Dr. Reddy’s Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 9,(cid:20)(cid:26)(cid:22),(cid:28)(cid:23)(cid:21)
`Reddy Exhibit 1024
`
`Exh. 1024
`
`

`
`ropean. ournal of Cancer Clinical nco I
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`Exh. 1024
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`

`
`Eur J Cancer C/in 0/l(·o/, Vol. 25, Suppl. I, pp. S67-S69, 1989
`Printed in Great Britain
`
`0277-5379/89 $3.00 + 0.00
`© 1989 Pergamon Press plc
`
`Pharmaceutical Development of Ondansetron
`Injection
`
`R.E. LEAK and J.D. WOODFORD
`Glaxo Group Research Ltd., Park Road, Ware, Hertfordshire, SG12 ODP, U.K.
`
`Abstract Ondansetron injection is an aqueous solution containing ondansetron base as the
`hydrochloride dihydrate. The pH of the injection was selected to achieve good physical and
`chemical stability. The shelf life is 3 years when stored below 30°C, protected from light.
`Ondansetron injection may be diluted for administration by slow intravenous injection or
`infusion and is compatible with several intravenous infusion fluids. In addition, specific
`concentrations of cisplatin, 5-fluorouracil, carboplatin, etoposide, ceftazidime, cyclophospha-
`mide and doxorubicin are compatible when administered via a giving set delivering ondansetron
`by infusion.
`
`PRESENTATIONS
`0NDANSETRON injection is an aqueous solution
`containing 2 mg/ml ondansetron base as
`the
`hydrochloride dihydrate. Sodium citrate and citric
`acid monohydrate are added to buffer the solution
`at pH 3.5 and sodium chloride is added to achieve
`isotonicity. The injection solution is filled into
`ampoules to provide dose volumes of 2 ml and
`4 ml, equivalent to 4 mg and 8 mg of ondansetron
`respectively, and is terminally sterilised by auto-
`claving.
`
`STABILITY
`The pH of the injection was selected to achieve
`good physical and chemical stability. The natural
`pH of solutions of ondansetron hydrochloride
`dihydrate is about 4.5, de.pending on the ondan-
`
`setron concentration. If pH is increased (e.g. by
`the addition of alkali), a precipitate of ondansetron
`free base is observed at about pH 5.7 (Fig. 1),
`therefore requiring the pH of the injection solu-
`tion to be maintained below this value.
`The stability of a 2.5 mg/ml solution of ondan-
`setron buffered at pH 3, 4 and 5 stored at elevated
`temperature and in intense light in a light cabinet
`is given in Figure 2. The results show that the
`solution is more stable to storage at elevated
`temperature at pH 3 and 4 than at pH 5, and that
`there is little difference in the stability of the
`solution in this pH range to intense light.
`These data indicate that a pH of 3.5 should
`achieve the required physical and chemical stabil-
`ity for ondansetron injection. In practice ondan-
`setron injections at pH 3.5 have been shown to be
`
`100
`90
`80
`c 70
`e 1i)
`(/) 60
`c
`Cl1 -c 50
`c
`0
`<1> 40
`Cl1 c 30
`<1>
`~
`<1> 20
`0..
`10
`0
`
`C)
`
`• LC
`0 1ooac
`
`i
`4
`pH
`Fig. 2. Effect of pH on stability of ondansetron 2.5 mg!ml in normal
`saline stored at 1 00°C or in a light cabinet (LC) for 28 days.
`
`i
`5
`
`Fig. 1. The effect of pH on the physical stability of ondansetron solutions.
`
`Exh. 1024
`
`

`
`S68
`
`R.E. Leak and J.D. Woodford
`
`very stable. An injection of the same formulation
`as that proposed for marketing but with a concen-
`tration of ondansetron of 2.5 mg/ml showed no
`change in ondansetron concentration, pH or drug-
`related impurities when stored for 3 years at 30°C.
`Stability data to date on ondansetron injection 2
`mg/ml show no change in ondansetron concen-
`tration (Fig. 3), pH or drug-related impurities for
`the injection stored for 1 year at 37°C. Ondan-
`setron injection is unstable when stored under
`intense light, but is stable for about a month in
`daylight supplemented with fluorescent lighting
`(Fig. 3).
