NOVARTIS EXHIBIT 2168
`Par v Novartis, IPR 2016-00084
`Page 1 of 4
`
`

`
`NOVARTIS EXHIBIT 2168
`Par v Novartis, IPR 2016-00084
`Page 2 of 4
`
`

`
`for possible revisions
`X10"7 M, the doses of leucovorin should be increased to 100
`mg/m2 q 3 hours IV until the MTX level is < 10-8 M When
`such doses are administered, a non-preserved diluent should
`be used (see WARNINGS). The rate of injection of leucovorin
`calcium should not exceed 17 5 mL (175 mg leucovorin) per
`minute.
`Megaloblastic Anemia: No more than or up to 1 mg daily.
`There is no evidence that doses > 1 mg daily have greater
`efficacy than those of 1 mg; additionally, loss of folate in
`urine becomes roughly logarithmic as the amount adminis-
`tered exceeds 1 mg
`Instructions for Reconstitution: Read WARNINGS for con-
`siderations in choice of diluent. The contents of each vial
`should be reconstituted with Bacteriostatic Water for Injec-
`tion, USP (benzyl alcohol preserved) or with Sterile Water
`for Injection, USP as follows
`
`The resulting solution in each case contains 10 mg leuco-
`vorin per mL
`When reconstituted with Bacteriostatic Water for Injection,
`the resulting solution must be used within 7 days. If reconsti-
`tuted with Sterile Water for Injection, use immediately and
`discard any unused portion.
`Parenteral drug products should be inspected visually for
`particulate matter and discoloration prior to administration,
`whenever solution and container permit
`HOW SUPPLIED
`25 mg/vial, Box of 1 (NDC 0081-0636-93); 50 mg/vial, Box of 1
`(NDC 0081-0637-93), 100 mg/vial, Box of 1 (NDC 0081-0638-
`93).
`Store dry powder and reconstituted solution at controlled
`room temperature 15“ to 30°C (59® to 86®F) Protect from light
`
`LEUKERAN® $
`[Id 'kuh-rdn ]
`(Chlorambucil)
`2 mg Sugar-coated Tablets
`
`WARNING: Leukeran (chlorambucil) can severely
`suppress bone marrow function. Chlorambucil is a car-
`cinogen in humans Chlorambucil is probably muta-
`genic and teratogenic in humans. Chlorambucil pro-
`duces human infertility. See "WARNINGS” and "PRE-
`CAUTIONS” sections.
`
`DESCRIPTION
`Leukeran (chlorambucil) was first synthesized by Everett et
`all It is a bifunctional alkylating agent of the nitrogen mus-
`tard type that has been found active against selected human
`neoplastic diseases Chlorambucil is known chemically as
`4-[bis(2-chlorethyl)amino]benzenebutanoic acid.
`Chlorambucil hydrolyzes in water and has a pKa of 5.8.
`Leukeran (chlorambucil) is available in tablet form for oral
`administration. Each sugar-coated tablet contains 2 mg
`chlorambucil and the inactive ingredients corn and wheat
`starch, gum acacia, lactose, magnesium stearate, polysor-
`bate 60, sucrose, and talc
`nuADuAnm ncv
`Chlorambucil is rapidly and completely absorbed from the
`gastrointestinal tract. After single oral doses of 0.6-1.2
`mg/kg, peak plasma chlorambucil levels are reached within
`one hour and the terminal half-life of the parent drug is esti-
`mated at 1.5 hours. Chlorambucil undergoes rapid metabo-
`lism to phenylacetic acid mustard, the major metabolite, and
`the combined chlorambucil and phenylacetic acid mustard
`urinary excretion is extremely low—less than 1% in 24
`hours The peak plasma levels of chlorambucil and phenyla-
`cetic acid mustard are similar, approximating 1 pg/ml; how-
`ever, the metabolite’s half-life is 1.6 times greater than the
`parent drug.2,3
`Chlorambucil and its metabolites are extensively bound to
`plasma and tissue proteins In vitro, chlorambucil is 99%
`bound to plasma proteins, specifically albumin.4 Cerebrospi-
`nal fluid levels of chlorambucil have not been determined.
