OTHER
`MERCK PROFESSIONAL HANDBOOKS
`
`THE MERCK INDEX
`First Edition, 1889
`
`THE MERCK VETERINARY MANUAL
`First Edition, 1955
`
`THE MERCK MANUAL OF GERIATRICS
`First Edition, 1990
`
`Merck Professional Handbooks
`are published on a nonprofit basis
`as a service to the scientific community.
`
`•
`
`t
`
`1
`
`SIXTEENTH EDITION
`
`THE
`MERCK
`MANUAL
`
`OF
`
`DIAGNOSIS AND THERAPY
`
`Robert Berkow, M.D., Editor-in-Chief
`Andrew J. Fletcher, M.B., B.Chir., Assistant Editor
`
`Editorial Board
`Philip K. Bondy, M.D.
`Preston V. Dilts, Jr., M.D.
`R. Gordon Douglas, Jr., M.D.
`Douglas A. Drossman, M.D.
`L Jack Fating, M.D.
`Eugene P. Frenkel, M.D.
`Robert A. Hoekelman, M.D.
`Fred Plum, M.D.
`John Romano, M.D.
`G. Victor Rossi, Ph.D.
`Paul H. Tanser, M.D.
`
`Published by
`MERCK REsEARCH LABORATORIES
`
`Division of
`MERCK & Co., INc.
`Rahway, N.J.
`1992
`
`NOVARTIS EXHIBIT 2138
`Par v Novartis, IPR 2016-00084
`Page 1 of 5
`
`

`
`MERCK & CO., INC.
`Rahway, N.J.
`U.S.A.
`
`MERCK HUMAN HEALTH DIVISION
`Rahway, N.J. '
`U.S. HUMAN HEALTH
`West Point, Pa.
`
`MERCK RESEARCH LABORATORIES
`Rahway, N .1.
`West Point, Pa.
`
`MERCK VACCINE DIVISION
`Rahway, N.J.
`
`MERCK AGVET DIVISION
`Woodbridge, N.J.
`
`HUBBARD FARMS, INC.
`Walpole, N.H.
`
`MERCK CONSUMER HEALTHCARE GROUP
`Woodbridge, N.J.
`
`MERCK MANUFACTURING DIVISION
`Rahway, N.J.
`
`CALGON CORPORATION
`WATER MANAGEMENT DIVISION
`Pittsburgh, Pa.
`CALGON VBSTAL LABORATORIES
`St. Louis, t-{o.
`
`KELCO DIVISION
`San Diego, Calif.
`
`Library of Congress Catalog Card Number l-31760
`ISBN Number 0911910-16-6
`ISSN Number 0076-6526
`
`First Printing-May 1992
`
`Copyright© 1992 by Mere~ & Co., Inc..
`.
`All rights reserved. Copyright under the Uruversal Copynght Convention
`and the International Copyright Convention. Copyright reserved
`under the Pan-American Copyright Convention.
`
`l'rinted in !be U.S .A.
`
`::0
`0
`IX
`m
`I~
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`0
`0
`N
`N
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`0
`N
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`fOREWORD
`
`It has been 93 years since THE MERcK MANUAL first appeared in 1899 as a slender
`262-page text titled MERcK'S MANuAL OF THE MATERIA MEDICA. It was expressly
`designed to meet the nee.:ls of general practitioners in selecting medications, noting that
`"memory is treacherous" and that even the most thoroughly informed physician needs a
`reminder ''to make him at once master of the situation and enable him to prescribe exactly
`what his judgment tells him is needed for the occasion." It was well received and, by the
`6th Edition (1934), THE MERcK MANUAL had become highly valued by medical student$
`and house staff as well; by the end of World War n the pocket-sized manual was an
`established favorite ready-reference book. Today THE MANuAL is the most widely used
`medical text in the world. While the book has grown to about 2800 pages, its primary
`purpose remains the same-to provide useful clinical information to practicing physicians,
`medical students, interns, residents, and other health care professionals.
