Frontier Therapeutics Exhibit 1007
`
`ANTARES Exhibit 1007
`
`Page 1 of 5
`
`

`
`Publisher _o_ED\_/I/ARI) R EARNHART
`Clrculauon Dlrector
`THOMAS S. KRAEMER
`Fulfillment Manager
`JAMES SCIURBA
`Research Director
`CHARLOTTE E. SIBLEY
`
`»
`Director«ofProduq:tIon
`,JERO‘MI_-I M. LEVINE
`‘Managing Edltor
`BARBARA B HUFF
`
`Meldical Consultant
`IRVING M. LEVITAS.‘ M D
`
`Manager 01 Production Services
`ELIZABETH H. CARUSO
`Index.Editor
`I
`ADELE L. DQWD
`
`Edltorlal Asslstants
`F. EDYTHE PATERNITI
`YVONNE HARLEY
`Associate Editor
`WILLIAM J. KNIPPING
`
`Dlrector at Prlnting
`RALPH G. PELUSO
`
`.
`
`'
`
`
`
`National sales Manager
`GARY J. GYSS
`Account Managers
`SALLY H. BERRIMAN
`DAVID M. IVIJOLSNESS
`PETER J. MURPHY
`
`Deslgn Dlrector
`JOHN NEWCOMB
`
`Assistant Deslgn Dlrector
`WILLIAM KLIHN
`
`I;
`
`:
`
`v
`
`‘I 7‘.
`
`\
`
`'11 ilon-301
`y rroan::
`,
`my ‘IJ.(—a1IiLI|I[
`-- uy ‘nc:
`pI.LL)II.<.-:h(>.r
`I5'1‘e,
`
`mu .n the Uhllofi
`
`ug.
`recouiung. or L-:I1»-w,=:s.-
`-.-
`..!.LI I"DR‘8 are lIaUL!In;]l|(S 0| NI-ml!-;.)I I€1~:,m«.uu..
`».
`
`
`
`Page 2 of 5
`
`

`
`762
`Product Information
`Always consult Supplement
`3. Methotrexate has caused fetal death and/
`Dosage and Administration:
`or congenital anomalies, therefore, it is not
`Breast cancer:
`160 mg/day (40 q.i.d.)
`recommended in women of childbearing po-
`Endometrial carcinoma: 40-320 mg/day in di-
`vided doses.
`tential unless there is appropriate medical
`At least two months of continuous treatment is
`evidence that the benefits can be expected to
`outweigh the considered risks. Pregnant pso-
`considered an adequate period for determining the
`efficacy of Megace (megestrol acetate).
`riatic patients should not receive methotrex-
`ate.
`How Supplied: Megace® is available as light
`blue, scored tablets containing 20 mg or 40 mg
`Iinpaired renal function is usually a con-
`4.
`traindication.
`megestrol acetate.
`5. Diarrhea and ulcerative stomatitis are
`NDCO087-0595-01, Bottles of 100 20 mg tablet
`NDC0087-0596-41, Bottles of 100 40 mg tablet
`frequent toxic effects and require interrup-
`NDCOOS7-0596-45, Bottles of 500 40 mg tablet
`tion of therapy; otherwise hemorrhagic enter-
`6505-01-070-1493 (Bottles of 100) (Defense)
`itis and death from intestinal perforation
`References:
`may occur.
`1. Gal I, Kirman B and Stern J: "Hormonal Preg-
`METHOTREXATE HAS BEEN ADMINIS-
`nancy Tests and Congenital Malformation,"
`TERED IN VERY HIGH DOSAGE FOL-
`LOWED BY LEUCOVORIN RESCUE IN
`I
`Nature 216283, 1967.
`2. Levy EP, Cohen A and Fraser FC: "Hormone 1
`EXPERIMENTAL TREATMENT OF CER-
`Treatment During Pregnancy and Congenital I
`TAIN NEOPLASTIC DISEASES. THIS PRO-
`Heart Defects," Lancet 1:611, 1973.
`|
`CEDURE IS INVESTIGATIONAL AND
`3. Nora J and Nora A: “Birth Defects and Oral
`HAZARDOUS.
`Contraceptives,” Lancet 1:941, 1973.
`
`4. Janerich DT, Piper JM and Glebatis DM: "Oral
`Description: Mexate (methotrexate sodium) is
`Contraceptives and Congenital Limb-Reduction
`an antimetabolite used in the treatment of certain
`Defects,” N Eng J Med, 291:697, 1974.
