h_.... ...— ._-_. ..r-.....-...,.__......_._._..
`
`l? --?::P;ENCE .
`
`_ PHYSICIANS
`DESK
`
`NOVARTIS EXHIBIT 2069
`Par v. Novartis, IPR 2016-01479
`Page 1 of 6
`
`

`

`sident,
`
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`: PDFl Drug lnloracltonfi and
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`Eltecls" and PDR Indications Index
`are trademarks at Medical Economics Company inc” registered in the United States Patent and Trademark Otllce.
`ident and Chief
`Inc.: Presrdent and Chief Executive Oillcer: Norman R Snesil, Scriror Vice Pres
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`NOVARTIS EXHIBIT 2069
`Par v. Novartis, IPR 2016-01479
`Page 2 of 6
`
`

`

`7.024
`
`Sandoz E‘harrm . ont.
`
`DOSAGE AND ADMINISTRATION
`The recommended usual adult dose is 30 mg before retiring.
`In some patients, 15 mg may be sufficient. As with all medi~
`cations, dosage should be individualized for maximal benefi—
`cial effects. In elderly and/or debilitated patients it is recom~
`mended that therapy be initiated with 15 mg until individual
`responses are determined.
`I-IOW SUPPLIED
`Restoril® (temazepsm) Capsules
`15 mg, maroon and pink, imprinted “RESTORIL 15 mg” and
`“FOR SLEEP" twice on each capsule; 30 mg, maroon and
`blue, imprinted “RESTORIL 30 mg" and “FOR SLEEP”
`twice on each capsule. Supplied in bottles of 100, 15 mg (NDC
`0078009805) and 30 mg (NDC 0078009905) and bottles of
`’ 500, 15 mg (NDC 00755-009808) and 30 mg (NDC 0078-000“.-
`08). ControlPak® (continuous reverse-numbered roll of
`scaled blisters) packages of 25 capsules, 15 mg (NDC 0078-
`009013) and 30 mg (NDC 0078009943). SandoPak® (unit-
`dose) packages of 100 individually labeled blisters, each c0n~
`training one capsule, 15 mg (NDC 0079009806) and 30 mg
`(NDC 00713-009906).
`‘
`[RES-212 Issued July 10, 1989]
`Shown in Product Identification Section, page 427
`
`SANDIMMUNE®
`[sari ’di-mewn]
`(cyclosporlne, USP) SOFT GELATIN CAPSULES
`SANDIMMUNE®
`(cyclosporlne) ORAL SOLUTION, USP
`SANDIMMUNE®
`(cyclosporine concentrate for injection) AMPULS, USP
`FOR INFUSION ONLY
`
`CAUTION: Federal law prohibits dispensing without pre-
`scription.
`The following prescribing information is based on official
`labeling in effect on August 1, 1991.
`
`WARNING
`Only physicians experienced in immunosuppressive
`therapy and management of organ transplant patients
`should prescribe Sandimmune® (cyclosporine, USP).
`Patients receiving the drug should be managed in facili-
`ties equipped and staffed with adequate laboratory and
`supportive medical resources. The physician responsi—
`ble for maintenance therapy should have complete in-
`formation requisite for the followup of the patient.
`Sandimmune® (cyclosporine, USP) should be adminis-
`tered with adrenal corticosteroids but not with other.
`immunosuppressive agents. Increased susceptibility to
`infection and the possible development of lymphoma
`may result from immunosuppression.
`
`The absorption of cyclosporine during chronic adminis—
`tration of Sandimmune® soft gelatin capsules and oral
`solution was found to be erratic. It is recommended that
`patients taking the soft gelatin capsules or oral solution '
`over a period of time be monitored at repeated intervals
`for cyclosporine blood levels and subsequent dose ad-
`justments be made in order to avoid toxicity due to high
`levels‘und possible organ rejection due to low absorption
`of cyclosporine. This is of special importance in liver
`transplants. Numerous assays are being developed to
`measure ' blood levels of cyclosporine. Comparison of
`levels in published literature to patient levels using
`current assays must be done with detailed knowledge of
`the assay methods employed. (Se'e Blood Level Monitor-
`ing under DOSAGE AND ADMINISTRATION)
`
`DESCRIPTION
`Cyclosporine, the active principle in Sandimmune® (cyclo
`sporine, USP) is a cyclic polypeptide immunosuppreasant
`agent consisting of 11 amino acids. It is produced as a metab-
`olite by the fungus species Tolypocladium inflatum 'Gams.