`Fewer physicians now attempt to manage the whole range of medical disorders that can
`occur in infants, children, and adults, but those who do must have available a broad spec(cid:173)
`trum of current and accurate information. Specialists require precise information about
`subjects outside their areas of expertise. All physicians need more and more information
`for study and examination purposes, as well as for patient care. Keeping up with the rapid
`and extranrdinary advances in cellular and molecular biology, molecular genetics, and
`medical technology is more challenging than ever, but THE MERcK MANuAL continues to
`try to meet these needs, excluding only details of surgical procedures.
`Precisely how do we attempt to meet these needs? First, from a disease orientation, THE
`MANUAL covers all but the most obscure disorders of mankind, not only those that a
`general internist might expect to encounter but also problems associated with pregnancy
`and delivery; common and serious disorders of neonates, infants, and children; and many
`special situations. Disorders are organized mainly according to the organ systems primarily
`affected, on the basis of their etiology (as with most of the infectious diseases and disor(cid:173)
`ders due to physical agents), or on the basis of disciplines (eg, gynecology, obstetrics,
`pediatrics, genetics, psychiatry). In addition, THE MANUAL contains information for spe·
`cial circumstances, such as radiation reactions and injuries, problems encountered in deep(cid:173)
`sea diving, and dental emergencies. The entire book is updated for each new edition, and
`new subjects are added, such as discussions of genetic evaluation and counseling, human
`immunodeficiency virus (HIV) infection in children, sports medicine, hospice medicine,
`cross-cultural issues in medicine, anabolic steroid abuse, and special considerations in per(cid:173)
`forming cardiopulmonary resuscitation on infants and children. This edition has 140 more
`pages of text (approximately 5%) than the preceding edition. We therefore urge you to
`check the Index whenever you peed information, even on unusual subjects or those not
`commonly found in other texts.
`A completely disease-oriented compendium, however, would have serious limitations.
`Since patients usually present with complaints or concerns that must be meticulously de(cid:173)
`scribed, sorted, and deciphered, many chapters are devoted to discussions of symptoms
`and signs and of how to elicit the historical and physical data required for diagnosis. Com(cid:173)
`mon clinical procedures and laboratory tests used as diagnostic and management aids are
`described, with emphasis on their indications, contraindications, and possible complica(cid:173)
`tions. New and sophisticated laboratory and technologic procedures are also described,
`with comments on their uses, interpretations, and limitations.
`Current therapy is presented for each disorder and supplemented with a separate section
`on clinical pharmacology that describes general principles, new advances (eg, the role of
`drug receptors, plasma concentration monitoring), and details of pharmacologic groups
`and specific agents; it even discusses the use of placebos. The use of complex equipment
`v
`
`NOVARTIS EXHIBIT 2138
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`

`
`Immunology; Allergic Disorders
`352
`evaluated by a lymphocytotoxic test between recipient seru';U ~d donor ly~phocytes ~n ~e
`presence of complement. A positive cross-match usually mdtcates Abs m the 1'7ctptent s
`serum directed against donor class I Ags, commonly forebodt~g ~~racute reJection o~ the
`allograft and therefore generally considered to be a contramdtcattOn to transplan~tton.
`Some Abs identified in the lymphocytotoxic cross-match are now known to be d~ected
`against HLA-DR or other Ags present on the B cell (and monocyte) subpopulatt.on. of
`peripheral blood but not on T cells, platelets, or ~ost other nucle~ted. c~lls. The stgntfi(cid:173)
`cance of a positive B cell cross-match is not clear, smce transplantatiOn m tts presence docs
`.
`.
`.
`.
`not necessarily result in early failure.
`The role of blood transfusions in dialysis and renal transplantatiOn ts controvers~aL Ht~­
`torically, transfusions to patients with end-stage renal failure were shlllUteli to avOid sensi(cid:173)
`tization of potential kidney transplant recipients.· However, ~ograft surviVal w~. seen to
`be improved in those recipients receiving transfusions who ~td not become !lel_lStt~~· ;At
`first it seemed that this transfusion effect was simply a selectiOn process by whtch tnd!VId(cid:173)
`uals with a vigorous immune response were excluded f~m ~eiving transplants ~ause of
`presensitization. However, careful analysis of presenstttzatton .frequency and of !~proved
`transplant survival following transfusions indicates that selec~10n could o~ly part~ally ac(cid:173)
`count for the improved survival rates. Some alte~d form (te, suppresston) of ~une
`responsiveness seemed to be induced by the transfuston~. Wtth the use of cyclosponne (see
`below), the beneficial effect of pretransplant transfusions seems t.o be greatly reduced.