`5. Heinonen OP, Slone D, Monson RR, Hook EB
`neoplastic diseases. It is the sodium salt of 4-
`amino-10-methylfolic acid. The structural formula
`and Shapiro S: "Cardiovascular Birth Defects
`is:
`and Antenatal Exposure to Female Sex Hor-
`mones," N Eng J Med, 296:67, 1977.
`Shown in Product Identification Section, page 407
`
`Description: Megestrol acetate is a white, crys-
`talline solid chemically described as 17a-acetoxy-
`6-methylpregna-4, 6-diene-3, 20-dione. Its molecu-
`lar weight
`is 384.5. The empirical formula is
`C24H320,, and the chemical structure is:
`
`?''acan
`"DE OCH,
`
`for
`
`MEGESTROL ACETATE‘
`'U.S. Patent No. 3,356,573
`Actions: While the precise mechanism by which '
`Megace (megestrol acetate) produces its antineo-
`plastic effects against endometrial carcinoma is
`unknown at the present time, an antiluteinizing
`effect mediated via the pituitary has been postu-
`lated. There is also evidence to suggest a local ef-
`fect as a result of the marked changes brought
`about by the direct instillation of progestational
`agents into the endometrial cavity. Likewise, the
`antineoplastic action of Megace (megestrol ace-
`tate) on carcinoma of the breast is unclear.
`Indications: Megace (megestrol acetate) is indi-
`cated for the palliative treatment of advanced
`carcinoma of the breast or endometrium (i.e., re"-
`:current,
`inoperable, or metastatic disease). It
`should not be used in lieu of currently accepted
`procedures such as surgery, radiation, or chemo-
`therapy.
`Contraindications: As a diagnostic test
`pregnancy.
`Warnings
`Ildniinisfrarlion for up to Fyerim ofmcgestml acetate
`tofenicrle rings is associated trail}: on increaseil inci-
`dence of bail: benign and niulignnnr nmmm of the
`breast. Ctimpumble slmlies in mils and angering
`studies in monkeys are not associated with an in-
`creased incidence of tunwrs. The relationship of the
`dog tumors to humans is unknown but should be
`oonsidered in assessing the benefit-to-risk ratio
`when prescribing Megace and in surveillance of
`patients on therapy.
`The use;of Megace (megestrol acetate) in other
`types of neoplastic disease is not recommended.
`Precautions: There are no specific precautions
`identified for the use of Megace (megestrol acetate)
`when used as recommended. Close, customary
`surveillance is indicated for any patient being
`treated for recurrent or metastatic cancer. Use
`with caution in patients with a history of thrombo-
`phlebitis.
`Adverse Reactions: No untoward effects have
`been ascribed to Megace (megestrol acetate) ther-
`apy. Reports have been received of patients devel-
`oping carpal tunnel syndrome, deep vein thrombo-
`phlebitis and alopecia while taking megestrol ace-
`tate.
`Overdosage: No serious side effects have re-
`sulted from studies involving Megace (megestrol
`acetate) administered in dosages as high as 800
`mg/day.
`‘
`
`MEXATE®
`[mé'k’sdt]
`(methotrexate sodium)
`FOR INJECTION
`This is the full text of the latest 0/ficial Package
`Circular dated July 1984 [3050 DIM-08].
`
`WARNINGS
`MEXATE (METHOTREXATE SODIUM)
`SHOULD BE ADMINISTERED UNDER
`THE SUPERVISION OF A QUALIFIED
`PHYSICIAN EXPERIENCED IN THE USE
`OF
`CANCER
`CHEMOTHERAPEUTIC
`AGENTS:
`BECAUSE OF THE POSSIBILITY OF FA-
`TAL OR SEVERE TOXIC REACTIONS THE
`PATIENT SHOULD BE FULLY INFORMED
`BY THE PHYSICIAN OF THE RISKS IN-
`VOLVED AND SHOULD BE UNDER HIS
`CONSTANT SUPERVISION.
`DEATHS HAVE BEEN REPORTED WITH
`THE USE OF METHOTREXATE IN THE
`TREATMENT OF PSORIASIS,
`IN THE
`TREATMENT OF PSORIASIS METHO-
`TREXATE SHOULD BE RESTRICTED TO
`SEVERE, RECALCITRANT, DISABLING
`PSORIASIS WHICH IS NOT ADEQUATELY
`RESPONSIVE TO OTHER‘ FORMS OF
`THERAPY, BUT ONLY WHEN THE DIAG-
`NOSIS HAS BEEN ESTABLISHED AS BY
`BIOPSY AND/OR AFTER DERMATO-
`LOGIC CONSULTATION
`notably
`1. Bone marrow suppression,
`thrombocytopenia and leukopenia, which
`may contribute m bleeding and overwhelm-
`ing infections in an already compromised
`patient, is the most common and severe of the
`toxic effects of Mexate (see “WARNINGS"
`and “ADVERSE REACTIONS").
