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`PHYSICIANS
`DESK
`REFERENCE
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`ISBN: 1-56363087-7
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`NOVARTIS EXHIBIT 2070
`Par v. Novartis, IPR 2016-01479
`Page 1 of 4
`
`

`

`‘-
`
`OVERDOSAGE
`Acute intoxication may be manifested by “Ore .
`and central nervous system stimulation (man’s? ...,
`sions), followed by megaloblastic anemia, leuko 1’1
`bocytopenia, glossitis and crystalluria. In acutepiem
`emesis and gastric lavage followed by purges mam"
`fit. The patient should be adequately hydrated
`renal damage. The renal and hematopoietic syg in
`be monitored for at least one month after
`I“
`the patient is having convulsions, the use 0
`barbiturate is indicated. For depressed plate}
`blood cell counts, folinic acid (leucovorin) shoufde
`tered in a dosage of 5 mg to 15 mg intramuscu
`days or longer.
`larlyd IF.
`DOSAGE AND ADMINISTRATION
`(See INDICATIONS AND USAGE section):
`(a) Treatment ofAcute Attack of malaria
`A single dose of the following number of Fansida T'.
`used in sequence with quinine or alone:
`r "
`Adults
`2 to 3 table .
`2 tablets
`9 to 14 years
`4 to 8 years
`1 tablet
`Under 4 years
`1/2 tablet
`03) Malaria Prophylaxis
`The first dose of Fansidar should be taken 1 0r 2 d I
`departure to an endemic area; administration shmfd -'
`tinued during the stay and for 4 to 6 weeks after
`Once Ev ,
`Once Weekly
`Two W. l,
`1 tablet
`2 tablets .
`3/, tablet
`11/2 table
`1 tablet
`1/2 tablet
`1/4 tablet
`1/2 tablet
`
`Adults
`9 to 14 years
`4 to 8 years
`Under 4 years
`.
`HOW SUPPLIED
`Scored tablets, containing 500 mg sulfadoxine and A
`pyrimethamine—Tel-E-Dose® packages of 25 (N
`0161-03). Imprint on tablets: FANSIDAR
`R
`Revised: October 1993
`Shown in Product Identification Guide, page
`
`'
`
`'
`
`'
`'
`
`FLUOROURACI L
`[flu “ro—u ‘ra-sil]
`INJECTION
`
`The following text is complete prescribing informatio -'
`on. off"me labeling in effect June 1, 1994.
`
`WARNING
`It is recommended that FLUOROURACIL he give ‘
`by or under the supervision of a qualified physi D
`is experienced in cancer chemotherapy and who
`versed in the use of potent antimetabolites.
`5
`»
`I
`the possibility of severe toxic reactions, it is
`mended that patients be hospitalized at least du q“
`initial course of therapy.
`
`2034/PHYSICIANS’ DESK REFERENCE®
`Roche Laboratories—Cont.
`
`DESCRIPTION
`Fansidar is an antimalarial agent, each tablet containing
`500 mg N1-(5,6rdimethoxy-4-pyrimidinyl) sulfanilamide (sul-
`fadoxine) and 25 mg 2,4—diamino-5—(pchlorophenylr6-ethyl-
`pyrimidine (pyrimethamine), Each tablet also contains corn
`starch, gelatin, lactose, magnesium stearate and talc.
`,
`CLINICAL PHARMACOLOGY
`Fansidar is an antimalarial agent which acts by reciprocal
`potentiation of its two components, achieved by a sequential
`blockade of two enzymes involved in the biosynthesis of fo-
`linic acid within the parasites. Fansidar is effective against
`certain strains of Plasmodium falciparum that are resistant
`to chloroquine.
`Both the sulfadoxine and the pyrimethamine ofFansidar are
`absorbed orally and are excreted mainly by the kidney. Fol-
`lowing a single tablet administration, sulfadoxine peak
`plasma concentrations of 51 to 76 mcg/mL were achieved in
`2.5 to 6 hours and the pyrimethamine peak plasma concen-
`trations of 0.13 to 0.4. mcg/mL were achieved in 1.5 to 8
`hours. The apparent half-life of elimination of sulfadoxine
`ranged from 100 to 231 hours with a mean of 169 hours,
`whereas pyrimethamine half-lives ranged from 54 to 148
`hours with a mean of 111 hours. Both drugs appear in breast
`milk of nursing mothers.