`Because of risk of transmission of infectious diseases (eg, hepatitis and HIV-see Drs(cid:173)
`EASE TRANSMISSION inCh. 94) and the availability of biosynthetic erythropoietin, many
`centers no longer routinely insist on pretransplant transfusion of organ recipients.
`Immunosuppression
`Immunosuppressive drugs are used to control the reje~~on reactio~ caused by ~tige~ic
`differences remaining after tissue typing and donor-rectptent matchmg and are pnmanly
`responsible for the present success of clinical transpl~tatic;>n. H~wever, the~ drugs sup(cid:173)
`press all immunologic reactions, making overwhelmmg infectton the leadmg cause of
`death in transplant recipients.
`Except with isografts, immunosuppressive therapy can rarely be sto~ped complet.ely af(cid:173)
`ter a transplant. However, intensive immunosuppression is usually reqmred only durmg the
`first few weeks after a transplant or during a rejection crisis. Subsequently, the graft often
`seems to become accommodated and can be maintained with relatively small doses of
`immunosuppressive drugs and fewer adverse effects.
`Prednisone (orally) or methylprednisolone (IV) u~ually.is given in high dosage (2 I? 20
`!llglkg) at the time of transplantation and then predmsone ts reduced grad~ally to a mamte·
`nance dosage of 0.2 mglkg/day given indefinitely. La~ after ~splantatl?n, the ~rug c~
`be given on alternate days to reduce side effect~, p~tcula:Iy I';Uportant m g_rowm~ chtl(cid:173)
`dren. Stopping prednisone late after transplantatiOn IS ~sstble m som~ multtdr:tg ~mmu­
`nosuppression regimens, but this appr?acb some~hat mcrea~s _the ns~ of ~Jectton. If
`allograft rejection occurs, the dosage ts sharply mcreased, nskin~ senous ."Stde effe~ts,
`especially increased susceptibili~ to infection. In pati~nts re~eivmg predmson~, whtc?
`causes persistent adrenal suppresston, supplemental contcostermds are needed dunng pen(cid:173)
`ods of stress (eg, infection, major trauma, surgery).
`Azathioprine, an antimetabolite and key immunosuppressant, is usually given beginning
`at the time of the transplant. Oral or IV dosages of 1 to 2.5 mg!kg/day generally are
`tolerated indefinitely. The primary toxic effects are bone marrow dep~ss1o~ and (rarely)
`hepatitis. When cyclosporine was introduced, most transplant centers dtsconttnued.the ~se
`of azathioprine, but many centers now use .azathioprine and lower dosages of cyclosponne
`to avoid severe cyclosporine toxicity.
`Cyclophotphamide has been substitut:d ~n patients who do not. t~lerate ~athioprine.
`Equivalent doses are apparently equal m unmunosuppresstve acttvtty. Thts alkylatmg
`
`Ch.21
`Transplantation 353
`agent also is used in much larger doses as one of the primary immunosuppressants in bone
`marrow transplantation. Severe toxicity is common with hemorrhagic cystitis, alopecia,
`and infertility.
`
`£yclosporine, a fungal metabolite, has been used as the primary immunosuppressive
`agent in .place of antimetabolic drugs in transplant immunosuppression during the last de·
`cade. Unlike ~timetabolites, cyclospcirine spares the bone marrow, acting instead more
`selectively to inhibit T cell proliferation and activation. The exact molecular mechanism of
`its action is unknown although it has recently been shown that cyclosporine reacts with a
`peptidyl-prolyl isomerase, cyclophilin, ultimately interfering with cytokine gene transcrip(cid:173)
`tion. In experimental models,· although helper cell activity is inhibited by cyclosporine,
`activation of suppressor T cells is not.