`2. Methotrexate may be hepatotoxic, partic-
`ularly at high dosage or with prolonged ther-
`apy. Liver atrophy, necrosis, cirrhosis, fatty
`changes, and periportal fibrosis have been
`reported. Since changes may occur without
`previous signs of gastrointestinal or hemato-
`logic toxicity, it is imperative that hepatic
`function be determined prior to initiation of
`treatment and monitored regularly through-
`out therapy. Special caution is indicated in
`the presence of preexisting liver damage or
`impaired hepatic function. Concomitant use
`of other drugs with hepatotoxic potential (in-
`cluding alcohol) should be avoided.
`
`Mexate for Injection is available in 20, 50, 100, and
`250 mg single dose vials of lyophilized sterile pow-
`der, containing no preservatives, to be adminis-
`tered parenterally.
`Each 20 mg vial contains methotrexate, 20 mg,
`prepared as the sodium salt; sodium hydroxide to
`adjust pH to about 8.5.
`Each 50 mg vial contains methotrexate, 50 mg,
`prepared as the sodium salt; sodium hydroxide to
`adjust pH to about 8.5?
`Each 100 mg vial contains methotrexate, 100 mg,
`prepared as the sodium salt; sodium hydroxide to
`adjust pH to about 8.5.
`Each 250 mg vial contains methotrexate, 250 mg,
`prepared as the sodium salt; sodium hydroxide to
`adjust the pH to about 8.5.
`-.
`Clinical Pharmacology: Methotrexate compet-
`itively inhibits dihydrofolate reductase, the en-
`zyme responsible for- converting folic acid to re-
`duced folate cofactors. Reduced folates are neces-
`sary for the metabolic transfer of onecarbon units
`in a variety of biochemical reactions. Those reac-
`tions which are of special importance in cellular
`proliferation are the biosynthesis of thymidylic
`acid, the nucleotide specific to DNA, and the bio-
`synthesis of inosinic acid, the precursor of purines
`necessary for both DNA and RNA synthesis. In
`human synthesis, methotrexate appears to inhibit
`DNA synthesis to a greater extent than RNA syn-
`thesis, suggesting that inhibition of thymidylate
`synthesis is the most important mechanism of
`methotrexate cytotoxicity. Hence the drug is
`highly cell cycle dependent, acting primarily dur-
`ing DNA synthesis (S-phase). Actively proliferat-
`ing tissues such as malignant cells, bone marrow
`cells, and cells of the dermal epithelium, buccal
`and intestinal mucosa, are in general more sensi-
`tive to this effect of methotrexate.
`After parenteral injection, peak serum levels are
`seen in about 30 to 60 minutes. Approximately
`one-half the absorbed methotrexate is reversibly
`bound to serum protein but exchanges with body
`fluids easily and diffuses into the body tissue cells.
`The terminal half-life is of the order of 24 hours
`Approximately 41% of an intravenously adminis-
`tered dose is excreted unchanged in the urine
`within 6 hours after administration, 90% within
`24 hours, and 95% within 30 hours. One to 2% is
`excreted in the stool as the parent compound and
`metabolites. The methotrexate metabolites ac-
`
`Page 3 of 5
`
`Bristol-Myers 0nco|ogy—Cont.
`
`
`
`
`
`
`
`
`
`
`increased risk of limb reduction defects in
`infants exposed in ulem to sex hormones (oral
`contraceptives, hormone withdrawal tests for
`pregnancy, or attempted treatment
`for
`threatened abortion).
`' Some of these exposures were very short and
`involved only a few days of treatment. The
`data suggest that the risk of limb reduction
`defects in exposed fetuses is somewhat less
`than 1 to 1,000.
`'
`j If the patient is exposed to Megace during the
`first four months of pregnancy or if she
`becomes pregnant while taking this drug, she
`should be apprised of the potential risks to the
`fetus.
`
`
`
`
`
`
`
`
`
`
`
`Page 3 of 5
`
`

`
`for possible revisions
`
`Product Information
`
`763
`
`count for less than 10% of the total dose adminis-
`tered when methotrexate is given intravenously.
`Repeated daily doses result in more sustained
`serum levels and some retention of methotrexate
`over each 24-hour period which may result. in accu-
`mulation of the drug within the tissues. The liver
`coils appear to retain certoi.n amounts of the drug
`for prolonged periods cvon after a single t-l1erapeii-
`t.ic dose. Methotrcxate is retained in tlieprcsencc
`of impaired renal function and may increase rap-
`idly in the serum and in the tissue cells under such
`conditions.