`The shelf life of ondansetron injection is 3 years
`when stored below 30°C, protected from light.
`
`ANALYTICAL METHODS
`The ondansetron content of ondansetron injec-
`tion is determined by the same HPLC method as
`is used for the assay of ondansetron tablets [ 1].
`Figure 4 shows a chromatogram of ondansetron
`injection. The method gives precise and accurate
`results for the ondansetron content of ondan-
`setron injection.
`
`COMPATIBILITY
`
`Compatibility with infusion fluids
`Ondansetron may be administered by slow intra-
`venous injection or by intravenous infusion by
`diluting ondansetron injection with an appropriate
`volume of intravenous infusion fluid.
`Ondansetron injection is compatible with the
`following intravenous infusion fluids:
`-Sodium Chloride Intravenous Infusion BP 0.9%
`w/v
`-Glucose Intravenous Infusion BP 5% w/v
`- Mannitol Intravenous Infusion BP 10% w/v
`- Ringers intravenous infusion
`-Potassium Chloride 0.3% w/v and Sodium
`Chloride 0.9% w/v Intravenous Infusion BP
`-Potassium Chloride 0.3% w/v and Glucose 5%
`w/v Intravenous Infusion BP.
`
`c: e (i)
`
`<f) c:
`<1l
`"0 c:
`0
`Q)
`Cl
`
`<1l c Q)
`
`~
`Q)
`0..
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Normal
`
`37"C
`100%
`
`Normal = daylight with
`fluorescent light
`LC = intense light in a
`light cabinet. One month
`in the light cabinet is
`approx. equivalent to 2-3
`years under ambient
`lighting conditions
`
`0
`
`7 days
`
`28 days
`
`1 year
`
`Fig. 3. The effect of storage on the ondansetmn concentration of
`ondansetmn injection 2 mglml in 2 ml ampoules.
`
`Ondansetron
`
`Cll
`<f) c:
`0 c. <f)
`Q) a:
`
`0
`
`1.87
`
`3.75
`
`5.62
`
`7.5
`Minutes
`
`9.37
`
`11.25
`
`13.12
`
`15
`
`Fig. 4. HPLC chromatogram of ondansetron injection.
`
`Compatibility was tested by adding 8 mg ondan-
`setron (4 ml of ondansetron injection) to 500 ml
`PVC infusion bags of each infusion. PVC giving
`sets were attached and primed and the test system
`stored under ambient conditions of temperature
`and light. Samples were taken for analysis via the
`giving set after 24 h storage and from the bags
`after 7 days storage. These showed no significant
`change
`in ondansetron concentration, drug-
`related impurities or numbers of particles for all
`of the infusions tested. Duplicate dilutions of the
`injection in 500 ml infusion bags stored at 4°C,
`protected from light, were also physically and
`chemically stable for 7 days.
`In addition, for Sodium Chloride Intravenous
`Infusion BP 0.9% w/v and Glucose Intravenous
`Infusion BP 5% w/v, 8 mg of ondansetron was
`added to 100 ml infusion bags and stored under
`ambient conditions or at 4°C. These solutions
`(sampled from the infusion bag) were also shown
`to be stable for 7 days.
`These results demonstrate that ondansetron is
`compatible with the infusion fluids tested and with
`PVC infusion bags and giving sets.
`
`Preparation of dilutions of ondansetron injection in
`advance of use. Provided diluti?ns of ondansetron
`injection are prepared under appropriate aseptic
`conditions, they may be prepared in advance of
`use. Dilutions of ondansetron irtiection in com-
`patible infusion fluids are stable for 7 days at 4°C
`or at room temperature ( <25°C) exposed to
`ambient light.
`Containers for dilutions. The above compatibility
`tests were performed in PVC infusion bags. It is
`considered that adequate compatibility would also
`be conferred on dilutions in polyethylene infusion
`bags or Type 1 glass bottles since these are known
`to be more inert than PVC.