`Chemically,
`cyclosporine
`is designated as
`[R-[R ‘,R‘-
`(E )]]-cyclic(Lalanyl-Dalanyl-N -methyl-L—leucyl—N-methyl—
`Lleucyl—N methyl —Ir valyl ~3— hydroxy~ N, 4dimcthyl—Irz-
`amino-Gcctenoyl‘L «x— amino-butyryl-N ~methylglycyl—N—
`methyl—Lieucyl-L-valbe-methyl-L-leucyl).
`Sandimmune® (cyclosporine, USP) soft gelatin capsules are
`available in 25 mg and 100 mg strengths.
`Each 25 mg capsule contains:
`..
`..
`cyclosporine, USP .
`alcohol, USP dehydrated
`
`25 mg
`127% by volume
`
`l hysicians’ Desk Heferencmo
`_T——_.——__——._—.___——
`Each 100 mg capsule contains:
`.. ..100 mg
`..
`..
`.
`..
`..
`.
`..
`..
`.
`cyclosporine, USP .
`..
`. mm 12.7% by volume
`.
`.
`alcohol, USPdchydi-ated
`Inactive Ingredients: corn oil, gelatin, glycerol, Labrafll M
`2125 CS (polyoxyethylated glycolysed glycerides), red iron
`oxide, sorbitol, titanium dioxide, and other ingredients.
`Sandimmune® (cyclosporine) oral solution, USP, is avail~
`able in 50 mL bottles.
`Each mL contains:
`mg
`.
`cyclosporine, USP .
`. 12.5% by volume
`..
`..
`alcohol, Ph. Helv.
`.
`dissolved in an olive oil, Ph. Helv./Labrafil M 1944 CS (pol-
`yoxyethylated oleic glycerides) vehicle which must be fur-
`ther diluted with milk, chocolate milk or orange juice before
`oral administration.
`Sandimmunc® (cyclosporinc concentrate for injection) am-
`puls, USP, are available in a 5 mL sterile ampul for LV. ad-
`ministration.
`Each mL contains:
`cyclosporine, USP
`'Cremophor EL
`.....650 mg
`(polyoxyethylated castor oil)
`32.9% by Volume
`.
`.
`alcohol, Ph. Helv.
`.
`..
`..
`..
`..
`..
`..
`.
`.
`..
`.qs
`nitrogen .
`..
`which must be diluted further with 0.9% Sodium Chloride
`Injection or 5% Dextrose Injection before use.
`The chemical structure of cyclosporine (also known as cyclo-
`.
`\
`sporin A) is:
`Hac
`CH
`at
`all“
`HO\é/Cl-I~CH3
`I
`
`
`
`.
`
`MeYal—PlJ—CH—Ev Abu*Mo(€-Iy
`Melon CH3
`0
`Mail.“
`Melisu~D~Alu—Ala—MQLw—Val
`M01. Wt 1202.63
`
`CSZHIIINI 1012
`CLINICAL PHARMACOLOGY
`Sandimmune® (cyclosporine, USP) is a potent immunosup
`pressive agent which in animals prolongs survival of allege
`neic transplants involving skin, heart, kidney, pancreas,
`bone marrow, small intestine, and. lung. Sandimmune®
`(cyclosporine, USP) has been demonstrated to suppress some
`humoral immunity and to a greater extent, cell-mediated
`reactions such as allograft rejection, delayed hypersensitiv-
`ity, experimental allergic encephalomyolitis, Freund's adju~
`'vant arthritis, and graft vs. host disease in many animal
`species for a variety of organs.
`Successful kidney, liver, and heart allogeneic transplants
`haVe been performed in man using Sandimmune® (cycle
`sporine, USP).
`The exact mechanism of action of Sandimmune® (cycle
`sporine, USP) is not known. Experimental evidence suggests
`that the effectiveness of cyclosporine is due to specific and
`reversible inhibition of immunocompetent lymphocytes in
`the Go or Gyphase of the cell cycle. T-lymphocytes are pref-
`erentially inhibited, The T-helper cell is the main target,
`although the T-suppressor cell may also be suppressed. San-
`dimmune® (cyclosporine, USP) also inhibits lymphokino
`production and release including interleukin~2 or Toell
`growth factor (TCGF).
`No functional effects on phagocytic (changes in enzyme se-
`cretions not altered, chemotactic migration of granulocyies,
`macrophage migration, carbon clearance in vino) or tumor
`cells (growth rate, metastasis) can be detected in animals.
`Sandimmune® (cyclosporine, USP) does not cause bone
`marrow suppression in animal models or man.