`'
`Distribution of methutreiiatc into interstitial fluid
`spaces,‘ such as cerchrospinal fluid, pleural and
`peritoneal cavities. occurs slowly and with charac-
`teristics that resembles passive transport system.
`ll’
`these "third spaces" are pathologically in-
`creased as in ascitcs and pleural effusion, they
`may act as reservoirs and prolong the presence of
`methotrexate in the plasma compartment. Metho-
`trexate does not penetrate the lilaorl ccrehrospinal
`fluid barrier in therapeutic arriounts when given
`parenterally. High concentrations of the drug
`when needed may be attained by direct inl:rnthccal
`administration.
`Indications and Usage:
`Antinecplastic Chemotherapy:
`Trophoblastic Tumors:
`Mexate is indicated for the treatment of gesta-
`tional choriocarcinoma, and hydatidiform mole
`Leukemia:
`Mexate is indicated for the treatment of acute
`lymphocytic leukemia and in the treatment and
`prophylaxis of meningeal leukemia. Greatest ef-
`fect has been observed in the treatment of acute
`lymphoblastic (stem—cell) leukemias in children. In
`combination with other anticancer drugs or suit-
`able agents Mexate may be used for induction of
`remission, but it is most commonly used, as de-
`scribed in the literature, in the maintenance of
`induced remission.
`Lymphomas:
`Mexate is effective in the treatment of the ad-
`vanced stages (III and IV) of non—Hodgkin's lym-
`phoma, particularlyin children and in advanced
`cases of mycosis fungoides.
`Psoriasis Chemotherapy (See
`INGS"):
`Because of high risk attending its use. Mex.-do is
`only indicated in the symptomatic (!EiIll.t‘{]l ol' se-
`vere, recalcitrant, disribfing psoriasis which is not
`adequately rr.=.spunsive to other forms of therapy,
`but onty when the diagnosis has been established,
`as by biopsy and/or after dermatologic consulta-
`tion.
`Contrainciicatiuns: Patients with known hy-
`persensitivity to rrietliotrexolo; pregnant psoriatic
`patient: psorintic patients with severe renal or
`-hopatic disorders; and risoriatic patiorils witli
`preexisting blood dysci'usiss.suc|1 as bone marrow
`hypoplasie. lcul-iopenin. throinliocylopcniaor anc-
`n1ia.shouId.not receive Mexate.
`Warnings:- See "BOX WARNINGST’.
`Precautions:
`.
`General:
`Me-sate has .1 high potential for serious toxicity
`which is usually dose—relutod. The pliysician
`should be familiar with the various characteristics
`of the drug and its established clinical usage. Pa-
`tients undergoing therapy should be subject to
`appropriate supervision so that signs or symptoms
`of possible ativerse reactions may be detected and
`evs'|u;tT.cd with niinimril delay. Pretreatment and
`periodic Iieniotologic studies are essential to the
`use of Mexate in chemotherapy iii-_‘L':II.l3t.| of its com-
`mon e'l'fe::l of heniatopoietic suppression. T11 is may
`"occur abruptly and on apparent safe dosage, and
`any profound drop in laloo-d—L'e|l count indicatfi
`inimctliato stoppinjg of the drug. in patients with
`malignant disease who have preexisting brine mar-
`row aplosia,
`leul-topenin,
`thrumh-ocytopenia or
`anemia, other than that caused by bone marrow
`involvement with tumor. the drug should be used
`with cauti<in.ifuta1l.
`Mexate is excreted principally by the kidneys. Its
`use in the presence of impaired renal function may
`result in accumulation of toxic amounts or even
`additional renal damage. The patient’s renal sta-
`
`"BOX WARN-
`
`tus should be determined prior to and during
`methotrexate therapy and proper caution exer-
`cised should significant renal impairment be dis-
`closed. Drug dosage should be reduced or discon-
`tinued until renal function is improved or re-
`stored. Mexate should be used with extreme cau-
`tion in the presence of infection, peptic ulcer, ul-
`cerative colitis, debility and in extreme youth or
`old age.
`_
`If profound leukopenia occurs during therapy,
`bacterial infection may occur or become a threat.
`Cessation of the drug and appropriate antibiotic
`therapy is usually indicated. In severe bone mar-
`row depression, blood or platelet transfusions may
`be necessary.
`'
`Since it is reported that methotrexate may have
`an immunosuppressive action, this factor must be
`taken into consideration in evaluating the use of
`the drug where immune responses i.n a patient
`may be important or essential.