`.
`INDICATIONS AND USAGE
`Fansidar is indicated for the treatment of P. falciparum ma-
`laria for. those patients in whom chloroquine resistance is
`suspected Malaria prophylaxis with Fansidar is indicated
`for travelers to areas where chloroquineresistant P. falcipa-
`rum malaria is endemic. However, strains of P. falciparum
`may be encountered which have developed resistance to
`Fansidar.
`CONTRAINDICATIONS
`Prophylactic (repeated) use of Fansidar is contraindicated in
`patients with severe renal insufficiency, marked liver paren-
`chymal damage or blood dyscrasias. Hypersensitivity to pyri-
`metharnine or sulfonamides. Patients with documented meg-
`aloblastic anemia due to folate deficiency. Infants less than
`two months of age. Pregnancy at term and during the nurs
`ing period because sulfonamides pass the placenta and are
`excreted in the milk and may cause kernicterus.
`WARNINGS
`
`FATALITIES ASSOCIATED WITH THE ADMINISTRA-
`TION OF FANSIDAR HAVE OCCURRED DUE TO SE-
`VERE REACTIONS, INCLUDING STEVENS-JOHNSON
`SYNDROME AND TOXIC EPIDERMAL NECROLYSIS.
`FANSIDAR PROPHYLAXIS SHOULD BE DISCONTIN-
`UED AT THE FIRST APPEARANCE OF SKIN HASH/IF
`A SIGNIFICANT REDUCTION IN THE COUNT OF ANY
`FORMED BLOOD ELEMENTS IS NOTED, 0R UPON
`THE OCCURRENCE OF ACTIVE BACTERIAL 0R FUN-
`GAL INFECTIONS.
`
`4. Drug Interactions: There have been reports which may
`indicate an increase in incidence and severity of adverse
`reactions when chloroquine is used with Fansidar as com-
`pared to the use of Fansidar alone. Fansidar is compatible
`with quinine and with antibiotics. However, antifolic drugs
`such as ,sulfonamides or trimethoprim—sulfamethoxazole
`combinations should not be used while the patient is receiv-
`ing Fansidar for antimalarial prophylaxis. Fansidar has not
`been reported to interfere with antidiabetic agents.
`If signs of folic acid deficiency develop, Fansidar should be
`discontinued. Folinic acid (leucovorin) may be administered
`in doses of5 mg to 15 mg intramuscularly daily, for 3 days or
`longer, for depressed platelet or white blood cell counts'in
`patients with drug-induced folic acid deficiency when recov-
`ery is too slow.
`5. Carcirwgenesis, mutagenesis, impairment of fertility: Pyri-
`methamine was not found carcinogenic in female mice or in
`male and female rats. The carcinogenic potential of pyri-
`methamine in male mice could not be assessed from the
`study because of markedly reduced lifespan. Pyrimetha-
`mine was found'to be mutagenic in laboratory animals and
`also in human bone marrow following 3 or 4 consecutive
`daily doses totaling 200 mg to 300 mg. Pyrimethamine was
`not found mutagenic in the Ames test. Testicular changes
`have been observed in rats treated with 105 mg/kg/day of
`Fansidar and with 15 mg/kg/day of pyrimethamine-alone.
`Fertility of male rats and the ability of male or female rats to
`mate were not adversely affected at dosages of up to 210 mg/
`kg/day of Fansidar. The pregnancy rate of female rats was
`'not affected following their treatment with 10.5 mg/kg/day,
`but was significantly reduced at dosage of 31.5 mg/kg/day
`or higher, a dosage approximately 30 times the weekly hu-
`man prophylactic dose or higher.
`6. Pregnancy: Teratogenic effects: Pregnancy Category C.
`Fansidar has been shown to be teratogenic in rats when
`given in weekly doses approximately 12 times the weekly
`human prophylactic dose. Teratology studies with pyrimeth-
`amine plus sulfadoxine (1:20) in rats showed the minimum
`oral teratogenic dose to be approximately 0.9 rug/kg pyri-
`methamine plus 18 mg/kg sulfadoxine. In rabbits, no terato—
`genic effects were noted at oral doses as high as 20 mg/kg
`pyrimetharnine plus 400 mg/kg sulfadoxine.
