propofol 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 propofol.
For minor surgical procedures (e.g., body surface) nitrous oxide
(60% to 70%) can be combined with a variable rate propofol 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 propofol
and/or opioids should be increased in order to provide adequate
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 propofol 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
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)
Compatibility and Stability: Propofol injectable emulsion
should not be mixed with other therapeutic agents prior to
Dilution Prior to Administration: Propofol injectable
emulsion is provided as a ready-to-use formulation. However, should
dilution be necessary, it should only be diluted with 5% Dextrose
Injection, USP, and it should not be diluted to a concentration
less than 2 mg/mL because it is an emulsion. In diluted form it has
been shown to be more stable when in contact with glass than with
plastic (95% potency after 2 hours of running infusion in
Administration with Other Fluids: Compatibility of
propofol injectable emulsion with the coadministration of
blood/serum/plasma has not been established. When administered
using a y-type infusion set, propofol injectable emulsion has been
shown to be compatible with the following intravenous fluids.
- 5% Dextrose Injection, USP
- Lactated Ringers Injection, USP
- Lactated Ringers and 5% Dextrose Injection
- 5% Dextrose and 0.45% Sodium Chloride Injection, USP
- 5% Dextrose and 0.2% Sodium Chloride Injection, USP
products should be inspected visually for particulate matter and
discoloration prior to administration whenever solution and
Propofol should only be administered through a filter with a
pore size of 5 micron or greater unless it has been demonstrated
that the filter does not restrict the flow of propofol and/or cause
the breakdown of the emulsion. Filters should be used with caution
and where clinically appropriate. Continuous monitoring is
necessary due to the potential for restricted flow and/or breakdown
of the emulsion.
Do not use if there is evidence of separation of the phases of
Refer to package insert for guidelines for aseptic technique for
general anesthesia/MAC sedation and for ICU sedation.
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 propofol by healthcare professionals have
also been reported, which have resulted in fatalities and other
injuries. Inventories of propofol should be stored and managed to
prevent the risk of diversion, including restriction of access and
accounting procedures as appropriate to the clinical setting.
If overdosage occurs, propofol
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
For additional information, please refer to the
Package Insert for full prescribing
To report SUSPECTED ADVERSE REACTIONS, contact Hikma
Pharmaceuticals USA Inc. at
1-877-845-0689 or FDA at 1-800-FDA-1088 or
Hikma Pharmaceuticals USA Inc.
(formerly West-Ward, a Hikma Company)
Eatontown, NJ 07724 USA
Document Identification Number: WW40008
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SOURCE Hikma Pharmaceuticals USA Inc.