`'
`In all instances where the use of Mexate is consid-
`ered fur r.-lieniotliernpy, the physician must evalu-
`ate the need and iiselulness ofthc drug against the
`risk for adverse reactions. Mo.-3|. such adverse reac-
`tions are reversililc ifcletecteci early. ifsevere reac-
`tions occur, the drug should he reduced in dosage
`or discontinued and appropriate corrective meas-
`ures should be taken according to the clinical judg-
`ment of the physician. Reinstitution of Mexate
`therapy should be carried out with caution, with
`adequate consideration of further need for the
`drug and alertness as to possible recurrence of
`toxicity.
`'
`Laboratory Tests:
`In general,
`the following laboratory tests are
`recommended as part of essential clinical evalua-
`tion and appropriate monitoring of patients
`chosen for or receiviiig methntrenate therapy‘,
`complete hcmogram, Ltr1'nalysis, renal
`function
`tests, and liver function tests, A chest spray is also
`recommended to determine the presence of pleu-
`rol effusion". The tests should be performed prior to
`therapy. at appropriate periods during therapy
`and after termination of therapy;
`Drug Interactions:
`Methotrcxnte is bound in part to serum albumin
`alter absorption‘ and toxicity may be increased
`because of displacement by certain drugs such as
`saiicylates, sulihnamides, phcnytoin, pi1enyll:uita-
`zone. and some snliba cterials such as lotracyclilie,
`chloraiiiphenicol. These drugs, especially salicyl-
`etes, phenylbutuono. and sulfonamidos. whether
`antibacterial. hypoglycemic ordiuratic, should not
`be given concurrently until
`the significance of
`these findings is established.
`Weak acids like sslicylutes and prohenecid may
`compete with methotroxate for renal tubular sc-
`cretion. As a result, concomitant administration
`with these tlgonls may prolong the scrum'half-life
`of Inethotrexato.
`Carcinogenesis. Mutegenesls. Impairment of Fer-
`tility:
`Like most other unticancer agents. Mexate. might
`have a carcinogenic potentioi [see "BOX WARN-
`l:‘~lGS"l
`'
`Pregnancy:
`[J"—McthoLrex:ite has
`Pregnancy "Catt-gory
`caused fetal death andfor congenital anonirtlies
`and is therefore not recommended in women of
`childbearing potential unless there is appropriate
`medical evidence that the hcliefits lo the mother
`can be expected to outweigh the considered risks to
`the fetus. Pro-gllzlnt psoriatic patients shouldnnt
`receive llulexntc isee."B{JX WARN[NGS"}.
`Nursing Mothers:
`Because of the potentiai for serious adverse reac-
`tions in nursing inlunts from Mexate, a. decision
`should he made whether I.o discontinue nursing or
`to discontinue the drug. taking into account the
`importance of‘ the drug to the niother.
`Adverse Reactions: The most common adverse
`reactions include uloerulive stunistitis,
`leukope—
`nia, nausea and abdorninal distress. Others re-
`ported are malaise, undue fatigue. chills and fever.
`dizziness and decreased resistance to infection. In
`general. the incidelicc and severity of side eifecte
`are considered to he dose-related. Adverse reac-
`
`tions as reported for the various systems are as
`follows:
`leukopenia,
`Blood: bone marrow depression,
`thrombocytopenia, anemia, hypogammaglobuline
`mia, hemorrhage from various sites, septicemia.
`Alimentary System: gingivitis, pharyngitis, sto-
`matitis, anorexia, vomiting, diarrhea, hemateme-
`sis, melena, gastrointestinal ulceration and bleed-
`ing, enteritis, hepatic toxicity resulting in acute
`liver atrophy, necrosis, fatty metamorphosis, peri-
`portal fibrosis, or hepatic cirrhosis.
`Urogenital System:
`renal failure, azotemia, cysti-
`tis, hematuria; defective oogenesis or spermato-
`genesis, transient oligospcrmia, menstrual dys-
`function; infertility, abortion, fetal defect, severe
`nephropathy.
`Skin: erythematous rashes, pruritus, urticaria,
`photosensitivity, depigmentation, alopecia, ecchy-
`mosis, telangiectasia, acne, furunculosis. Lesions
`of psoriasis may be aggravated by concomitant
`exposure to ultraviolet radiation.
`Central Nervous System:
`lientlalllhcfi. drowsiness.
`blurred vision. Aphasia. herni
`resis, parcels anrl
`convulsions havonlso occurredufollowing adminis-
`tration of methotrexste.
`There have been reports of leucoencephalopathy
`following intravenous administration of _metho-
`trexate to patients who have had craniospinal
`irradiation.