`The absorption of cyclosporine from the gastrointestinal
`tract is incomplete and variable. Peak concentrations (Cm)
`in blood and plasma are achieved at about 3.5 hours. Cm,ilx
`and area under the plasma or blood concentration/time
`curve (AUC) increase with the administered dose; for blood
`the relationship is curvilinear (parabolic) between 0 and
`1400 mg. As determined by a specific assay, Cm“ is approxi—
`mately 1.0 ng/mL/mg of dose for plasma and 2.7—1.4 ng/
`mL/mg of dose for blood (for low to high doses). Compared to
`an intravenous infusion, the absolute bioavailability of the
`oral solution is approximately 30% based upon the results in
`2 patients. The bioavailability of Sandimmune® (cyclo-
`sporine, USP) soft gelatin capsules is equivalent to Sandim-
`mune® (cyclosporine) oral solution, USP.
`Cyclosporiue is distributed largely outside the blood volume.
`In blood the distribution is concentration dependent. Ap-
`proximately 33%—47% is in plasma, 4%—9% in lymphocytes,
`5%—12% in granulocytes, and 41%—5B% in erythrocytes. At
`high concentrations, the uptake by leukocytes and eryth-
`rocytes becomes saturated. In plasma. approximately 90% is
`bound to proteins, primarily lipoprotoins.
`The disposition of cyclosporine from blood is biphasic with a
`terminal half-life of approximately 19 hours (range: 10-27
`'Cremophor is the registered trademark of BASF Aktien—
`gesellschait.
`
`..
`
`..
`
`..
`
`.
`
`.
`
`,
`
`.
`
`.......50 mg
`
`1mu:
`:43”my:
`type:
`
`
`
`=-:‘nrr’us:
`
`._.--~..._ia_.~i
`
`
`Consult 1992 Supplements for rauisio’“
`hours). Elimination is primarily biliary w
`\
`ith only 6% am]
`dose excreted in the urine.
`5
`Cyclosporine is extensively metabolized but there is no m
`jor metabolic pathway. Only 0.1% of the dose is excreted 3‘
`the urine as unchanged drug. Of 15 metabolites chamm"1
`ized in human urine, 9 have been assigned structumv L
`major pathways consist of hydroxylation of the Cream,“ 6
`2 of the leucine residues, CT] carbon hydroxylation, and cur
`clic ether formation (with oxidation of' the double bond)
`the side chain of the amino acid El-hydroxyl-I‘IA-dimelh’1l
`L-Zaminodoctenoic acid and Ndemethylation ofN .mcthyl'
`leucine residues. Hydrolysis of the cyclic peptide chaing
`conjugation of the aforementioned metabolites do not a r
`pear to be important biotransformatio'n pathways.
`D
`INDICATIONS AND USAGE
`Sandimmune® (cyclosporine, USP) is indicated for the pm
`phylaxis of organ rejection in kidney, liver. heart allogeneic
`transplants. It is always to be used with adrenal cortisone.
`raids. The drug may also be used in the treatment of chronic
`rejection in patients previously treated with other immuno
`suppressive agents.
`Because of the risk of anaphylaxis, Sandimmune® (cvm
`sporine concentrate for injection) ampuls, USP, should be
`reserved for patients who are unable to take the soft gelatin
`capsules or oral solution.
`CONTRAINDICATIONS
`Sandimmune® (cyclosporinc concentrate for injection) am,
`puls, USP, are contraindicated in patients with a hypersensi.
`tivity to Sandimmune® (cyclosporine, USP) and/or Creme
`phor® EL (polyoxyethylated castor oil).
`WARNINGS
`(See boxed WARNINGS)
`Sandimmune® '(cyclosporine, USP), when used in high
`doses, can cause hepatotoxicity and uephrotoxicity.
`It is not unusual for serum creatinine and BUN levels to be
`elevated during Sandimmune® (cyclosporine, USP) ther.
`apy. These elevations in renal transplant patients do not
`necessarily indicate rejection, and each patient must be fully
`evaluated before dosage adjustment is initiated.
`Nephrotoxicity has been noted in 25% of cases of renal trans
`plantation, 38% of cases of cardiac transplantation, and 37%
`of cases of liver transplantation. Mild nephrotoxicity was
`generally noted 2—3 months after transplant and consisted of
`an arrest in the fall of the pro-operative elevations of BUN
`and creatinine at a range of 85—45 mg/dl and 204.5 mg/dl
`respectively. These elevations were often responsive to due
`age reduction.