`Ondansetron injection may also be diluted with
`compatible infusion fluids and stored for up to 7
`
`Exh. 1024
`
`

`
`Pharmaceutical Development of Ondansetron Injection
`
`S69
`
`Ondansetron
`1 mg/h
`
`Intravenous infusion of
`cisplatin,
`5-fluorouracil,
`carboplatin,
`etoposide
`
`Bolus injections of
`cyclophosphamide,
`doxorubicin,
`ceftazidime
`
`Fig. 5. Co-administration of ondansetron infusion and other therapeutic agents.
`
`days at 4°C or at room temperature in polypropy-
`lene neoprene rubber syringes (e.g. Plastipak,
`Becton Dickinson & Co. Ltd.) fitted with syringe
`caps (e.g. Universal Plug, Vygon).
`
`Compatibility with other therapeutic agents
`Ondansetron may be administered at 1 mg/h by
`intravenous infusion from an infusion bag or
`syringe pump with an attached giving set. Other
`drugs, such as anticancer agents or antibiotics, may
`need to be co-administered intravenously via the
`Y -site of the giving set delivering ondansetron.
`Other medication should not be mixed directly
`with ondansetron injection in an infusion bag,
`syringe or any other administration system.
`The drugs may be administered by intravenous
`infusion or bolus injections as appropriate. Those
`drugs which are compatible with ondansetron are
`shown in Figure 5, along with their route of
`administration.
`Doses of anticancer agents are variable and
`therefore extremes of concentrations were evalu-
`ated where appropriate. The compatibility data
`support the co-administration of the following
`concentration/doses of the drugs listed in Figure 5.
`The following drugs may be administered via
`the Y -site of the ondansetron giving set delivering
`ondansetron at 1 mg/h for ondansetron concen-
`trations of 16 to 160 }Lg/ml (e.g. 8 mg/500 ml and
`8 mg/50 ml, respectively).
`Cisplatin. Concentrations up to 0.48 mg/ml (e.g.
`240 mg in 500 ml) administered over 1-8 h.
`5-fluorouracil. Concentrations up to 0.8 mg/ml
`(e.g. 2.4 g in 3 litres or 400 mg in 500 ml)
`administered at a rate of at least 20 mllh (500 mil
`24 h). Higher concentrations of 5-fluorouracil may
`
`cause precipitation of ondansetron. The 5-
`fluorouracil infusion may contain up to 0.045%
`w/v magnesium chloride in addition to other
`excipients shown to be compatible.
`Carboplatin. Concentrations in the . range 0.18
`mg/ml to 9.9 mg/ml (e.g. 90 mg in 500 ml to 990
`mg in 100 ml), administered over 10 min to 1 h.
`Etoposide. Concentrations in the range 0.144
`mg/ml to 0.25 mg/ml (e.g. 72 mg in 500 ml to 250
`mg in 1litre), administered over 30 min to 1 h.
`Cyclophosphamide. Doses in the range 100 mg to
`1 g, reconstituted with Water for Injections BP,
`5 ml per 100 mg cyclophosphamide, as recom-
`mended by the manufacturer, and given as an
`intravenous bolus injection over approximately 5
`mm.
`Doxorubicin. Doses in the range 10 mg to 100 mg
`reconstituted with Water for Injections BP, 5 ml
`per 10 mg doxorubicin, as recommended by the
`manufacturer and given as an intravenous bolus
`injection over approximately 5 min.
`Ceftazidime. Doses in the range 250 mg to 2 g
`reconstituted with Water for Injections BP as
`recommended by the manufacturer (e.g. 2.5 ml
`for 250 mg and 10 ml for 2 g ceftazidime) and
`given as an intravenous bolus injection over ap-
`proximately 5 min.
`
`PHARMACEUTICAL PRECAUTIONS
`Ondansetron injection should be protected from
`light, and should only be admixed with those
`infusion solutions which are recommended.
`Ondansetron injection should not be mixed in
`the same syringe or infusion as any other medi-
`cation, and it must not be reautoclaved.
`
`REFERENCE
`1. Leak RE, Woodford JD. Pharmaceutical development of ondansetron tablets. Eur J Cancer Clin
`Oneal (this issue).
`
`Exh. 1024