`There are no adequate and well-controlled studies in preg-
`nant women. However, due to the teratogenic effect shown in
`animals and because pyrimethamine plus sulfadoxine may
`interfere with folic acid metabolism, Fansidar therapy
`should be used during pregnancy only if the potential benefit
`justifies
`the potential
`risk to the fetus. Women of
`childbearing potential who are traveling to areas where ma--
`laria is endemic should be warned against becoming preg-
`nant.
`Nonteratogenic Effects: See “CONTRAINDICATIONS”
`section.
`I
`“CONTRAINDICATIONS”
`7. Nursing Mothers: S
`section.
`8. Pediatric Use: Fansidar should not be given to infants
`less than two months of age because of inadequate develop-
`ment of the glucuronide-forming enzyme system.
`
`
`
`istered dose is metabolized, primarily 1“
`
`ADVERSE REACTIONS
`Fatalities associated with the administration of sulfona-
`For completeness, all major reactions to sulfonamides and to
`mides, although rare, have occurred due to severe reactions,
`pyrimethamine are included below, even though they may
`including fulminant hepatic necrosis, agranulocytosis, aplas-
`not have been reported with Fansidar. See WARNINGS
`tic anemia and other blood dyscrasias. Fansidar prophylactic
`and
`PRECAUTIONS
`(Information
`for
`the Patient)
`regimen has been reported to cause leukopenia during a
`sections.
`treatment of two months or longer. This Ieukopenia is gener-
`Blood lb'scrosios: Agranulocytosis, aplastic anemia, mega-
`ally mild and reversible.
`loblastic anemia, thrombopenia, leukopenia, hemolytic ane-
`PRECAUTIONS
`mia, purpura, hypoprothrombinemia, methemoglobinemia
`1. General: Fansidar should be given with caution to pa-
`and eosinophilia.
`tients with impaired renal or hepatic function, to those with
`Allergic Reactions: Erythema multiforme, Stevensdohn—
`possible folate deficiency and to those with severe allergy or
`son'syndrome, generalized skin eruptions, toxic epidermal
`bronchial asthma. As with some sulfonamide drugs, in glu-
`necrolysis, urticaria, serum sickness, pruritus, exfoliative
`cose-6-phosphate dehydrogenase-deficient
`individuals, he-
`dermatitis, anaphylactoid reactions, periorbital edema, con-
`junctiva] and scleral injection, photosensitization, arthral-
`molysis may occur. Urinalysis with microsco ic examination
`and renal function tests should be performe during therapy
`gia and allergic myocarditis.
`Gastrointestinal Reactions: Glossitis, stomatitis, nausea,
`of those patients who have impaired renal function.
`2. Information for the Patient: Patients should be warned
`emesis, abdominal pains, hepatitis, hepatccellularnecrosis,
`that at the first appearance of a skin rash, they should stop
`diarrhea and pancreatitis.
`use of Fansidar» and seek medical attention immediately.
`CNS. Reactions: Headache, peripheral neuritis, mental
`Adequate fluid intake must be maintained in order to pre-
`depression, convulsions, ataxia, hallucinations,
`tinnitus,
`vent crystalluria and stone formation.
`vertigo, insomnia, apathy, fatigue, muscle weakness and
`nervousness.
`.
`Patients should also be warned that the appearance of sore
`throat, fever, arthralgia, cough, shortness of breath, pallor,
`Respiratory Reactions: Pulmonary infiltrates.
`purpura, jaundice or glossitis may be early indications of
`Miscellaneous Reactions.- Drug fever, chills, and toxic ne
`serious disorders which require prophylactic treatment to be
`phrosis with oliguria and anuria. Periarteritis nodosa and L.
`stopped and medical treatment to be sought.
`E. phenomenon have occurred.
`The sulfonamides bear certain chemical similarities to some
`Females should be cautioned against becoming pregnant and
`should not breast feed their infants during Fansidar therapy
`goitrogens,‘ diuretics (acetazolamide and the thiazides) and
`or prophylactic treatment.
`oral hypoglycemic agents. Diuresis and hypoglycemia have
`Patients should be warned to keep Fansidar out of reach of
`occurred rarely in patients receiving sulfonamides. Cross-
`children.