`Although cyclosporine can be given as a sole immunosuppressant, it usually is used with
`other drugs including prednisone, allowing a rapid reduction in corticosteroid dosage and
`its adverse effects. At the time pf transplantation, initial doses of cyclosporine are 6 to 12
`I\lglkg!day orally, reduced to a maintenance level of 3 to 5 mg!kglday soon after transplan(cid:173)
`tation. Counterbalancing optimism over .cyclosporine's efficacy is its considerable toxicity;
`pephrotoxicity, hepatotoxicity, refractory hypertension, increased incidence of neoplasms
`(especially B cell lymphomas), m1d several less serious side effects. B cell lymphomas and
`polyclonal B celllymphoproliferative disorders are related to Epstein-Barr virus (EBV) acti(cid:173)
`vation and have been observed more often in patients receiving bigh dosages of cyclospor·
`ine or combinations of cyclosporine and other immunosuppressants .directed at T cells.
`Nephrotoxicity is of special concern. Cyclosporine appears to cause vasoconstriction of the
`afferent preglomerular arterioles leading ultimately to myonecrosis and refractory glomeru(cid:173)
`lar bypoperfusion. There is a concern that long-term use may cause chronic irreversible
`kidoey failure. Although the blood level of cyclosporine can be measured easily. there is
`no adequate means of determining the therapeutically effective amount of cyclosporine
`necessary for a given patient. Moreover, .cyclosporine blood levels do not correlate reliably
`with its toxic effects.
`. Antilymphocyte &Jobulin {ALG) and antlthymocyte globulin (ATG): Attempts to obtain
`more selective immunosuppression include the use of antisera to human lymphocytes or
`thymus cells in an effort to suppress cellular immunity while leaving the recipient's hu(cid:173)
`moral immunologic response intact, preserving defenses against many bacterial infections.
`f.LG and ATG .are useful adjuncts, allowir\g .other immunosuppressants to be used in
`lower, less toxic dosages. The use of ALG and ATG at the time of transplantation may
`show a small benefit in terms of a decreased incidence of rejection; moreover, their use
`allows a delay in the initiation of cyclosporine therapy and its toxicities. The use of ALG
`or ATG to control established rejection episodes has clearly led to improved graft survival
`rates. Possible adverse reactions to heterologous sera include anaphylactic reactions, se(cid:173)
`rum sickness, or Ag-Ab-induced glomerulonephritis. Using highly purified serum frac(cid:173)
`tions, giving them N, and combining them with other immunosuppressive agents ha~
`greatly reduced the incidence of these reactions. The dosage and route of administration
`of heterologous lymphocyte preparations depend on the purity and activity of each
`preparation.
`
`·Monoclonal Abs against T cells offer a much greater concentration of specifically reac(cid:173)
`tive Ab molecules and a greatly reduced amount of irrelevant serum proteins compared to
`polyclonal antiglobulin fractions. The murine monoclonal Ab, OKT3, has been shown to
`reverse rejection most effectively. This monoclonal Abreacts with the 20-kilodalton epsi(cid:173)
`lon CD3 glycoprotein that is part of the T cell Ag-receptor complex (TCRICD3).
`· Binding of the TCRICD3 complex by OKT3 leads initially to nonspecific T cell activa(cid:173)
`tion and a prominent clinical syndrome caused by the ensuing cytokine release character(cid:173)
`ized by fevers, rigors, myalgia, arthralgia, and CNS and GI irritation. Subsequently,
`OKT3 blocks binding of the TCR to Ag and results in modulation of the entire TCR com(cid:173)
`plex from the T cell surface. OKT3 5 mg/day IV for 10 to 14 days is given at the time of an
`
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`
`1696 Genitourinary Disorders
`microscopic hematuria and sometimes associated with other conditions (eg, chronic IC
`disease, chronic infection, dnlg-jnduced statc;:s, neopl<~Sm, and cQ14tgef\~vascular ~1\S\!),
`With mesan&ial proliferative GN. NS occurs in > 75% of cases, microscQpic h!ol~ ill
`20%, and hypertension in 35%.
