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`Certification
`
`VERIFIED TRANSLATION OF DOCUMENT & DECLARATION
`
`The undersigned, of the below address, hereby certifies and declares that he/she knows well both the English
`and Dutch languages, and that the attached Is an accurate translation of the document listed below:
`
`(Dutch LabellO mg) SmPC RVG 25809
`
`I hereby declare that all statements in the translation made herein of my own knowledge are true and that all
`statements made in the translation on information and belief are believed to be true. Further, these
`statements in the translation were made with the knowledge that willful false statements and the like so
`made are punishable by fine, imprisonment, or both, under Section 1001 of Title 18 of the United States Code.
`Signed this 5th day of February, 2015
`
`
`
`Signature ----~.l..---------1~r:::::: __
`
`Name: Robert Endoy
`
`Address: Rochester, Ml48306
`
`Subscribed and sworn to before me, a Notary Pub1ic in and for the County of Cook, State of Illinois, on
`February 5, 2015.
`
`.
`(h
`)~
`Mari~otary
`
`a:FICIAL SEAL
`MMIGRACE CLARK
`. NOTARY P\BJC ·STATE~ ILLINOIS
`MV COMMSSION EXPIRES:1MW18
`
`Dr. Reddy's Laboratories
`v.
`Fresenius Kabi USA, LLC
`U.S. Patent No. 8,476,01 0
`Ex hibit 1028
`
`Exh. 1028
`
`

`
`1. Name of the drug
`
`Propofol I 0 mg/ml Fresenius, injectable emulsion
`
`2. Qualitative and quantitative composition
`
`One m1 Propofol. 10 mg/ml Fresenius, injectable emulsion contains 10 mg Propofol. Each
`ampoule of20 ml, injection vial of 50 ml and 100 ml contains respectively 200 mg, 500 mg
`and l 000 mg Propofol.
`For the additives refer to point 6. 1.
`
`3. Pharmaceutical form
`
`Injectable emulsjon.
`Isotonic, white oil-in-water emulsion.
`
`4. Clinical information
`
`4.1 Therapeutic indications
`
`Propofol Fresenius is an intravenous short acting total anesthetic for:
`1. Inducing and maintaining total anesthesia.
`2. Sedation of ventilated patients in intensive care units.
`3. Sedation for diagnostic and surgical procedures, in isolation or in combination with
`local or regional anesthesia.
`
`4.2 Dosage and method of administering
`
`4.2.1 Special warnings
`
`Propofol Fresenius should only be administered in hospitals or well-equipped medical
`centers by physicians trained in anesthesia or in the treatment of intensive care patients.
`Continuous monitoring of the blood circulation and the respiration (ex. ECG, pulse oximeter)
`is necessary. Equipment for prevention of respiratory tract obstruction, artificial respiration
`and other reanimation equipment must be immediately available at all times. When used for
`sedation during surgical or diagnostic procedures, Propofol Fresenius should not be
`administered by the same person who is performing the surgical or diagnostic procedure.
`Additional analgesics are usually necessary in combination with Propofol Fresenius.
`
`4.2.2. Recommended dosage and treatment time
`
`Propofol Fresenius is administered intravenously. The dosage is adjusted individually based
`on the response of the patient.
`
`Exh. 1028
`
`