`More overt nephrotoxicity was seen early after transplanta-
`tion and was characterized by a rapidly rising BUN and are
`atinine. Since these events are similar to rejection episodes
`care must be taken to differentiate between them. This form
`of nephrotoxicity is usually responsive to Sandimnumefi'>
`(cyclosporine, USP) dosage reduction.
`Although specific diagnostic criteria which reliably differen-
`tiate renal graft rejection from drug toxicity have not been
`found, a number of parameters have been significantly [550
`ciated to one or the other. It should benched however, tth PP
`to 20% of patients may have simultaneous nephrotoxicll)‘
`and rejection.
`[See table on next page]
`A form. of chronic progressive cyclosporine-associated nePh‘
`'roioxicity is characterized by serial deterioration in Ten“
`function and morphologic changes in the kidneys. Fm“
`5%»15% of transplant recipients will fail to show a {901%
`tion in a rising serum creatinine despite a decrease or disco"
`tinuation of cyclosporinc therapy. Renal biopsies from the“
`patients will demonstrate an interstitial fibrosis with tub“
`lar'atrophy. In addition, toxic tubulopathy, peritubular 03?
`illary congestion, arteriolopathy, and a striped form of In)”;
`stitial fibrosis with tubular atrophy may be present. Th0“?
`none of these morphologic changes is entirely specific, 3 h”
`tologic
`diagnosis
`of
`chronic
`progressive
`.C’
`sporineassociated nephromxicity requires evidence of
`When considering the development of chronic nephrOWu n
`ity it is noteworthy that several authors have reported 3.5
`association between the appearance of interstitial fl
`and higher cumulative doses or persistently high circum.
`trough levels of cyclosporine. This is particularly true dunnlg
`the first 6 posttransplant months when the desage lends [a
`be highest and when, in kidney recipients, the organ a???”e
`to be most vulnerable to the toxic effects of cyclofil’orlri'n;
`Among other contributing factors to the developrnel'll 0f W
`terstitial fibrosis in these patients must be included) P i'
`longed perfusion time, warm ischemia time, as Wei.l $319
`sodas of acute toxicity, and acute and chronic rejectloll- r?
`reversibility of interstitial fibrosis and its correlatioD w
`nal function have not yet been demrmined.
`'
`.W.
`Impaired renal function at any time requires close mm“ 1,,{1
`ing, and frequent dosage adjustment may be indicated'
`'.
`patients with persistent high elevations of BUN and crazier.
`nine who are unresponsive to dosage adjustments. 00"“
`ation should be given to switching to other immuuosul’P .ec.
`sive therapy. In the event of severe and unremittmE 1'er
`tion, it is preferable. to allow the kidney transplant W be
`
`NOVARTIS EXHIBIT 2069
`Par v. Novartis, IPR 2016-01479
`Page 3 of 6
`
`

`

`eh
`
`Physicians’ Desk Huiaranca-Ts
`Nophrotoxicity vs Rejection
`
`Parameter _
`
`Nephrotoxielty
`Rejection
` History
`Donor > 50 years old or hypotensive
`Antidonor immune response
`Prolonged kidney preservation
`Retransplant patient
`Prolonged anastamosis time
`Concomitant nephrotoxic drugs
`Often > 6 weeks postop"
`Prolonged initial nonfunction
`(acute tubular necrosis)
`
`Clinical
`
`Often < 4 weeks postop”
`Fever > 375°C
`Weight gain > 0.5 Kg
`Graft swelling and tenderness
`Decrease in daily urine volume
`> 500 ml, (or 50%)
`CyA serum trough level < 150 ng/mL
`Rapid rise in Cr (> 0.3 mg/dl/day) *1
`Cr> 25% above baseline
`BUN/Cr < 20
`Endovasculitisc (proliferation‘, intimal ‘
`arteritisb, necrosis, sclerosis)
`
`’l‘ubulitis with RBCh and WBCh casts,
`some irregular vacuolization
`Interstitial edemac and hemorrhageb
`Diffuse moderate to severe
`mononuclear infiltrates“
`Glomerulitis (Mononuclear Cells)c
`Inflammatory infiltrate with mono
`nuclear phagocytes, macrophages,
`lymphoblastoid cells, and activated
`T-cells
`These strongly express HLA-DR
`antigens
`Degenerative tubular cells, plasma