`·
`Secondary causes of NS, including drugs (see TABLE 152-6), should be sougbt. Uri~
`nary and serum protein electrophoresis and immunoelectrophoresis differentiate glomerql~
`from tubular proteinuria and detect light chains (Bence Jones protein) or a monoclo!l31
`gammopathy. Screening for common underlying systemic diseases, such as diabetes l{lel~
`litus, amyloidosis, multiple myeloma, and SLE, sb9uld be performed. If the bU•tol•Pgy
`confirms MGN, and particularly if the patient has lost weight or is eJderly, ~ search
`.•
`malignancy should be undertaken, HB.Ag is present in 22% of pritpary glo.ffij:lrulo~
`associated with MGN, MPGN, illld lgA nephfopalhy.
`Prognosis
`Prognosis varies with specilic etiology. Complete remissions may occur if NS is second·
`ary to treatable disorders (eg, infection, malignancy, drug-induced states), which occur in
`about 50% of cases in childhood but at a lower r;tte in adulthood. The prognosis generally
`is favorable in the corticosteroid-responsive disorders and in patients who are immunosup:.:
`pressed and frequently relapse (see Treatment, below). Certain of these diseases, sueh as
`MGN, remit spontaneously even after 5 yr.
`·
`MCD has the best prognosis, with 90% of children and nearly as many adults responding
`to therapy. Relapses are common, but progression to renal failure is rare. It has been
`suggested that after a year of remission a recurrence is unlikely during pregnancy.
`· ·
`MGN, a disease mainly of adults, runs an indolent course, progressing to renal failure in
`50% of patients over 15 yr; 50% will be in remission or have persistent proteinuria or NS
`with adequate renal function. The majority of children will have complete spontaneous
`·
`remission of proteinuria within 5 yr of diagnosis.
`FGS and MPGN respond poorly to therapy, and the prognosis is guarded. Over 50% of
`patients with FGS have renal failure within 10 yr; in 20% the course is more malignllllt;
`with end-stage renal disease occurring witl:lin 2 yr; and the disease is more rapidly pro~
`sive in adults than in children. Similarly, 50% of patients with MPGN progress to renal
`failure within 10 yr, with remission in only a few(< 5%). Those with mesan&ial proliflnt.
`tive GN are virtually always nonresponsive to corticosteroids. In SLE. amyloidosl-. im,q
`diabetic nephropathy, treatment is chiefly palliative, although newer treatment protocol&
`are improving the prognosis for SLE. In diabetic NS, end·stage renal disease us~~.AA~
`velops within 3 to 5 yr.
`In all cases of NS, the prognosis may be altered drastically by infection, hypertens~Ol!,
`significant azotemia, hematuria, or thromboses in cerebral, pulmollary. perip¥ra1, or
`renal veins.
`·
`·
`·
`There is a high recurrence rate of NS in transplanted kidneys in patients whq have
`FGS, SLE, lgA nephropathy, and especially type ll MPGN, butless so in type I Mf(iN
`f:!tie~~· RGecNurrence in transplants also occurs jn some cases of MGN lllld me~~~ Jlflf.
`mera .. ve
`.
`.
`.
`.
`.
`. ....
`
`Treatment
`Treatment of NS is directed at the underlying pathogenetic process and is dependent on
`the renal pathology determined from biopsy tissue (see TABLE 152-3).
`In MCD, spontaneous remissions do occur, but several drug regimens have proved c;:ffec.,.