`,
`the
`After the intrathecal use of methotrexate,
`central nervous system toxicity which may occur
`can be classified as follows:
`(1) chemical arachnoiditis manifested by such
`symptoms as headache, back pain, vomiting, nu-'
`chai rigidity, fever. and cerebrospinal fluid pleocy-
`tosis mimicking bacterial meningitis.
`V
`(21 motor dysfunction of the brain or the spinal
`cord. Paraplegic, qllndraplugia, cerebellar dys-
`function. cranial nerve palsies and seizures may
`occur a few weeks after starting treatment.
`(3) leucoencephalopathy manifested by confusion,
`dysarthria,
`irritability, somnolence, ataxia, de-
`mentia, and occasionally major convulsions and
`coma. The risk for this toxicity seems to be propor-
`tional to the amount of methotrexate given.-
`Other reactions related to or attributed to the use
`of methotrexate, such as interstitial pneumonitis;
`metabolic changes precipitating diabetes: osteopo '
`rotic effects, abnormal tissue cell changes, and
`even sudden death. have been reported.
`.Uverdusage: Leucovorin Calcium Injection,
`USP [citrovorum factor] is a Potent agent for neu-
`tralizing the immediate toxic effects of Mexate on
`the hematopoietic system. Where large doses or
`overdoses.-are given, Leucovorin Calcium Injec-
`tion. USP may be administercrl by intravenous
`int‘us_ion in doses up to 1'5 mg within 12 hours,_fol-
`lowed by 12 i'u.g.intran1uscularly every six hours
`for four doses. Where average doses of Mexate
`appear to have an adverse effect, 2 to 4 ml (6 to 12
`mg) of_Leucovorin Calcium Injection. USP may be
`given lntrnmuscularly every six hours for four
`closes. In general, where _overdor5age is su'spec_ted.
`the dose of Leucovorin CalciIJui-Injection, USP
`should bsequ.-11 to or higher than the offending
`dose of Mexate and should best be administered
`within the first hour. Use of Leucovorin Calcium
`Injection, USP after an hour delay is much less
`effective.
`Dosage and Administration:
`Antineoplastic Chemotherapy
`Mexate for injection may be given by intramuscu-
`lar,
`intravenous,
`intraarterial or
`intrathecal
`route. Initial
`treatment is usually undertaken
`with the patient under hospital care.
`Chorlocarcinoma and similar trophoblastic disea-
`ses: Mexate is administered intramuscularly in
`doses of 15 to 30 mg daily for a five-day course.
`Such courses,are usually repeated three to five
`times as required, with rest periods of one or more
`weeks interposed between courses,
`to allow any
`manifesting toxic symptoms to subside. The effec-
`tiveness of therapy is ordinarily evaluated by
`serum 24-hour quantitative analysis of beta-chori-
`onic gonadotropin hormone (/3-HCGl which should
`
`Continued on next page
`
`Page 4 of 5
`
`Page 4 of 5
`
`

`
`764
`
`M_UTAMYClN®
`[rmi” -£e'-mi’-sin]
`(mitomycin for injection)
`This is the full text of the latest Official Package
`Circular dated October 1983 [3001DIM-17 ].
`
`B.
`
`Product Information
`Always consult Supplement
`
`
` ate maybe used in combination therapy in doses of How Supplied: Mexate (methotrexate sodium)
` Bristol-Myers Onco|ogy—Cont.
`
`0.625 to 2.5 mg/Kg per day.
`'
`for Injection.
`In mycosis fungoides therapy with Mexate appears
`NDC 0015-3050-20—2O mg vial
`to produce clinical remissions in about one-half of
`NDC 0015-3051-20-50 mg vial
`the cases treated. Dosage is usually daily by mouth
`NDC 0015-3052—2l0—100 mg vial
`for weeks or months. Drug dose levels and their
`NDC 0015-3053-20—‘250 mg vial
`subsequent adjustment are guided by patient re-
`sponse and hematologic monitoring. Mexate has
`also been given intramuscularly in doses of 50 mg
`once weekly _or 25 mg two times weekly.
`Psoriasis Chemotherapy:
`The patient should be fully informed of the risks
`involved and should be under the ‘constant super-
`vision of a physician.
`Assessment of renal function, liver function, and
`blood elements should be made by history, physi-
`cal examination, and laboratory tests (such as
`CBC, urinalysis, serum creatinine, liver function
`studies, and liver biopsy if indicated) before begin-
`ning Mexate, periodically during Mexate therapy,
`and before reinstituting Mexate therapy after a
`rest period. Appropriate steps should be taken to
`avoid conception during and for at least 8 weeks
`following Mexate therapy.