`
`General anesthesia of adults:
`
`Induction of anesthesia
`
`Propofol must be titrated for the induction of anesthesia (20-40 mg Propofol every 10
`seconds), while continuously monitoring the reaction of the patient until clinical signs signal
`the onset of anesthesia. In general, an adult patient, not older than 55 years, will require I ,5-
`2.5 mg Propofol per kg body weight.
`
`For older patients and patients with an ASA (American Society of Anesthesiologists)
`classification III or IV, in particular with deteriorated heart function, the requirement will be
`less and the total dose of Propofol Fresenius can be reduced to a minimum of I mg
`PropofoVkg body weight. The administration rate must also be reduced with these patients
`(approximately 20mg (2 ml Propofol 10 mg/ml Fresenius) per 10 seconds).
`
`Maintenance of the anesthesia :
`
`The anesthesia can be maintained by administering Propofol I 0 mg/ml as continuous
`infusion or as repeated bolus injections. If the last mentioned method is applied, dosages
`from 25 mg (2.5 ml Propofoll O mg/ml Fresenius) to 50 mg (5 ml Propofol lO mg/ml
`Fresenius) must be administered depending on the clinical need.
`
`For maintenance of anesthesia by means of a continuous infusion, the dosage requirement
`wi II usually be 4 to 12 mg Propofol/kg body weight/hour. With older patients, patients in
`poor general condition, patients with ASA classification lll or IV and hypovolemic patients
`the dosage can be further reduced depending on the patient's condition and the applied
`anesthesia technique.
`
`General anesthesia of children older than one month of age:
`
`Induction of anesthesia:
`
`For the induction of anesthesia Propofol must be slowly titrated w!hile continuously
`monitoring the reaction of the patient, until clinical signals announce the set in of anesthesia.
`
`The dosage must be adjusted to the age and/or the body weight.
`
`In general, a patient older than 8 years will require for induction 2.5 mg Propofol/kg body
`weight. H igher dosages may be required for younger children (2.5- 4 mg/kg).
`
`In absence of clinical experience, lower dosages are recommended for younger patients with
`increased risk (ASA classification III and IV).
`
`Maintenance oft:he anesthesia:
`In general, a satisfactory anesthesia level can be obtained by means of a continuous infusion
`w ith a dosage of 9- 15 mg Propofol/kg body weight/hour.
`
`2
`
`Exh. 1028
`
`

`
`In comparison with older children, children under 3 years of age may need a higher dose
`within the recommended dosage range. The dosage must be adjusted individually and special
`attention must be paid to adequate analgesia (see also point 4.2.1 Special warnings).
`
`The administration time in chi ldren younger than 3 years of age was usually 20 minutes with
`a maximum duration of 75 minutes. A maximum duration of 60 minutes should therefore not
`be exceeded, except if there is a specific indication for longer duration such as for instance
`malign hyperthermia whereby volatile substances must be avoided.
`
`Propofol Freseni us should not be used for induction and maintenance of anesthesia in
`children younger than I month.
`
`Sedation of ventilated patients during intensive care
`
`Administration of a continuous infusion ofPropofol Fresenius is recommended for sedation
`of ventilated patients under intensive care conditions. The infusion rate should be adjusted to
`the required sedation level. In general, a satisfactory sedation is obtained with a dosage of0.3
`to 4.0 mg Propofol per kg body weight per hour (see 4.4 Special warnings and precautions
`with use).
`
`Propofol Fresenius should not be used for sedation under intensive care conditions of
`children under 16 years of age or younger (see 4.3: Contraindications).
`
`It is not recommended to administer Propofol via a TCI system for sedation under intensive
`care.
`
`Sedation for diagnostic and surgical procedures in adults:
`
`For diagnostic and surgical procedures, the sedation dosage and administration rate must be
`adapted to the clinical response. As introduction, most patients need 0.5- 1 mg Propofol per
`kg body weight per hour for 1 - 5 minutes.
`
`Maintenance of the sedation is obtained by titration of a Propofol Fresenius infusion until the
`desired sedation level is obtained. In general, 1.5-4.5 mg Propofol per kg bodyweight per
`hour will be required.
`
`When using Propofol I 0 mglm l Fresenius, a bolus injection of I 0-20 mg Propofol (l-2 ml
`Propofol I 0 mg/ml Fresenius) can be used in addition to the infusion, if a fast increase of the
`sedation depth is required. With patients older than 55 years of age and patients with ASA
`classification III or IV, it may be necessary to lower the dosage and administration rate.
`
`Propofol Fresenius should not be used to sedate children 16 years of age or younger during
`diagnostic or surgical procedures.
`
`4.2.2 Method of administration and duration
`
`3
`
`Exh. 1028
`
`