`Evidence of human teratogenicity suggests that the drug
`crosses the placenta.5,6
`Chlorambucil is extensively metabolized in the liver primar-
`ily to phenylacetic acid mustard which has antineoplastic
`activity.2,3 Chlorambucil and its major metabolite spontane-
`ously degrade in vivo forming monohydroxy and dihydroxy
`derivatives 2 After a single dose of radiolabeled chlorambucil
`(14C) approximately 15% to 60% of the radioactivity appears
`in the urine after 24 hours. Again, less than 1% of the uri-
`
`Product Information
`
`nary radioactivity is in the form of chlorambucil or phenyla-
`cetic acid mustard.2 In summary, the pharmacokinetic data
`suggest that oral chlorambucil undergoes rapid gastrointes-
`tinal absorption and plasma clearance and that it is almost
`completely metabolized, having extremely low urinary ex-
`cretion.
`INDICATIONS AND USAGE
`Leukeran (chlorambucil) is indicated in the treatment of
`chronic lymphatic (lymphocytic) leukemia, malignant lym-
`phomas including lymphosarcoma, giant follicular lym-
`phoma and Hodgkin’s disease. It is not curative in any of
`these disorders but may produce clinically useful palliation.
`CONTRAINDICATIONS
`Chlorambucil should not be used in patients whose disease
`has demonstrated a prior resistance to the agent. Patients
`who have demonstrated hypersensitivity to chlorambucil
`should not be given the drug. There may be cross-hypersen-
`sitivity (skin rash) between chlorambucil and other alkylat-
`ing agents 8
`WARNINGS
`Because of its carcinogenic properties, chlorambucil should
`not be given to patients with conditions other than chronic
`lymphatic leukemia or malignant lymphomas. Convulsions,9
`infertility,10 leukemia11,12 and secondary malignancies13
`have been observed when chlorambucil was employed in the
`therapy of malignant and non-malignant diseases.
`There are many reports of acute leukemia arising in patients
`with both malignant15 and non-malignant16 diseases follow-
`ing chlorambucil treatment In many instances, these pa-
`tients also received other chemotherapeutic agents or some
`form of radiation therapy. The quantitation of the risk of
`chlorambucil-induction of leukemia or carcinoma in humans
`is not possible. Evaluation of published reports of leukemia
`developing in patients who have received chlorambucil (and
`other alkylating agents) suggests that the risk of leukemo-
`genesis increases with both chronicity of treatment and
`large cumulative doses However, it has proved impossible to
`define a cumulative dose below which there is no risk of the
`induction of secondary malignancy. The potential benefits
`from chlorambucil therapy must be weighed on an individ-
`ual basis against the possible risk of the induction of a sec-
`ondary malignancy
`Chlorambucil has been shown to cause chromatid or chromo-
`some damage in man 17,18 Both reversible and permanent
`sterility have been observed in both sexes receiving chloram-
`bucil
`A high incidence of sterility has been documented when
`chlorambucil is administered to prepubertal and pubertal
`males.19 Prolonged or permanent azoospermia has also been
`observed in adult males20 While most reports of gonadal
`dysfunction secondary to chlorambucil have related to
`males, the induction of amenorrhea in females with alkylat-
`ing agents is well documented and chlorambucil is capable of
`producing amenorrhea. Autopsy studies of the ovaries from
`women with malignant lymphoma treated with combination
`chemotherapy including chlorambucil have shown varying
`degrees of fibrosis, vasculitis, and depletion of primordial
`follicles.21,22
`Pregnancy: "Pregnancy Category 0”: Chlorambucil can
`cause fetal harm when administered to a pregnant woman
`Unilateral renal agenesis has been observed in two offspring
`whose mothers received chlorambucil during the first tri-
`mester.5,6 Urogenital malformations including absence of a
`kidney were found in fetuses of rats given chlorambucil14
`There are no adequate and well-controlled studies in preg-
`nant women. If this drug is used during pregnancy, or if the
`patient becomes pregnant while taking this drug, the patient
`should be apprised of the potential hazard to the fetus.
`Women of childbearing potential should be advised to avoid
`becoming pregnant.
`PRECAUTIONS
`General: Many patients develop a slowly progressive lym-,
`phopenia during treatment. The lymphocyte count usually
`rapidly returns to normal levels upon completion of drug
`therapy Most patients have some neutropenia after the
`third week of treatment and this may continue for up to ten
`days after the last dose. Subsequently, the neutrophil count
`usually rapidly returns to normal. Severe neutropenia ap-
`pears to be related to dosage and usually occurs only in pa-
`tients who have received a total dosage of 6.5 mg/kg or more
`in one course of therapy with continuous dosing. About one-
`quarter of all patients receiving the continuous-dose sched-
`ule, and one-third of those receiving this dosage in eight
`weeks or less may be expected to develop severe neutrope-
`nia.23
`While it is not necessary to discontinue chlorambucil at the
`first evidence of a fall in neutrophil count, it must be remem-
`bered that the fall may continue for ten days after the last
`dose and that as the total dose approaches 6 5 mg/kg there is
`a risk of causing irreversible bone marrow damage The dose
`of chlorambucil should be decreased if leukocyte or platelet
`counts fall below normal values and should be discontinued
`for more severe depression.