`There are 3 commonly used general types of dos-
`age schedules:
`1. weekly oral or parenteral intermittent large
`doses
`'
`2. divided dose intermittent oral schedule over a
`36-hour period
`-
`3. daily oral with a rest period
`All schedules should be.continually‘tai1ored to the
`individual patient. Dose schedules cited below
`pertain to an average 70 Kg adult.
`Recommended starting dose schedule:
`Weekly single’ IM or IV dose schedule:
`10 to 25 mg per week until adequate response is
`achieved. With this dosage schedule, 50 mg per
`week should ordinarily not be exceeded.
`that
`Special Note: Available data suggest
`schedule 3 (daily oral dose with a rest period) may
`carry an increased risk of serious liver pathology.
`Dosages may be gradually adjusted to achieve
`optimal clinical response, but not to exceed the
`maximum stated in the schedule.
`Once optimal clinical response has been achieved.
`the dosage schedule should be reduced to the low-
`at possible amount of drug and to the longest pos-
`sible rest period. The use of Mexate may permit
`the return to conventional topical therapy, which
`should ,be encouraged.
`Caution:
`to cause
`Pharmacist: Because of its potential
`severe toxicity, :Mexate therapy requires close
`‘supervision of the patient by the physician.
`Parenteral drug products should be inspected visu-
`ally for particulate matter_ and discoloration prior
`to administration, whenever solution and con-
`tainer permit.
`Directions for Use: - Intramuscular or intrave-
`nous adrninistration: reconstitute with 2 to 10 ml
`of Sterile Water for Injection, USP, 0.9% Sodium
`Chloride Injection, USP, or Bacteriostatic Water
`for Injection, USP with Parabens or Benzyl Alco-
`hol.
`Intrathecal administration: reconstitute immedi-
`ately prior to use with an appropriate sterile, pre-
`servative-free medium such as 0.9% Sodium Chlo-
`ride Injection, USP. The concentration for intra-
`thecal injection should be 1 mg to 2.5 mg ml.
`As with other potentially toxic compounds, cau-
`tion should be exercised in handling the powder
`and preparing the solution of methotrexate. Skin
`reactions associated with accidental exposure to
`Mexate may occur. The use of gloves is recom-
`mended. If Mexate powder or solution contactskin
`or mucosa, immediately wash the skin or mucosa
`thoroughly with soap and water.
`Stability
`Mexate for Injection is stable for four weeks at
`room temperature (25°C) at concentrations of 2 to
`125 mg/ml in Sterile Water for Injection, USP,
`0.9% Sodium Chloride Injection, USP or Bacterio-
`static Water for Injection, USP with Parabens or
`Benzyl Alcohol. These solutions are stable for
`three months under refrigeration (4°C) or frozen
`(— 15'C). For intrathecal use, reconstitute immedi-
`ately prior to use.
`
`return to normal, usually after the 3rd or 4th
`course. The complete resolution of measurable
`lesions usually occurs within 4 to 6 weeks. One to
`two courses of Mexate after normalization of /3-
`HOG is usually recommended. Before each course
`of the drug, careful clinical assessment is essen-
`tial; Cyclic combination therapy of Mexate with
`other antitumor drugs has been reported as being
`useful.
`4
`precede
`may
`Since
`hydatidiform mole
`chemotherapy
`choriocarcinoma,
`prophylactic
`with Mexate has been recommended. Mexate is
`administered in these disease states in doses simi-
`lar to those recommended for choriocarcinoma
`Leukemia: Acute lymphatic (lymphoblastic) leu-
`kemia in children and young adolescents is the
`most responsive to present-day chemotherapy. In
`young adults and older patients, clinical remission
`is more difficult to obtain and early relapse is more
`common. In chronic lymphatic leukemia, the prog-
`nosis for adequate response is less encouraging.
`Mexate alone or in combination with other agents
`appears to be the drug of choice for securing main-
`tenance of drug-induced remissions. When remis-
`sion' is achieved and supportive care has been pro-
`duced general clinical improvement, maintenance
`therapy may be initiated, as follows: Mexate is
`administered two times-weekly intrarnuscularly
`in doses of 30 mg/M2. It has also been given in
`doses of 2.5 mg/kg intravenously every 14 days. If
`and when relapse does occur, reinduction of remis-
`sion can usually be obtained by repeating the ini-
`tial
`induction regimen. A variety of dosage
`schedules exist for. both induction and mainte-
`nance of remission with various combinations of
`alkylating agents plant products and anti.me'tabo-
`lites. The physician should be familiar with the
`new advances in antileukemic therapy.