`
`Method of administration
`
`Propofol I 0 mg/ml Fresenius must be administered 'intravenously as injection or as
`continuous infusion, either undiluted or diluted with a 5% glucose solution or a 0.9% sodium
`chlmide solution. Solutions in glass bottles and in PVC bags can both be used and must be
`thoroughly mixed prior to the administration.
`
`It is possible to simultaneously administer Propofol 10 mg/ml Fresenius together with a 5%
`glucose or a 0.9% sodium chloride infusion via a Y connector near the injection spot.
`
`Prior to use, the neck of the ampoule and the rubber stopper of the injection vial must be
`disinfected with medicinal alcohol (spray or patches:). After use, the leftovers must be
`destroyed.
`
`Propofol Fresenius does not contain preservatives and promotes the growth of
`microorganisms. Therefore, after opening of a Propofol Fresenius ampoule or pricking
`through a vial, the content must be drawn immediately in antiseptic manner in a sterile
`syringe or infusion system. Administration should take place immediately afterwards. The
`sterility of the Propofol Fresenius and the infusion system must be maintained during the
`administration.
`
`Drugs or liquids added to a running Propofol Fresenius infusion must be introduced close to
`the catheter. Propofol Fresenius should not be administered via infusion systems equipped
`with microbial filters. The content of one ampoule or one vial ofPropofol Fresenius is
`intended for one time use in one patient. The leftover must be destroyed after use.
`
`Infusion ofundiluted Propofol 10 mg/ml Fresenius
`
`When Propofol Fresenius is adlministered by means of a continuous infusion it is
`recommended to control the infusion rate by means of a burette, a dropper, a syringe pump or
`a volumetric infusion pump.
`
`As applicable for parenteral administration of all sorts of fat emulsions, the use of one
`infusion system for continuous infusion of Propofol Fresenius must be limited to maximum
`12 hours. The infusion system and the container must be removed and replaced after
`maximum 12 hours. Leftovers ofPropofol Fresenius that remain at the end of the infusion
`period or after changing the system must be destroyed.
`
`Infusion of diluted Propofol 10 mg/ml Fresenius
`
`When diluted Propofol Fresenius 10 mglml is administered by means of a continuous
`infusion, it is recommended to control the infusion rate by means of a burette, a dropper, a
`syringe pump or a volumetric infusion pump, in order to prevent accidental administration of
`too large doses of diluted Propofol Fresenius.
`
`4
`
`Exh. 1028
`
`

`
`The maximum dilution should not exceed 1 part Propofol 10 mg/ml Fresenius in 4 parts 5%
`glucose, or 0.9% sodium chloride (minimum concentration 2 mg Propofol per ml). The
`mixture must be aseptically prepared immediately prior to the administration and must be
`used within 6 hours after preparation.
`
`For infusion or injection, Propofol I 0 mg/ml Fresenjus should not be mixed with other
`solutions than those mentioned in section 6.6.
`
`In order to reduce the pain at the beginning of the injection, Propofol 10 mg/ml IFresenius can
`be mixed with a 1% lidocaine solution for injection without preservatives (mix 20 parts
`Propofol I 0 mglml Fresenius with 1 part 1% lidocaine solution for injection). See section 4.4
`and 4.8 for the specific risks of lidocaine.
`
`Before administering atracurium of mivacurium, after administering Propofol 10 mg/ml
`Fresenius, through the same infusion system, it is recommended to rinse the infusion system.
`
`Administration time
`
`Propofol Fresenius can be administered for maximum 7 days.
`
`4.3 Contraindications
`
`l.
`2.
`3.
`
`Propofol Fresenius should not be used:
`in patients with known oversensitivity for Propofol or one of the emulsion additives.
`in patients wl10 arc allergic for soya and peanuts.
`For sedating patient 16 years of age or younger during intensive care (see 4.4 Special
`warnings and precautions with use)
`
`4.4 Special warnings and precautions with use
`
`Use caution with patients with deteriorated cardiac, respiratory, renal or hepatic function or
`with hypovolemic, debilitated or epileptic patients who require Propofol Fresenius to be
`administered at reduced administration rate (see dosage). If possible, hypovolemia, cardiac
`insufficiency, blood circulation problems or respiratory problems must be compensated
`before administering Propofol Fresenius.
`
`Verify that epileptic patients are being treated for epilepsy.
`Although several studies prove its effectiveness in treating epileptic status, the administration
`of Propofol to epileptic patients can increase the risk of epileptic s,eizure.
`Propofol Fresenius must be administered witch caution to patients who are undergoing
`surgery whereby unexpected movements are not desirable, for instance in eye surgery.
`
`The use of Propofol with shock therapy is not recommended.
`With patients with severely deteriorated cardiac function it is recommended to administer
`Propofol Fresenius with great caution under intensive supervision.
`
`5
`
`Exh. 1028
`
`