`sensitivity may exist with these agents. Rats appear to be
`especially susceptible to the goitrogenic effects of sulfona-
`3. laboratory Tests: Periodic blood counts and analysis of
`mides, and long-term administration has produced thyroid
`axis.
`prine for crystalluria are desirable during prolonged prophy-
`malignancies in the species.
`Information will be superseded by supplements and subsequent editions
`
`DESCRIPTION
`FLUOROURACIL INJECTION, an antineoplasnc
`tabolite, is a sterile, nonpyrogenic injectable so "
`intravenous administration. Each 10—mL cont?” ""-
`fluorouracil; pH is adjusted to apprOXimately 9'
`“
`dium hydroxide.
`.
`.
`Chemically, fluorouracil, a fluorinated Pym?“
`fluoroZA (1H,3Hlpyrimidinedione. It IS a white h
`cally white crystalline powder which is spaflllgly
`;
`water. The molecular weight of fluorouracil 15
`CLINICAL PHARMACOLOGY
`There is evidence that the metabolism of flu" "r.
`the anabolic pathway blocks the methylationnr.1
`deoxyuridylic acid to thymidylic acid. In thls 1?: n I,
`uracil interferes with the synthesis of decryrl£5211 “
`(DNA) and to a lesser extent inhibits the forum gm,
`cleic acid (RNA). Since DNA and RNA are
`a
`division and growth, the effect of fluoroumCl 1‘;
`ate a thymine deficiency which provokes unbé‘R
`and death of the cell. The effects of DNA an w m
`tion are most marked on those cells whlch gm id ‘
`and which take up fluorouracil at a more “a;
`_"
`Following intravenous injection,
`fluorourali
`4
`into tumors. intestinal mucosa, bone marrol‘f’l'ni
`,-i.
`tissues throughout the body. In spite of 1‘35
`‘ the t p
`bility, fluorouracil diffuses readin 803'055 fluid
`barrier and distributes into cerebr'OSP1n
`tissue.
`is
`,1
`Seven percent to 20% of the parent drug 90”
`changed in the urine in 6 hours; of this Over 6 Di. _.
`in the first hour. The remaining persentfg t},
`-
`
`|
`
`;
`
`_
`
`NOVARTIS EXHIBIT 2070
`Par v. Novartis, IPR 2016-01479
`Page 2 of 4
`
`

`

`
`
`PRODUCT INFORMATION/2035
`
`
`
`
`Thrombocytopenia (platelets under 100,000).
`Hemorrhage from any site.
`The administration of 5-fluorouracil has been associated
`with the occurrence of palmar—plantar erythrodysesthesia
`syndrome, also known as hand-foot syndrome. This syn-
`drome has been characterized as a tingling sensation of
`hands and feet which may progress over the next few days to
`pain when holding objects or walking. The palms and soles
`become symmetrically swollen and erythematous with ten-
`derness of the distal phalanges, possibly accompanied by
`desquamation. Interruption of therapy is followed by grad-
`ual resolution over 5 to 7 days. Although pyridoxine has been
`reported to ameliorate the palmar-plantar erythrodyses-
`thesis syndrome, its safety and effectiveness have not been
`established.
`Information for Patients: Patients should be informed of
`expected toxic effects, particularly oral manifestations. Pa-
`tients should be alerted to the possibility of alopecia as a re-
`sult of therapy and should be informed that it is usually a
`transient effect.
`laboratory Tests: White blood counts with differential are
`recommended before each dose.
`Drug Interactions: Leucovorin calcium may enhance the
`toxicity of fluorouracil.
`Also see WARNINGS section.
`Carcinogenesis, Mutagenesis, Impairment of Fertility: Car-
`cinogenesis: Long-term studies in animals to evaluate the
`carcinogenic potential of fluorouracil have not been con-
`ducted. However, there was no evidence of carcinogenicity in
`small groups ofrats given fluorouracil orally at doses of0.01 ,
`0.3, 1 or 3 mg per rat 5 days per week for 52 weeks, followed
`by a 6-month observation period. Also, in other studies, 33
`mg/kg of flourouracil was administered intravenously to
`male rats once a week for 52 weeks followed by observation
`for the remainder of their lifetimes with no evidence of carci-
`nogenicity. Female mice were given 1 mg of fluorouracil in-
`travenously once a week for 16 weeks with no effect on the
`incidence of lung adenomas. On the basis of the available
`data, no evaluation can be made of the carcinogenic risk of
`fluorouracil to humans.