`Meningeal leukemia: Patients with leukemia are
`subject to leukemic invasion of the central ner-
`yous system. This may manifest /characteristic
`signs or symptoms or may remain silent and be
`diagnosed only by examination of the cerebrospi-
`nal fluid (CSF) which contains leukemic cells in
`such casesl Therefore, the CSF should be examined
`in all pediatric acute lymphoblastic leukemia pa-
`tients. Since penetration of Mexate from the blood
`to the cerebrospinal fluid is minimal; the drug is
`administered intrathecally for‘ adequate therapy.
`It is now commonvpractice because of the noted
`increased frequency of meningeal
`leukemia to
`administer Mexate intrathecally as prophylaxis in
`all cases of lymphocytic leukemia.
`'
`For intrathecal injection, the sodium salt of Mex-
`ate-is administered in solution as a 12 mg/M2 dose.
`The solution is made in a’ strength of up to-2.5
`mg/ml with an appropriate, sterile, preservative-
`free medium such as 0.9% Sodium Chloride Injec-
`tion, USP.’
`“For the treatment of meningeal leukemia, Mexate
`is given at intervals of two to five days. Mexate is
`7 administered until the leukemia cell count of the
`cerebrospinal fluid disappears. At this point one
`additional dose is advisable. For prophylaxis
`against meningeal leukemia, the dosage is the
`name as for treatmelil. except for the intervals of
`administration. On this subject. it is advisable for
`the physician to consult the medical literature.
`Largo doses may cause convulsions. Untoward side
`oifects may occur with any given intrathecal injec-
`tion and are commonly neurological in character.
`Mexate given by intrathecal route appears in sig-
`nificant concentrations in the systemic circulation
`and may cause systemic Mexate toxicity. There-
`fore concurrent systemic antileukemic therapy
`should be appropriately adjusted. Focal leukemic
`involvement of the central nervous system may
`not respond to intrathecal chemotherapy and is
`best treated with radiotherapy.
`Lymphomas:
`In stage III and IV non-Hodgkins
`lymphdrnas, Mexate is commonly given concomi-
`tantly with other antitumor agents. Treatment
`usually consists of several courses of the drug in-
`terposed with seven to ten day rest periods. Mex-
`
`WARNING
`Mutamycin should be administered under the
`supervision of a qualified physician experi-
`enced in the use of cancer chemotherapeutic
`agents. Appropriate management of therapy
`and complications is possible only when ade-
`quate diagnostic and treatment facilities are
`readily available.
`Bone marrow suppression, notably thrombo-
`cytopenia and leukopenia, which may con-
`tribute to overwhelming infections in an al-
`ready compromised patient, is the most com-
`mon and severe of the toxic effects of Muta-
`‘mycin (see "Warnings" and "Adverse Reac-
`tions” sections).
`
`
`
`Description: Mutamycin (also known as mito-
`mycin and/or mitomycin-Ci is an antibiotic iso-
`lated from the broth of Streptomyces caespitosus
`which has been shown to have antitumoractivity.
`The compound is heat stable, has a high melting
`point, and is freely soluble in organic solvents.
`Action? Mutamycin selectively inhibits the syn-
`thesis of deoxyribonucleic acid (DNA); The gua-
`nine and cytosine content correlates with the de-
`gree of Mutamycin—induced cross—linking. At high
`concentrations of the drug, cellular RNA and pro-
`tein synthesis are also suppressed.
`In humans, Mutamycin is rapidly cleared from the
`serum after intravenous administration. Time
`required to reduce the serum concentration by
`50% after a 30 mg bolus injection is 17 minutes.
`After injection of 30 mg., 20 mg., or l_0 mg. I.V., the
`maximal serum concentrations were 2.4 mcg./ml.,
`1.7 rncg./ml., and 0.52 mcg./ml.,
`respectively
`Clearance is effected primarily by metabolism in
`the liver, but metabolism occurs in other tissues as
`well. The rate of clearance is inversely propor-
`tional to the maximal serum concentration be-
`cause, it is thought, of saturation of the degrada-
`tive pathways.
`Approximately 10% of a dose of Mutamycin is
`excretedunchanged in the urine. Since metabolic
`pathways are saturated at relatively low doses, the
`percent of a dose excreted in urine increases with
`increasing dose. In children, excretion of intrave-
`nously administered Mutamycin is similar.
`Animal Toxicology—Mutamycin has been found
`to be carcinogenic in rats and mice. AL doses ap-
`proximating the recommended clinical dose in
`man, it produces a greater than 100 percent in-
`crease in tumor incidence in male Sprague-Dawley
`rats, and a greater than 50 percent increase in
`tumor incidence i