`
`The risk of a relative vagotonia may increase because Propofol Fresenius does not display
`any vagolytic activity. The intravenous administration of an anticholinergic should be
`considered prior to the induction or during the maintenance anesthesia, in particular in
`situations where the vagal tonus will probably dominate or when Propofol Fresenius is used
`in combination with other drugs who may cause bradycardia.
`
`The safety and efficiency of Propofol Fresenius for (background) sedation of children
`younger than 16 years of age is not proven.
`
`Propofol is not recommended for general anesthesia of children younger than J month.
`
`Although a causal connection has not been established, severe undesired side effects (among
`which fatalities) have been reported during (background) sedation of patients younger than
`16 years of age during the period prior to the registration. It mainly involved the occurrence
`of metabolic acidosis, hyperlipidemia, rhabdomyolysis, and/or heart failure. These effects
`were often observed in children with respiratory tract infections who received larger doses
`than advised for adults for sedation in intensive care.
`
`Similar rare reports were received regarding the occurrence of metabolic acidosis,
`rhabdomyolysis, hyperkalemia and/or quickly progressing heart failure (in some cases with
`fatality) in adults who were treated more than 58 hours with doses greater than 5 mglkg body
`weight per hour. This exceeds the maximum dosage of 4 mglkg body weight per hour which
`is currently advised for sedation in intensive care. The involved patients mainly had (but not
`exclusively) head injuries and !had increased intracranial pressure. In such cases did the heart
`failure usually not react to positive inotropic medication.
`
`Prescribers are reminded not to exceed a dosage of 4 mg/kg body weight per hour.
`Prescribers must be alert for these possible undesirable effects and reduce the dose or switch
`to another sedative at the first signs that these undesirable effects are occurring. In patients
`with increased intracranial pressure the blood flow through the brain must be supported in the
`correct manner, during the adjustment of the treatment.
`
`Attention must be paid to deviations of the fat metabolism and/or diseases which require
`special caution w hen dealing with the use of fat emulsions.
`
`The application of Propofol Fresenius for anesthesia of babies and infants up to age 3
`deserves extra attention, although recent data demonstrates that there are no distinct
`differences relatEve to safety after comparison with children older than 3.
`
`If the patient is receiving parenteral feeding, it is necessary to take into account the quantity
`of lipids in Propofol Fresenius: I ml Propofol contains 0.1 g fat.
`
`Plasma lipid levels must be checked after 3 days during treatment in the intensive care unit.
`
`6
`
`Exh. 1028
`
`

`
`As a result of the higher doses usually applied for patients who are severely overweight,
`increased risk of undesirable hemodynamic side effects must be taken into account.
`
`Extra attention is required for patients with increased intracranial pressure and low arterial
`pressure because there is a risk of significant reduction of the intracerebral perfusion
`pressure.
`
`Dilutions with a lidocaine solution should not be applied to patients with hereditary
`predisposition for acute porphyria.
`
`In rare cases postoperative unconsciousness occurs, accompanied by increased muscle
`tension. This phenomenon is not related to the fact whether the patient was awake or not.
`Although the consciousness returns spontaneously, unconscious patients must be carefully
`observed.
`
`Before discharging the patient> verify that the patient has fully recovered from the general
`anesthesia.
`
`For use during breast feeding, refer to 4.6 Pregnancy and breast feeding.
`
`4.5 Interactions with other drugs and other forms of interaction
`
`Propofol Fresenius can be appl ied in combination with other drugs (premedication, inhalation
`anesthetic, analgesics, muscle relaxants, local anesthetics) for anesthesia. No serious
`interactions with these drugs have been reported to date. Some of these centrally acting drugs
`can cause circulatory or respiratory depression. Their effect can be enhanced in combination
`with Propofol Fresenius. Extension of the anesthesia and reduction of the respiratory
`frequency have been reported after simultaneous use with benzodiazepines,
`parasympathicolytic drugs or inhalation anesthetics.
`
`After additional premedication with opioids, a higher incidence and longer duration of apnea
`can occur.
`
`Bradycardia and heart stoppage can occur after treatment with suxamethonium or
`neostigmine.
`
`It should be taken into account that simultaneous use of Propofol with drugs for
`premedication, inhalation anesthetics or analgesics can strengthen the anesthesia and the
`cardiovascular side effects. Simultaneous use with substances which can lead to depression
`of the central nervous system such as alcohol, general anesthetics or narcotic analgesics will
`result in increase of their sedative effects.
`After administering fentanyl, the blood concentration of Propofol can be temporarily higher
`in addition to an increase of apnea.
`
`Leuco-encephalopathy has been observed after administration of fat emulsions, such as
`Propofol, to patients who were also taking cyclosporine.
`
`7
`
`Exh. 1028
`
`