`'
`Mntogenesis: Oncogenic transformation offibroblasts from
`mouse embryo has been induced in vitro by fluorouracil, but
`the relationship between oncogenicity and mutagenicity is
`not clear. Fluorouracil has been shown to be mutagenic to
`several strains of Salmonella typhimurium,
`including TA
`1535, TA 1537 and TA 1538, and to Saccharomyces cerevisiae,
`although no evidence of mutagenicity was found with Salmo-
`nella typhimurium strains TA 92, TA 98 and TA 100. In addi-
`tion, a positive effect was observed in the micronucleus test
`on bone marrow cells of the mouse, and fluorouracil at very
`high concentrations produced chromosomal breaks in ham-
`ster fibroblasts in vitro.
`Impairment of Fertility: Fluorouracil has not been ade-
`quately studied in animals to permit an evaluation of its
`effects on fertility and general reproductive performance.
`However, doses of 125 or 250 mg/kg, administered intraperi—
`toneally, have been shown to induce chromosomal aberra-
`tions and changes in chromosomal organization of spermato-
`gonia in rats. Spermatogonial differentiation was also inhib-
`ited by fluorouracil, resulting in transient infertility. How-
`ever, in studies with a strain of mouse which is sensitive to
`the induction of sperm head abnormalities after exposure to
`a range of chemical mutagens and carcinogens, fluorouracil
`did not produce any abnormalities at oral doses of up to 80
`mg/kg/day. In female rats, fluorouracil, administered intra-
`peritoneally at weekly doses of 25 or 50 mg/kg for 3 weeks
`during the pre-ovulatory phases of oogenesis, significantly
`reduced the incidence of fertile matings, delayed the develop-
`ment of pre« and postimplantation embryos, increased the
`incidence of pro-implantation lethality and induced chromo-
`somal anomalies in these embryos. In a limited study in rab—
`bits, a single 25 mg/kg dose offluorouracil or 5 daily doses of
`5 mg/kg had no effect on ovulation, appeared not to affect
`implantation and had only a limited effect in producing zy-
`gote destruction. Compounds such as fluorouracil, which
`interfere with DNA, RNA and protein synthesis, might be
`expected to have adverse effects on gametogenesis.
`Pregnancy: Pregnancy Category D. See WARNINGS
`section.
`Nonteratogenic Effects: Fluorouracil has not been studied
`in animals for its effects on peri- and postnatal development.
`However, fluorouracil has been shown to cross the placenta
`and enter into fetal circulation in the rat. Administration of
`fluorouracil has resulted in increased resorptions and em-
`bryolethality in rats. In monkeys, maternal doses higher
`than 40 mg/kg resulted in abortion of all embryos exposed to
`fluorouracil. Compounds which inhibit DNA, RNA and pro-
`tein synthesis might be expected to have adverse effects on
`peri~ and postnatal development.
`Nursing Mothers:
`It is not known whether fluorouracil is
`excreted in human milk. Because fluorouracil inhibits DNA,
`RNA and protein synthesis, mothers should not nurse while
`receiving this drug.
`.
`Pediatric Use: Safety and effectiveness in children have not
`been established.
`
`thrombocytopenia, agranulo—
`
`ADVERSE REACTIONS
`Stomatitis and esophagopharyngitis (which may lead to
`sloughing and ulceration), diarrhea, anorexia, nausea and
`emesis are commonly seen during therapy.
`Leukopenia usually follows every course of adequate thcr~
`apy with Fluorouracil. The lowest white blood cell counts are
`commonly observed between the 9th and 14th days after the
`first course of treatment, although uncommonly the maxi-
`mal depression may be delayed for as long as 20 days. By the
`30th day the count has usually returned to the normal range.
`Alopecia and dermatitis may be seen in a substantial num-
`ber of cases. The dermatitis most often seen is a pruritic mac.
`ulopapular rash usually appearing on the extremities and
`less frequently on the trunk. It is generally reversible and
`usually responsive to symptomatic treatment.
`Other adverse reactions are:
`Hematologic: pancytopenia,
`cytosis, anemia.