`tive, and children especially experience a predictable, rapid recovery. Response to treat~
`ment is indicated by cessation of proteinuria and a diuresis if edema is present. Ninety
`percent of children respond to initial therapy (prednisone 60 mglm2 or 2 mglkglday orally
`for 4 wk), but 75% of these relapse. Adults are less responsive to corticosteroid therapy
`(prednisone 1.0 to 1.5 mg!kglday orally for not more than 4 to 6 wk), and responders
`relapse at about the same rate as children. Adults are more prone to iatrogenic complica(cid:173)
`tions, particularly with increasing age and hypertension. For all patients who respond, after
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`
`2672 Clinical Pharmacology
`TABLE 286-2. COMMON ADVERSE REACTIONS OF
`SaECTEO CALCIUM ANTAGONISTS
`
`Diltiazem
`Side Effect
`
`Headache
`Dizziness
`Nausea
`Dependent edema
`Rash
`A.V block
`Bradycardia
`
`HypotenSion
`Headache
`Nausea
`Bradycardia
`
`Incidence
`(%)
`Flushing
`12.0
`Headache
`7.0
`Pedal edema
`1.3
`Dizziness
`6.0
`Asthenia
`1.0
`Increased angina
`7.6
`Palpitation
`6.0
`Nimodipine
`Side Effect
`Incidence
`(%)
`3.8
`1.2
`1.2
`1.0
`
`Nicardipine
`Side Effect
`tnci<ience
`(%)
`
`Nifedipine
`Side Effect
`
`Dizziness
`9.7
`Headache
`8.2
`Flushing
`8.0
`Dependent edema
`6.9
`Tinnitus
`5.8
`Nausea
`3.0
`Nasal congestion
`3.0
`Verapamit
`Side Effect
`Incidence
`(%)
`
`Constipation
`Dizziness
`Nausea
`Headache
`Hypotension
`A·V block
`Heart failure
`
`7.3
`3.3
`2.7
`2.2
`2.5
`2.0
`1.8
`
`Incidence
`(%)
`27.0
`23.0
`25.0
`7.0
`6.0
`11.0
`6.0
`
`Nitrendipine is an effective antihypertensive agent. Peak plasma levels are reached in I
`to 2 h. A long half-life of 8 to 12 h allows once-daily dosing. It is a potent peripheral
`arterial dilator and in clinical doses does not produce cardiac electrophysiologic effects,
`but it can cause a reflex tachycardia that may precipitate ischemia in patients with coronary
`artery disease. Clinical experience will define the role of this drug in the management of
`hypertension relative to other agents.
`felodipine is approved for the treatment of hypertension; it can be used as a single agent
`and is also compatible with other antihypertensive agents. The antihypertensive effect of
`felodipine is through peripheral vasodilation, and there is no effect on the cardiac conduc(cid:173)
`tion system. Although felodipine has not demonstrated significant negative inotropic ef(cid:173)
`fects in preliminary studies in patients with mild to moderate heart failure, its safety in
`patients with heart failure has not been established. A reflex increase in heart rate com(cid:173)
`monly occurs and is most noticeable during the first week of therapy. The increase in heart
`rate typically declines over time to levels of 5 to 10 beats/min elevation over baseline with
`chronic therapy. Following oral administration, felodipine is almost completely absorbed
`and undergoes extensive first-pass hepatic metabolism. A reduction in BP is noted within 2
`to 5 h. The mean plasma half-life is between II and 16 h, which allows once-daily admin(cid:173)
`istration. Caution is advised when using felodipine in patients > 65 yr of age or in patients
`with impaired liver function because of the potential for elevated plasma levels.
`Adverse Reactions
`The pharmacologic profiles of diltiazem, nifedipine, and verapamii predict their major
`side-effect profiles (see TABLE 286-2). The most important side effects are direct exten·
`sions of their therapeutic actions. Diltiazem is usually well tolerated and has the lowest
`incidence of side effects, Negative inotropic and chronotropic effects are mild compared
`with those of verapamil. The effects on the A- V node are less than for verapantil, and
`peripheral vasodilator effects are Less pronounced than those of nifedipine.
`The predominant cardiovascular effect of nifedipine is peripheral vasodilation. Its car(cid:173)
`diac side effects are secondary to the decrease in systemic vascular resistance; eg, retlex
`tachycardia and possible exacerbation of myocardial ischemia.