`
`When used as supplement with regional anesthesia it may be necessary to lower the dose of
`Propofol Fresenius.
`
`4.6 Pregnancy and breast feeding
`
`The very limited data about the use of this substance with human pregnancy shows no
`increased risk of congenital deviations. So far, animal tests show no indications of
`harmfulness. Propofol passes t!hrough the placenta. In view of the pharmacological effect of
`this substance, with perinatal use there is a possibility of respiratory depression in neonates.
`Propofol can be used during pregnancy.
`
`Propofol is excreted in small quantities in mother milk. After application of Propofol in
`anesthesia, breast feeding can be resumed as soon as the mother is capable of it.
`
`4.7 Influence on driving ability a nd the ability to operate machinery
`
`After administering Propofol the conscious patient must be observed long enough to ensure
`that he/she has recovered sufficiently. It is not recommended for the patient to drive, to
`operate machinery or to work in potentially dangerous situations. Patients must be
`accompanied back home and must be instructed not to use alcohol.
`
`4.8 Side effects
`
`Hypotension and respiratory depression arc the most often occurring side effects. ofPropofol.
`The effects depend on the administered quantity of Propofol but also on the type of
`premedication and other simultaneously administered drugs. The following side effects were
`specifically observed:
`
`Immune system d isorders:
`Rare (< I: 1000. > 1: 10000)
`Severe oversensitive reactions (anaphylactic) among which Quincke edema, bronchospasms,
`erythema and hypotension.
`
`Psychic disorders:
`Rare (< I: 1000. > 1: 10000)
`Euphoria and uninhibited sexual drive during the recovery period.
`
`Nervous system disorders:
`Often (< 1: 10, > 1: 1 00)
`During the induction of the anesthesia it is likely that spontaneous movements and myocloni
`will be observed.
`Rare (< I: 1000. > 1: 10000)
`Headache, dizziness, shivers and cold feeling can occur during the recovery period, besides
`epileptic convulsions including opisthotonus.
`Very rare: (< 1:1 0000)
`
`8
`
`Exh. 1028
`
`

`
`Delayed epileptic seizures with a delay which can vary between a few hours and several
`days.
`Convulsions have been observed (in incidental cases) after admini stration ofPropofol to
`epileptic patients.
`Cases of postoperative unconsciousness (see section 4.4 Special warnings and precautions
`with use).
`
`Cardiovascular disorders:
`Often(< 1:10, > 1: 100)
`Distinct hypotension.
`This may necess-itate the use of intravenous liquids, if necessary vasoconstrictive drugs and
`slower administration of Propofol Fresenius.
`The possibility of a severe drop in blood pressure must be considered in patients with
`reduced coronary or cerebral perfusion or with hypovolemia.
`Rare (< I: 1000, > I : 10000)
`Heart arrhythmias during the recovery period.
`Bradycardia has occurred during the general anesthesia, incidentally progressive (asystole).
`The intravenous administration of an anticholinergic prior to induction or during
`maintenance anesthesia must be considered (see also 4.4 Special warnings and precautions
`with use).
`
`Disorders of the respiratory system, chest and mediastinum:
`Often ( < I : 1 0, > 1: 1 00)
`Hyperventilation, apnea and coughing can occur during the induction of anesthesia.
`Sometimes ( 1: 100, > 1: 1000)
`Coughing during the maintenance phase.
`Rare (< I : 1000, > 1: 1 0000)
`Coughing during the recovery period.
`Very rare(< l : l 0000)
`Isolated cases of pulmonary edema after administering Propofol have been described.
`
`Gastrointestina• disorders:
`Often(< l: 10, > l : 100)
`H iccups at the induction of anesthesia.
`Rare(< l:1000, > 1:10000)
`Nausea and vomiting during the recovery period.
`Very rare(< 1: 10000)
`Pancreatitis was observed after administration of Propofol. A causal I ink could however not
`be established.
`
`Kiidney and urinary tract disorders:
`Rare (< l : 1000, > 1: I 0000)
`Cases of urine discoloration after long lasting administration of Pwpofol Fresenius.
`
`9
`
`Exh. 1028
`
`