`
`787
`
`Chlorambucil should not be given at full dosages before four
`weeks after a full course of radiation therapy or chemother-
`apy because of the vulnerability of the bone marrow to dam-
`age under these conditions. If the pretherapy leukocyte or
`platelet counts are depressed from bone marrow disease pro-
`cess prior to institution of therapy, the treatment should be
`instituted at a reduced dosage.
`Persistently low neutrophil and platelet counts or periph-
`eral lymphocytosis suggest bone marrow infiltration If con-
`firmed by bone marrow examination, the daily dosage of
`chlorambucil should not exceed 0.1 mg/kg. Chlorambucil
`appears to be relatively free from gastrointestinal side ef-
`fects or other evidence of toxicity apart from the bone mar-
`row depressant action. In humans, single oral doses of 20 mg
`or more may produce nausea and vomiting.
`Children with nephrotic syndrome9 and patients receiving
`high pulse doses of chlorambucil24 may have an increased
`risk of seizures. As with any potentially epileptogenic drug,
`caution should be exercised when administering chlorambu-
`cil to patients with a history of seizure disorder, head trauma
`or receiving other potentially epileptogenic drugs.
`Information for Patients: Patients should be informed that
`the major toxicities of chlorambucil are related to hypersen-
`sitivity, drug fever, myelosuppression, hepatotoxicity, infer-
`tility, seizures, gastrointestinal toxicity, and secondary ma-
`lignancies Patients should never be allowed to take the drug
`without medical supervision and should consult their physi-
`cian if they experience skin rash, bleeding, fever, jaundice,
`persistent cough, seizures, nausea, vomiting, amenorrhea, or
`unusual lumps/masses. Women of childbearing potential
`should be advised to avoid becoming pregnant.
`Laboratory Tests: Patients must be followed carefully to
`avoid life-endangering damage to the bone marrow during
`treatment. Weekly examination of the blood should be made
`to determine hemoglobin levels, total and differential leuko-
`cyte counts, and quantitative platelet counts. Also, during
`the first 3 to 6 weeks of therapy, it is recommended that
`white blood cell counts be made 3 or 4 days after each of the
`weekly complete blood counts. Galton et al23 have suggested
`that in following patients it is helpful to plot the blood counts
`on a chart at the same time that body weight, temperature,
`spleen size, etc., are recorded It is considered dangerous to
`allow a patient to go more than two weeks without hemato-
`logical and clinical examination during treatment.
`Drug Interactions: There are no known drug/drug interac-
`tions with chlorambucil.
`Carcinogenesis, Mutagenesis, Impairment of Fertility: See
`WARNINGS section for information on carcinogenesis, mu-
`tagenesis and impairment of fertility.
`Pregnancy: Teratogenic Effects: Pregnancy Category D:
`See WARNINGS section.
`Nursing Mothers: It is not known whether this drug is ex-
`creted in human milk Because many drugs are excreted in
`human milk and because of the potential for serious adverse
`reactions in nursing infants from chlorambucil, a decision
`should be made whether to discontinue nursing or to discon-
`tinue the drug, taking into account the importance of the
`drug to the mother
`Pediatric Use: The safety and effectiveness in children have
`not been established
`ADVERSE REACTIONS
`Hematologic: The most common side effect is bone marrow
`suppression.25 Although bone marrow suppression fre-
`quently occurs, it is usually reversible if the chlorambucil is
`withdrawn early enough. However, irreversible bone mar-
`row failure has been reported 26,27
`Gastrointestinal: Gastrointestinal disturbances such as
`nausea and vomiting, diarrhea and oral ulceration occur
`infrequently.
`CNS: Tremors, muscular twitching, confusion, agitation,
`ataxia, flaccid paresis and hallucinations have been reported
`as rare adverse experiences to chlorambucil which resolve
`upon discontinuation of drug. Rare, focal and/or generalized
`seizures have been reported to occur in both children9,28,29
`and adults24,30-33 at both therapeutic daily doses, pulse dos-
`ing regimens and in acute overdose (see PRECAUTIONS-
`General).