`
`Some Trade Names of Generic (Npnproprietary) ~ 2673
`Ch.287
`Since verapantil's major effects are on ~tie cardiac conduction system and myocardial
`contractility, potential side effects are high-grade A-V block and heart failure. Constipa,
`lion is also a common problem and may be particularly troublesome in the elderly.
`Adv•r-.e 0~ Interaction$
`· Adver&¢ drug inwractioll$ with Ca ~gonists typically fall into 3 general Clltegories.
`~Jt:Je Pta.rm;teqkinetic in!:erac1ions COf!llllOnJY occqc when !here is an allel'lltion in the
`metabolism of one agent due to a second agent This is qsually manifeste<l by ;w altered
`plasma level of one of tbe l!gents. ~em "-mociYMmic i.,-actio~ often occur when a
`Ca antagonist is used with a secolld agent possessing similar actions, such as combination
`therapy widl an antihypertensive agent. Ca antagonists also have the potential for adverse
`electrophY$ioloalc interactions when used with Qtber agents that affect myocatdial conduc(cid:173)
`tion. In certain clinical situations, drug interactions can provide therapeutic advantages
`over single-agent therapy; however, unwanted responses can result when the physician is
`unaware. of potential interactions. The drugs listed below are commonly used in patients
`receiving Ca antagonists. This list is not a complete guide of possible drug interactions,
`and the physician should consult other reference sources f()f more information.
`P·Adrenerak; bloekinJ apnts: Verapantil and diltiazem can exaceroate the suppressive
`effects of certaip ~blockers on heart rate, A-V conduction, and myocardial contractility.
`When us¢ in combination, close monitoring of the patient and these pal:ameters is war-
`!'3f}ted. Qther Ca ~tagof,lists ~ ge~rally well tol~.
`,
`· Dilitalis:. Verap~ ~ bee~ ~ported to si&mncantly increase digitalis levels in patients
`on chronic combination therapy. This effect is more prQnounced .in patients with bver
`dysfunction. Isolated reports have noted elevated digitalis levels with both nifedipine and
`diltiazem, while other studies failed to identify this change. Monitoring of digitalis levels
`is recommended when used in combination with any of these agents. Nicardipine and
`nimodipine have not been shown to alter digitalis levels during chronic therapy.
`Cime~if'e: Plasma levels Qf nifedipine, diltiazem, and ni,cardipine are significantly ele(cid:173)
`vated with cimetidine therapy. Patients taking ranitidine have demonstrated smaller and
`nonsignificant changes in diltiazem and nifedipine leveJs. Verapatnil and nimodipine have
`not been weJI ~~ed· .
`.
`Cyclotporine: Posttransplant patients receiving cyclosporine present a special clinical situa(cid:173)
`tion. Adequate plasma levels of cyclnsporine are important in controlling organ rejection,
`while significantly elevated plasma levels can lead to devastating side effects. Consequently,
`the physician must tx; aware of poteptial adverse drug in~ons. Significant increases in
`cyclosporine level!!·~ occor with ·botll nicardipine and verapa:mil. Diltiazem has been
`shown to increase cyclnsporine levels; however, conflicting <lata exist. Isolated repons also
`indicate that nifedipine may increase cyclosporine levels. Careful monitoring of cyclnsporine
`levels is warranted when cyclosporine is used in combination with Ca antagonists.
`
`<, ~ '
`
`'
`
`'
`
`;
`
`·;l '
`
`'.
`
`'
`
`287. SOME TRADE NAMES OF GENERIC
`.(NONPROPRIETARY) DRUGS
`..
`Mnst prescription <lrugs plafed on tbe tnarlret are given trade names (also called proprie(cid:173)
`tary, brand, or specialty names) to distinguish them as being prodnced and marketed exclu(cid:173)
`sively by a particular manufacturer. In the USA these names are usually registered as
`trademarks with the Patent Office and conftt on the registrant certain legal rights with respect
`to their use. A trade name may be registered as representing a product containing a single
`active ingredient (with or without additives) or one containing 2 or more active ingredients.
`
`'
`
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`NOVARTIS EXHIBIT 2138
`Par v Novartis, IPR 2016-00084
`Page 5 of 5