`
`General diseases and disorders at the location of administration:
`Often ( < 1 : 1 0, > 1 : 1 00)
`Hot flash during the induction of anesthesia.
`Rare (< I: I 000, > 1: I 0000)
`Fever after the surgery.
`Very rare(< I: 1 0000)
`Rhabdomyolysis, metabolic acidosis, hyperkalemia or heart fai lure sometimes with fatal
`ending were observed after administering Propofol in dosages of 4 mg/kg body weight per
`hour for sedation in the intensive care (see also 4.4 Special warnings and precautions with
`use).
`Very often (> 1 : W)
`Local pain during the first injection. Prophylaxis or treatment see below.
`Rare (< 1:1000, > 1:10000)
`Thrombosis and phlebitis.
`Very rare(< 1: 1 0000)
`Incidental cases of severe tissue reactions after accidental extravascular administration.
`
`Local pain occurring during the first injection ofPropofol Fresenius can be reduced by
`simultaneous administration of lidocaine (see under 4.2.3 Method of administration) and by
`usi ng the larger vessels in the Lower arm and the elbow cavity. After simultaneous
`administration of lidocaine the following side effects can occur: dizziness, vomiting,
`drowsiness, convulsions, bradycardia, heart arrhythmias and shock
`
`4.9 Overdose
`
`Cardiorespiratory depression can occur in case of overdose. Respiratory depression must be
`treated with by artificial ventilation with oxygen. In case of cardio~vascular depression the
`head is positioned lower (Trendelenburg position) and if necessary, p lasma substituting
`agents and blood pressure raising medication are administered.
`
`5 Pharmacologic properties
`
`5. 1 Pharmacodynamic properties
`
`Pharmacotherapeutic group: other anesthetics.
`
`ATC code: NOlAX I O
`
`A hypnotic effect occurs very rapidly after intravenous injection of Propofol Fresenius.
`Depending on the injection rate, the anesthesia induction time is 30 to 40 secondls. The effect
`of a single bolus injection lasts 4-60 minutes because of fast metabolism and excretion.
`
`With the recommended dosage schedule, no relevant accumulation ofPropofol was observed
`after repeated bolus injections. Patients return quickly to consciousness.
`
`10
`
`Exh. 1028
`
`

`
`Bradycardia and hypotension can occur incidental ly during the induction of anesthesia,
`probably due to a lack of vagolytic activity. The cardiac and circulatory situations usually
`normalize during the maintenance of anesthesia.
`
`5.2 Pharmacokinetic properties
`
`After intravenous administration approximately 98% of Propofol is bonded to plasma
`protein.
`
`After intravenous bolus injection the initial blood concentration of Propofol quickly drops as
`result of a quick distribution over the different compartments (a phase). The distribution half
`value time is calculated at 2-4 minutes.
`
`During the elimination phase the blood level drops Jess fast. The elimination half value time
`during the ~phase is 30-60 minutes. Afterwards a third compartment is observed reflecting
`the redistribution of Propofol from tissue with low perfusion.
`
`The clearing is higher in children than in adults.
`
`The central distribution volume varies from 0.2 to 0.79 1/kg body weight, the steady state
`distribution volume is 1.8-5.3 1/kg body weight. Propofol is quickly eliminated from the body
`(total clearing approximately 2 l/min). The clearing takes place through metabolism, mainly
`in the liver, whereby glucuronides of Propofol and g lucuronides and sulfate compounds of
`the metabolite quinol are formed. All metabolites are inactive. Approximately 88% of an
`administered dose is excreted in the urine in the form of metabolites. Only 0.3% is excreted
`in the urine unchanged.
`
`5.3 Information from the preclinical safety study
`
`Preclinical information, based o n conventional studies of the tox icity after repeated
`administration and genotoxicity have shown to present no special risks for humans.
`Carcinogenicity has not been studied.
`
`Pharmacologic effects were observed in studies of reproduction toxicity w ith high doses.
`Teratogenic effects were not observed.
`
`Local tolerance studies w ith intramuscular injections showed tissue damage around the
`injection spot.
`
`6 Pharmaceutical data
`
`6.1 List of additives
`
`Soy bean oil, purified egg lecithin, glycerol, oil acid, sodium hydroxide, water for injections.
`
`6.2 Cases of incompatibility
`
`11
`
`Exh. 1028
`
`