`cells, and lymphocyturia > 20% of
`sediment
`Intracapsular pressure > 40 mm Hgb
`Increase in graft cross sectional area
`A? diameter 2 Transverse diameter
`Loss of distinct corticomedullary
`junction, swelling, image intensity of
`parachyma approaching that of
`psoas, loss of hilar fat
`Patchy arterial flow
`Decrease in perfusion > decrease in
`tubular function
`Increased uptake of Indium 111
`labeled platelets or 'l‘c—99m in colloid
`Responds to increased steroids or
`antilymphocyte globulin
`
`Laboratory
`
`Biopsy
`
`Aspiration
`Cytology
`
`Urine Cytology
`
`Manometry
`Ultrasonogrsphy
`
`Magnetic
`Resonance
`Imagery
`Radionuclide
`Scan
`
`Therapy
`
`WA serum trough level > 200 ng/mL
`Gradual rise in Cr (<0.15 mg/dl/day)‘
`Cr plateau < 25% above baseline
`BUN/Cr 2 20
`Arteriolopathy (medial hypertrophy“,
`hyalinosis, nodular deposits, intimal
`thickening, endothelial vacuolization,
`progressive scarring)
`Tubular atrophy, isometric
`vacuolization, isolated calcifications
`Minimal edema
`Mild‘focal infiltratesc
`
`Diffuse interstitial fibrosis, often
`striped form
`CyA deposits in tubular and
`endothelial cells -
`Fine isometric vacuolization of
`tubular cells
`'
`
`Tubular cells with vacuoliration and
`granularization
`
`lntracapsular pressure < 40 mm Hgh
`Unchanged graft cross sectional area
`
`Normal appearance
`
`Normsl or generally decreased
`perfusion
`-
`I
`Decrease in tubular function
`(191 l-hippuran) > decrease in
`perfusion (99m Tc DTPA)
`Responds to decreased
`Sandimmune® (cyclosporine, USP)
`
`ap < 0:05, hp < 0.01, °p < 0.001, dp < 0.0001
`
`consult 1992 Supplements for revisions
`
`PRECAUTIONS
`General
`
`Patients with malabsorption may have difficulty in achiev-
`ing therapeutic levels with Sandimmune® soft gelatin cap-
`sules or oral solution.
`'
`HYPertension is a common side effect of Sandimmune®
`(°¥Closporine, USP) therapy. (Sec ADVERSE REACTIONS)
`lild or moderate hypertension is more frequently encoun-
`l“6d than severe hypertension and the incidence decreases
`0Ver time. Antihypertensive therapy may be required. Con-
`trol of blood pressure can be accomplished with any of the
`Common antihypertensive agents. However, since cyclo-
`§P°Yine may cause hyperkalemia, potassium-sparing diuretr
`“33 Should not be used. While calcium antagonists can be
`‘9 ective agents in treating cyclosporinc—armciated hyper~
`“Elan, care should be taken since interference with cyclo«
`SWine metabolism may require a dosage adjustment. (See
`"‘12 Interactions)
`During treatment with Sandimmune® (cyclosporinc, USP),
`vacflirtation may be less effective; and the use of live attenu-
`“ ed vaccines should be avoided.
`
`{)nmfmatlon for Patients
`EmOuts should be informed ofthe necessity of repeated labo«
`{SON tests while they are receiving, the druu. The; hould
`EiVen careful dosage instructions, advised ol'tht potential
`
`janfli ill'ld l'El‘IIIIJW-I'l rllblilrl'll‘in El Irma-5L! ihefimldimmu .-_.:{r_|:
`(cyclosporine, USP) dosage to a very high level in an attempt-
`,” reverse the rejection.
`Occasionally patients have developed a syndrome ofthrom-
`bwytopenia and microangiopathic hemolytic anemia which
`may result in graft failure. The vasculopathy can occur in
`the absence of rejection and is accompanied by avid platelet
`consumption within the graft as demonstrated by Indium111
`labeled platelet studies. Neither the pathogenesis nor the
`management of this syndrome is clear. Though resolution
`has occurred after reduction or discontinuation of Sandim-
`mune® (cyclooporine, USP) and 1') administration ofstrepto
`kinase and heparin or 2) plasmapheresis, this appears to
`depend upon early detection with IndiumJul labeled platelet
`scans. (See ADVERSE REACTIONS)
`Significant hyperkalemia (sometimes associated with hyper-
`chloremic metabolic acidosis) and hyperuricemia’have‘ been
`seen occasionally in individual patients.