`Cardiovascular: myocardial ischemia, angina.
`Gastrointestinal: gastrointestinal ulceration and bleeding.
`Allergic Reactions: anaphylaxis and generalized allergic
`reactions.
`Neumlogr'c: acute cerebellar syndrome (which may persist
`following discontinuance of treatment), nystagmus, head-
`ache.
`Dermatologic: dry skin;
`fissuring; photosensitivity, as
`manifested by erythema or increased pigmentation of the
`skin; vein pigmentation, palmar-plantar erythrodysesthesia
`syndrome, as manifested by tingling of the hands and feet
`followed by pain, erythema and swelling.
`Ophthalmic:
`lacrimal duct stenosis, visual changes, lacri-
`mation, photophobia.
`Psychiatric: disorientation, confusion, euphoria.
`Miscellaneous:
`thrombophlebitis, epistaxis, nail changes
`(including loss of nails).
`OVERDOSAGE
`The possibility of overdosage with Fluorouracil is unlikely in
`view ofthe mode of administration. Nevertheless, the antici»
`pated manifestations would be nausea, vomiting, diarrhea,
`gastrointestinal ulceration and bleeding, bone marrow de-
`pression (including thrombocytopenia,
`leukopenia and
`agranulocytesis). No specific antidotal therapy exists. Pa-
`tients who have been exposed to an overdose of Fluorouracil
`should be monitored hematologically for at least four weeks.
`Should abnormalities appear, appropriate therapy should be
`utilized.
`The acute intravenous toxicity of fluorouracil is as follows:
`LDw
`
`SE.
`in /
`340:}: 17
`165i26
`27$5.1
`31.51233
`
`smiles
`Mouse
`Rat
`Rabbit
`Dog
`DOSAGE AND ADMINISTRATION
`General Instructions: Fluorouracil Injection should be ad-
`ministered only intravenously, using care to avoid extrava-
`sation. No dilution is required.
`All dosages are based on the patient’s actual weight. How-
`ever, the timated lean body mass (dry weight) is used ifthe
`patient is obese or if there has been a spurious weight
`gain due to edema, ascites or other forms of abnormal fluid
`retention.
`It is recommended that prior to treatment each patient be
`carefully evaluated in order to estimate as accurately as
`possible the optimum initial dosage of Fluorouracil.
`Dosage:
`12 rug/kg are given intravenously once daily for 4
`successive days. The daily dose should not exceed 600 mg. If
`no toxicity is observed, 6 mg/kg are given on the 6th, 8th, 10th
`and 12th days unless toxicity occurs. No therapy is given on
`the 5th, 7th, 9th or 11th days. Therapy is to be discontinued at
`the end of the 12th day, even if no toxicity has become appar-
`ent. (See WARNINGS and PRECAUTIONS sections.)
`Poor risk patients or those who are not in an adequate nutri-
`tional state (see CONTRAINDICATIONS and WARNINGS
`sections) should receive 6 mg/kg/day for 3 days. Ifno toxicity
`is observed, 3 mg/kg may be given on the 5th, 7th and 9th
`days unless toxicity occurs. No therapy is given on the 4th, 6th
`or 8th days. The daily dose should not exceed 400 mg.
`A sequence of injections on either schedule constitutes a
`"course of therapy.”
`In instances where toxicity has not
`Maintenance Therapy:
`been a problem, it is recommended that therapy be contin-
`ued using either of the following schedules:
`1. Repeat dosage of first course every 30 days after the last
`day of the previous course of treatment.
`2. When toxic signs resulting from the initial course of ther-
`apy have subsided, administer a maintenance dosage of 10
`wee .
`to 1:mg/kg/week as a single dose. Do not exceed 1 gm per
`The patient’s reaction to the previous course of therapy
`should be taken into account in determining the amount of
`the drug to be used, and the dosage should be adjusted so-
`
`Continued on next page
`
`uracil should be used with extreme caution in poor
`' nts with a history ofhighdose pelvic irradiation or
`use of alkylating agents, those who have a wide-
`involvement of bone marrow by metastatic tumors or
`' with impaired hepatic or renal function.
`. all number of patients, deficiency of dihydropyrimi—
`ehydrogenase has been reported.1 This condition may
`. prolonng elevated blood levels of dfluorouracil and
`(led toxicity in patients receiving 5-fluorouracil, par-
`ly when administered in combination with other anti-
`ratio agents.