`
`Propofol I 0 mg/ml Fresenius must not be diluted WEth solutions for infusion or injection
`other than as indicated in 6.6 ' Instructions for use and processing".
`
`Muscle relaxants such as atracurium and mivacurium should only be administered after flush
`of the same infusion spot as the one used for Propofol.
`
`6.3 Shelf life
`
`Propofol 10 mg!ml Fresenius (original packaging): 36 months.
`
`Administration sets with undiluted Propofol 10 mg/ml Fresenius must be replaced 12 hours
`after opening the ampoule or vial. Dilutions with 5% glucose intravenous infuse solution or
`0.9% sodium chloride intravenous infuse solution must be prepared aseptically immediately
`prior to the administration and must be used within 6 hours of the preparation.
`
`6.4 Special precautions for storage
`
`Store below 25°C. Do not store in the freezer.
`Store in original packaging.
`
`6.5 Type and content of the packaging
`
`Colorless glass ampoules (20 ml), type I glass according to Ph. Eur.
`Colorless glass injection vials (50 ml and 100 ml), type ll glass according to Ph. Eur.
`Bromobutyl rubber closure, type I according to Ph. Eur.
`Packaging with 5 glass ampoules with 20 ml emulsion.
`Packaging with 1 glass injection vial with 50 or 100 ml emulsion.
`Packaging with 10 glass injection vials with 50 or l 00 ml emulsion.
`Not all mentioned packaging sizes are introduced in commerce.
`
`6.6 Instructions for use and processing
`
`The recipient must be shaken before use.
`
`Use only homogenous preparations and undamaged packaging.
`
`Prior to use, the neck of the ampoule or the rubber membrane of the bottle must be cleaned
`with an alcohol spray or a patch drenched in alcohoH (see also 4.2 " Dosage and method of
`administration'.
`
`After the first use, the leftovers of the solution must be destroyed.
`
`Propofol 10 mg/ml Fresenius should be mixed for administration only w ith a 5% glucose
`solution, a 0.9% sodium chloride solution or with a 1% lidocaine (see 4.2 'Dosage and
`
`12
`
`Exh. 1028
`
`

`
`method of administration'). The final Propofol concentration should not be lower than 2
`mg/ml.
`
`Dilution and co-administration of Propofol with other drugs or infusion liquids
`
`Co-
`administration
`teclmique
`Mix prior to
`administering
`
`Additive or dilu(ion
`agent
`
`Preparation
`
`Precautions
`
`Prepare the mixture aseptically
`inunediately prior to
`administration. Use the
`mixture within 6 hours.
`
`5% glucose infusion
`solution or 0.9%
`sodium chloride
`infusion solutiom
`
`Mix in a PVC i111fusion bag or
`in a glass infusion bottle I part
`Propofol I 0 mglml Fresenius
`with maximum 4 parts 5%
`glucose infusion solution or
`0.9% sodium chloride inf11sion
`solution
`
`Tf dilution takes place in a PVC
`infusion bag, the volume to be
`mixed of Propofol I 0 mglml
`Fresenius must be added after
`the same volume 5% glucose
`infusion solution or 0.9%
`sodium chloride· infi.tsion
`solution has been removed
`from a full infusion bag.
`
`Mix 20 parts Propofol I 0
`mg/ml Fresenius with
`maximum I part 1.0% lidocaine
`injection solution.
`Administration via a Y
`COIUleCtOr
`
`Prepare the mixture aseptically
`prior to administration. Use
`only for induction of general
`anesthesia.
`Place the Y connector close to
`the injection spot.
`
`1.0% lidocaine
`injection solution
`(without preservatives)
`
`Co·
`administration
`via a Y connector
`
`5% glucose infusion
`solution or 0.9%
`sodium chloride
`infusion solutio111
`
`7 Holder of the commercial license
`
`Fresenius Kabi Netherlands B . V.
`Amersfoortseweg I OE
`3705GJ Zeist
`Netherlands
`
`8 Number of tbe £ommercial license
`
`RVG 25809 (Propofol lO mg/ml Fresenius)
`
`9 Da te of tbe first approval/renewal of tbe license
`
`License issued on: December 5, 2000
`
`10 Summary revision date
`
`13
`
`Exh. 1028
`
`

`
`Last partial change point 7: May 5, 2014
`
`14
`
`Exh. 1028