`Hepatotoxicity has been noted in 4% of cases of renal trans-
`plantation, 7% of cases of cardiac transplantation, and 4% of
`cases of liver transplantation. This was usually noted during
`the first month of therapy when high doses of Sandim-
`mune® (cyclosporine, USP) were used and consisted of ele
`vations of hepatic enzymes and bilirubin. The chemistry
`elevations usually decreased with a reduction in dosage.
`A5 in patients receiving other immunosuppressants, those
`patients receiving Sandimmune® (cyclosporine, USP) are at
`increased risk for development of lymphomas and other ma-
`lignancies, particularly those of the skin. The increased risk
`appears related to the intensity and duration ofimmunosup-
`pression rather than to the use of specific agents. Because of
`the danger of oversuppression of the immune system, which
`can also increase susceptibility to infection, Sandimmune®
`(cyclosporine, USP) should not be administered with other
`immunosuppresaive agents except adrenal corticosteroids.
`The efficacy and safety of cyclosporine in combination with
`other immunosuppressive agents has not been determined.
`There have been reports of convulsions in adult and pediat-
`ric patients receiving cyclosporine, particularly in combina-
`tion with high dose methylprednisolone.
`Rarer (approximately 1 in 1000), patients receiving Sandirn~
`niune® (cyclosporine concentrate for injection) ampuls,
`USP, have experienced ansphylactic reactions. Although
`the exact cause of these reactions is unknown, it is believed
`to be due to the Cremophor® EL (polyoxyethylated castor
`oil) used as the vehicle for the I.V. formulation These reac~
`lions have consisted of flushing of the face and upper thorax,
`acute respiratory distress with dyspnea and wheezing, blood
`pressure changes, and tachycardia. One patient died after
`respiratory arrest and aspiration pneumonia. In some cases,
`the reaction subsided after the infusion was stopped.
`Patients receiving Ssndimmune® (cyclcsporlne concen-
`trate for injection) ampuls, USP. should be under continuous
`observation for at least the first 30 minutes following start
`of the infusion and at frequent intervals thereafter. If ana-
`phylaxis occurs, the infusion should be stopped. An aqueous
`solution of epinephrine 1:1000 should be available at the
`bedside as well as a source of oxygen.
`Anaphylactic reactions have not been reported with the soft
`gelatin capsules or oral solution which lack Cremophor® EL
`(Polyoxyethylated castor oil), In fact, patients experiencing.
`anaphylactic reactions have been treated subsequently with
`the soft gelatin capsules or oral solution without incident.
`Care should be taken in using Sandimmune® (cyclosporine,
`USP) with nephrotoxic drugs. (See PRECAUTIONS)
`‘
`
`in“ ‘ '0" L'IY C if“:
`
`
`Mr
`
`isks during pregnancy, and informed ofthe increasedrisk of
`neoplasia.
`Laboratory Tests
`Renal and liver functions should be assessed repeatedly by
`measurement of BUN, serum creatinine, serum bilirubin,
`and liver enzymes.
`Drug Interactions
`All of the individual drugs cited below are well substantiated
`to interact with Sandimmune® (cyclosporine, USP).
`Drugs That Exhibit Nephrotoxic Synergy
`gentamicin
`amphoicricin B
`tobramycin
`ketoconazole
`vancomycin
`melphslan
`cimetidine
`trimethoprim with
`ranitidine
`sulfamethoxazole
`diclofenac
`azapropazon
`Careful monitoring of renal function should be practiced
`when Sandimmune® (cyclosporine, USP) is used with neph-
`rotoxic drugs.
`_
`Drugs That Alter Cyclosporine Levels
`Cyclosporine is extensively metabolized by the liver. There-
`fore, circulating cyclosporine levels may be influenced by
`drugs that affect hepatic microscmal enzymes, particularly
`the cytochrome P450 system. Substances known to inhibit
`these enzymes will decrease hepatic metabolism and in-
`crease cyclosporine levels. Substances that are inducers of
`cytochrome P450 activity will increase hepatic metabolism
`and decrease cyclosporine levels. Monitoring of circulating
`cyclosporine levels and appropriate Sandimmune® (cyclo-
`sporine, USP) dosage adjustment are essential when these
`drugs are used concomitantly (see Blood Level Monitoring).