`my: Teratogenic effects: Pregnancy category D.
`uracil may cause fetal harm when administered to a
`.
`twoman. Fluorouracil has been shown to be terato-
`in laboratory animals. Fluorouracil exhibited maxi-
`ratogenicity when given to mice as single intraperito-
`Jections of 10 to 40 mg/kg on day 10 or 12 of gestation.
`II.
`1y, intraperitoneal doses of 12 to 37 mg/kg given to
`tween days 9 and 12 of gestation and intramuscular
`tf3 to 9 mg given to hamsters between days 8 and 11 of
`'won were teratogenic. Malformations included cleft
`‘_ :_ skeletal defects and deformed appendages, paws and
`I e dosages which were teratogenic in animals are 1 to
`u the maximum recommended human therapeutic
`nmonkeys, divided doses of 40 mg/kg given between
`-'I and 24 of gestation were not teratogenic.
`- an} no adequate and well-controlled studies with Fluo-
`.‘
`In pregnant women. While there is no evidence of
`_'-.
`{city in humans due to Fluorouracil, it should be
`mlnd that other drugs which inhibit DNA synthesis
`_ bIEthotrexate and aminopterin) have been reported to
`I‘_- enlc in humans. Women of childbearing potential
`,1‘
`_adv1sed to avoid becoming pregnant. If the drug is
`“"313 Pregnancy, or if the patient becomes pregnant
`_ “(mg the drug, the patient should be told of the poten-
`-' Hi to the fetus. Fluorouracil should be used during
`_- CY Only ifthe potential benefit justifies the potential
`I ill? fetus.
`_” ‘ “"1 Therapy: Any form of therapy which adds to
`'
`0f the patient, interferes with nutrition or de-
`. “a? marrow function will increase the toxicity of
`IONS
`fluorouracil is a highly toxic drug with a narrow
`.fEtY- Therefore, patients should be carefully
`Since therapeutic response is unlikely to occur
`,9 evidence of toxicity. Severe hematological tox-
`r01ntcstinal hemorrhage and even death may re—
`9 use chluorouracil despite meticulous selection
`h manld careful adjustment of dosage. Although so
`9 cl 13 more likely in poor risk patients, fatalities
`m gained occasionally even in patients in rela-
`,.l
`.
`1 ion.
`"1,. be dlscontinued promptly whenever one of the
`“I: ’3’"! 0f toxicity appears:
`Id;if;"Phagopharyngitis, at the first visible sign:
`ml
`BC under 3500) or a rapidly falling white
`’ intractable.
`'frtfxluent bowel movements or watery stools.
`"131 ulceration and bleeding.
`
`-
`
`in
`
`"
`
`- metabOlism of fluorouracil results in degradation
`- (eg, 002, urea and a—fluoro—B—alanine) which are
`l
`‘ The inactive metabolites are excreted in the urine
`next 3 to 4 hours. When fluorouracil is labeled in the
`p(,sition, thus preventing the 14C metabolism to
`oximately 90% ofthe total radioactivity is excreted
`Pplne' When fluorouracil is labeled in the two carbon
`“2 proximately 90% of the total radioactivity is ex-
`" p
`ted 002. Ninety percent of the dose is ac-
`I,
`in expi
`,
`.
`.
`or during the first 24 hours followmg intravenous
`ram“-
`.
`.
`.
`.
`1nmavenous administration of fluorouracil, the
`Ijrdife of elimination from plasma is approximately
`"we with a range of 8 to 20 minutes, and is dose de-
`I: N’o intact drug can be detected in the plasma 3
`-".j
`" am, an intravenous injection.
`I' GATIONS AND USAGE
`,
`c
`'1
`fl
`is effective in the palliative management
`‘
`‘ [$1113 of the colon, rectum, breast, stomach and
`
`:.
`
`I:
`
`. AINDICATIONS
`'uracil therapy is contraindicated for patients in a
`“tritiunal state, those with depressed bone marrow
`flan, those with potentially serious infections or those
`‘ a known hypersensitivity to Fluorouracil.