`Drugs That Inc—rmflz Cyclosporinc Levels
`diltiazom
`ketoconazole
`uicurdipinc
`fluconszole
`verapamil
`itraconazole
`danazol
`erythromycin
`bromocriptine
`methylprednisolone
`metnclopramide
`
`Drugs That Decrease Cyclasporine Levels
`rifampin
`phenytoin
`phenobarbital
`carbamazepine
`Other Drug Interactions
`Reduced clearance of prcdnisolone, digoxin and lovastatin
`have been observed when these drugs are administered with
`Sandimmune® (cyclosporine, USP). In addition, a decrease
`in the apparent volume of distribution of digoxin has been
`reported after Sandimmune® (cyclosporine, USP) adminis
`tration. Severe digitalis toxicity has been seen within days of
`starting cyclosporine in several patients taking digoxin. San—
`dimmune® (cyclosporine, USP) should not be used with
`potassiumsparing diuretics because hyperkalemia can oc—
`cur. During treatment with Sandimmune® (cyclosporine,
`USP), vaccination may be less effective; and the use of live
`vaccines should be avoided. Myositis has occurred with con
`comitant
`lovastatin, frequent gingival hyperplasia with
`nifedipine, and convulsions with high dose methylpredniso—
`lone. Further information on drugs that have been reported
`to interact with Sandimmune® (cyclosporine, USP) is avail-
`able from Sandoz Pharmaceuticals Corporation.
`Carcinogenesis, Mutagenesls, and Impairment of Fertility
`Cyclosporine gave no evidence of mutagenic or terstogenic
`effects in appropriate test systems. Only at dose levels toxic
`to dams, were adverse effects seen in reproduction studies in
`rats. (See Pregnancy)
`Carcinogenicity studies were carried out in male and female
`rats and mice. In the 78-week mouse study, at doses of 1, 4,
`and 16 mg/kg/day, evidence of a statistically significant
`trend was found for lymphocytic lymphomas in females, and
`the incidence of hcpatocellular carcinomas in mid—dose
`males significantly exceeded the control value, In the 24»
`month rat study, conducted at 0.5, 2, and 8 mg/kg/day, pan~
`creatic islet cell adenomas significantly exceeded the control
`rats in the low dose level. The hepatov-ellular carcinoma
`and pancreatic islet cell ndenonias were not dose related.
`N0 impairment in fertility was demonstrated in studies in
`male and female rats.
`
`
`
`v"
`
`NOVARTIS EXHIBIT 2069
`Par v. Novartis, IPR 2016-01479
`Page 4 of 6
`
`

`

`l !
`
`Consult 1992 Supplements for revisionsm“.
`“hysicians’ 'iesk 3919“;an
`Renal Transplant Patients in Whom Therapy was Discontinued
`Randomized Patients
`
`Reason for Discontlnuation
`
`Sandimmune®
`(N:227)
`it
`
`Azathioprine
`(N=228)
`it
`l
`
`Renal Toxicity
`Infection
`Lack of Efficacy
`Acute Tubular Necrosis
`Lymphoma/
`Lymphoproliferative Disease
`Hypertension
`Hematological Abnormalities
`Other
`
`5.7
`0
`2.6
`2.6
`
`0.4
`0
`0
`0
`
`
`
`
`
`Cyclosporine has not been found mutagenic/genotoxic in the
`Amos Test. the V79-HGPRT Test, the micronucleus test in
`mice and Chinese hamsters,
`the chromosome-aberration
`tests in Chinese hamster bone-marrow, the mouse dominant
`lethal assay, and the DNA-repair test in sperm from treated
`mice. A recent study analyzing sister chromatid exchange
`(SCE) induction by cyclosporine using human lymphocytes
`in uitro gave indication of a positive effect (i.e., induction of
`SCE). at high concentrations in this system.
`An increased incidence of malignancy is a recognized compli-
`cation of immunosuppression in recipients of organ trans-
`plants. The most common forms of neoplasms are non-Hodg-
`kin’s lymphoma and carcinomas of the skin. The risk of ma-
`lignancies in cyclosporine recipients is higher than in the
`Sandimmune® (cyclosporine, Udli') was discontinued on a temporary basis and then restarted in .18 additional patths.
`normal, healthy population but similar to that in patients
`_—.—-—.—~———————-—-———-—————————_~_.
`receiving other immunosuppressive therapies. It has been
`allergic reactions, anemia, anorexia, confusion, conjunctivi.
`followed up to 4 years, postnatal development was said to be
`reported that reduction or discontinuance of immunosup
`normal. More information on cyclosporine use in pregnancy
`tis, edema, fever, brittle fingernails, gastritis, hearing loss,
`pression may ‘cause the lesions to rcgrem.
`is available from Sandoz Pharmaceuticals Corporation.
`hiccups, hyperglycemia, muscle pain, peptic ulcer, thrombo.
`Pregnancy
`Nursing Mothers
`cytopcnia, tinnitus.
`Pregnancy Category (I Sandimmune® (cyclosporine) oral
`Since Sandimmune® (cyclosporine) is excreted in human
`The following reactions occurred rarely: anxiety, chest pain,
`solution, USP, has been shown to be embryo- and fetotoxic in
`milk, nursing should be avoided.
`constipation, depression, hair breaking, hematuria,
`joint
`rats and rabbits when given in doses 2—5 times the human
`Pediatric Use
`pain, lethargy, mouth sores, myocardial infarction, night
`dose. At toxic doses (rats at 30 mg/kg/day and rabbits at 100
`Although no adequate and well controlled studies have been
`sweats, pancreatitis, pruritue, swallowing difficulty, tin.
`mg/kg/day), Sandimmune® (cyclosporine) oral solution,
`conducted in children, patients as young as 6 months of age
`gling, upper GI bleeding, visual disturbance, weakness,
`USP, was embryo- and fetotoxic as indicated by increased
`weight loss.
`[See table above and on next page]
`have received the drug with no unusual adverse effects.
`pre- and postnatal mortality and reduced fetal weight to
`Cremophor® EL (polyoxyethylated caster oil) is known to
`ADVERSE REACTIONS
`gether with related skeletal retardations. In the well-toler-
`cause hyperlipemia and electrophoretic abnormalities of
`ated dose range (rats at up to 17 mg/kg/day and rabbits at up
`The principal adverse reactions of Sandimmune® (cyclo-
`lipopruteins. These effects are reversible upon discontim
`to 30 mg/kg/day), Sandimmune® (cyclosporine) oral solu-
`sporine, USP) therapy are renal dysfunction, tremor, hirsutr
`uation of treatment but are usually not a reason tostop
`tion, USP, proved to be without any embryolethal or terato-
`treatment.
`ism, hypertension, and gum hyperplasia.
`genie effects.
`Hypertension, which is usually mild to moderate, may occur
`OVERDOSAGE
`There are no adequate and well—controlled studies in preg~
`in approximately 50% of patients following renal transplan
`nant women. Sandimmune® (cyclosporine, USP) should be
`There is a minimal experience with overdosage. Because of
`tation and in most cardiac transplant patients.
`used during pregnancy only if the potential benefit justifies
`the slow absorption of Sandimmune® soft gelatin capsules
`Glomerular capillary thrombosis has been found in patients
`the potential risk to the fetus.
`or oral solution, forced emesis would be of value up to 2 hours
`treated with cyclosporine and may progress to graft failure.
`after administration. Transient hepatotoxicity and nephro
`The following data represent the reported outcomes of 116
`The pathologic changes resemble those seen in the hemo—
`toxicity may occur which should resolve following drug with-
`pregnancies in women receiving Sandimmune® (cyclo-
`lytic—uremic syndrome and include thrombosis of the renal
`sporine, USP) during pregnancy, 90% of whom were trans-
`drawal. General supportive measures and symptomatic
`microvasculature, with plateletrfibrin thrombi occluding
`plant patients, and most of whom received Sandimmune®
`treatment should be followed in all cases of overdosage:
`glomerular capillaries and efferent arterioles, microangio-
`(cyclosporine, USP) throughout the entire gestational pe-
`Sandimmune® (cyclosporine, USP) is not dialyzable to any
`pathic hemolytic anemia, thrombocytopenia, and decreased
`riod. Since most of the patients were not prospectively identi-
`great extent, nor is it cleared well by charcoal hemoperfu-
`renal function. Similar findings have been observed when
`fied, the results are likely to be biased toward negative out-
`sion. The oral LDw is 2329 mg/kg in mice, 1480 nag/kg in
`other
`immunosuppressives have been employed post-
`comes. The only consistent patterns of abnormality were
`rats, and > 1000 mg/kg in rabbits. The I.V. LDm is 148 mg/
`transplantation.
`premature birth (gestational period of 28 to 36 weeks) and
`kg in mice, 104 mg/kg in rats, and 46 mg/kg in rabbits.
`Hypomagnesemia has been reported in some, but not all,
`low birth weight for gestational age. It is not possible to sepa-
`DOSAGE AND ADMINISTRATION
`patients exhibiting convulsions while on cyclosporine ther-
`rate the effects of Sandimmune® (cyclosporine, USP) on
`Sandimmune® (cyclosporine, USP) Soft Gelatin Capsules
`apy. Although magnesium-depletion studies in normal sub-
`these pregnancies from the effects of the other immunosup-
`and Sendimmune® (cyclospor