`3
`GS
`. AILY DOSE OF FLUOROURACIL IS NOT TO EX-
`“ 500 MG. IT IS RECOMMENDED THAT PATIENTS
`,l, FITALIZED DURING THEIR FIRST COURSE OF
`
`T.
`
`'
`
`'
`
`Consult 1995 supplements and future editions for revision:
`
`
`NOVARTIS EXHIBIT 2070
`Par v. Novartis, IPR 2016-01479
`Page 3 of 4
`
`

`

`W”.r
`
`J.
`
`2038/PHYSIClANS‘ DESK REFERENCEGD
`_____.__.——-———
`Roche Laboratorles—Cont.
`
`cordlngly. Some patients have received from 9 to 45 courses
`of treatment during periods which ranged from 12 to
`60 months.
`Procedures for proper handling and disposal of anticancer
`drugs should he considered. Several gUidelines on this sub
`ject have been publishee:i.l"“1 There is no general agreement
`that all of the procedures recommended in the guidelines are
`necessary or appropriate.
`Note: Parenteral drug products should be inspected visu-
`ally for particulate matter and discoloration prior to admin«
`istration. whenever solution and container permit. Although
`the Fluorouracil solution may discolor slightly during stor
`age, the potency and safety are not adversely affected. If a
`precipitate occurs due to exposure to low temperatures,
`resolubllim by heating be 140‘F and shaking vigorously; al-
`low to cool to body temperature before using.
`-
`HOW SUPPLIED
`' For intravenous use—10mL single-use vials, boxes of 10
`(NDC 0004-1977411). Each 10 mL contains 500 mgfluoroura-
`oil in a colorless to faint yellow aqueous solution, with pH
`adjusted to sppmximately 9.2 with sodium hydroxide.
`Store at room temperature (59‘ to 86°F; 15' to 30°C). Protect
`from light-
`'
`REFERENCES
`.
`1. Harris BE, Carpenter J'I‘, Diasio RB: Severe D-Fluumura'
`cil Toxicity Secondary to Dlhydropyrimidine mhydmge-
`nase Deficiency. A potentially more common pharmacuge-
`netic syndrome, Cancer. August I, 1991; 68:499—501.
`. Recommendations for the safe handling of parenteral an~
`tinwplmtic drugs. Washington, DC, US. Government
`Printing Office (MEI Publication No. 83-2621).
`. AMA Council Report. Guidelines for handling parenteral
`antineoplastics. JAMA. Mar 16, 1985; 253:15W1592.
`. National Study Commission on Cytotoxic Exposure: Rec-
`ommendations for handling cytotoxic agents. Available
`from Louis P. Jeffrey, ScD, Director of Pharmacy Services,
`Rhode Island Hospital, 593 Eddy Street, Providence.
`Rhode Island 02902.
`. Clinical Oncological Society of Australia: Guidelines and
`recommendations for safe handling of antinooplnstic
`agents. Med J Aust. Apr 80, 1983; 1:426428.
`6.-Jones RB, Frank E. Moss '1‘: Safe handling of chemothsrs-
`peutic agents: a report from the Mount Sinai Medical Cen-
`.
`ter. CA. Sept—Oct 1983; 33:258-263.
`7. ASHP technical assistants bulletin on handling cytotoxic
`drugs in hospitals. Am J Hosp Pharm Jan 1985;
`42:131—137.
`Revised: October 1993
`
`STERILE
`FU DR
`[sfvuvdee‘am]
`(floxurldins)
`
`!
`
`FOR INTRA‘AR’I‘ERIAL INFUSION ONLY
`The following text is complete prescribing information based
`on. official labeling in effect June 1, 1994.
`WARNING
`It is recommended that FUDR be given only by or under
`the supervision of squaliilsd physician who is experi~
`oncad in cancer chemotherapy and intraAart‘erial drug
`therapy and is well versed in the use of potent an-
`timetabolites.
`.
`Because of the possibility of severe toxic reactions, all
`patients should be hospitalized for initiation of the first
`course of therapy.
`
`DESCRIPTION
`Sterile FUDR (floxuridine), an untinaoplastic antimetabo
`life, is available as a sterile, nonpyrogsnic, lyophilizod pow-
`der for reconstitution. Each vial contains 500 mg of floxuri—
`dine which is to be reconstituted with ii mL of sterile water
`for injection. An appropriaie amount o