`Miscellaneous: Other reported adverse reactions include:
`pulmonary fibrosis, hepatotoxicity and jaundice, drug fever,
`skin hypersensitivity, peripheral neuropathy, interstitial
`pneumonia, sterile cystitis, infertility, leukemia and sec-
`ondary malignancies (see WARNINGS).
`OVERDOSAGE
`Reversible pancytopenia was the main finding of inadver-
`tent overdoses of chlorambucil.34,35 Neurological toxicity
`ranging from agitated behavior and ataxia to multiple grand
`mal seizures has also occurred.28,34 As there is no known
`antidote, the blood picture should be closely monitored and
`general supportive measures should be instituted, together
`with appropriate blood transfusions if necessary. Chloram-
`bucil is not dialyzable.
`
`Continued on next page
`
`NPC02237262
`
`NOVARTIS EXHIBIT 2168
`Par v Novartis, IPR 2016-00084
`Page 3 of 4
`
`

`
`788
`
`Burroughs Wellcome—Cont.
`
`Product Information
`6. Steege JF, Caldwell DS: Renal agenesis after first tri-
`mester Exposure to chlorambucil South Med J
`1980;73.1414-1415.
`Oral LD^ single doses in mice are 123 mg/kg In rats, a sin-
`7. Knisley RE, Settipane GA, Albala MM. Unusual reac-
`gle intraperitoneal dose of 12.5 mg/kg of chlorambucil pro-
`tion to chlorambucil in a patient with chronic lympho-
`duces typical nitrogen-mustard effects; these include atro-
`cytic leukemia. Arch Dermatol 1971;104:77-79.
`phy of the intestinal mucous membrane and lymphoid tis-
`8. Weiss RB, Bruno S: Hypersensitivity reactions to cancer
`sues, severe lymphopenia becoming maximal in four days,
`chemotherapeutic agents. Ann Intern Med 1981;
`anemia and thrombocytopenia. After this dose, the animals
`94.66-72.
`begin to recover within three days and appear normal in
`9. Williams SA, Makker SP, Grupe WE. Seizures: A signif-
`about a week although the bone marrow may not become
`icant side effect of chlorambucil therapy in children. J
`completely normal for about three weeks. An intraperito-
`Pediatr 1978;93:516-518.
`neal dose of 18 5 mg/kg kills about 50% of the rats with de-
`10. Freckman HA, Fry HL, Mendez FL, et al: Chlorambucil-
`velopment of convulsions. As much as 50 mg/kg has been
`prednisolone therapy for disseminated breast carci-
`given orally to rats as a single dose, with recovery. Such a
`noma. JAMA 1964;189:23-26
`dose causes bradycardia, excessive salivation, hematuria,
`11. Aymard JP, Frustin J, Witz F, et al: Acute leukemia
`after prolonged chlorambucil treatment for non-malig-
`convulsions, and respiratory dysfunction.
`nant disease: A report of a new case and literature sur-
`DOSAGE AND ADMINISTRATION
`vey Acta Haematol 1980;63:283-285.
`The usual oral dosage is 0.1 to 0.2 mg/kg body weight daily
`12. Berk PD, Goldberg JD, Silverstein MN, et al: Increased
`for three to six weeks as required This usually amounts to 4
`incidence of acute leukemia in polycythemia vera asso-
`to 10 mg a day for the average patient. The entire daily dose
`ciated with chlorambucil therapy. N Engl J Med,
`may be given at one time These dosages are for initiation of
`1981;304:441-447.
`13. Lerner HJ' Acute myelogenous leukemia in patients
`therapy or for short courses of treatment. The dosage must
`receiving chlorambucil as long-term adjuvant chemo-
`be carefully adjusted according to the response of the patient
`therapy for stage II breast cancer. Cancer Treat Rep
`and must be reduced as soon as there is an abrupt fall in the
`1978;62:1135-1138
`white blood cell count Patients with Hodgkin’s disease usu-
`14. Monie IW: Chlorambucil-induced abnormalities of the
`ally require 0.2 mg/kg daily whereas patients with other
`urogenital - system of rat fetuses. Anat Rec
`lymphomas or chronic lymphocytic leukemia usually re-
`1961;139:145-153
`quire only 0.1 mg/kg daily. When lymphocytic infiltration of
`15. Zarrabi MH, Griiwald HW, Rosner F: Chronic lympho-
`the bone marrow is present, or when the bone marrow is
`cytic leukemia terminating in acute leukemia. Arch
`hypoplastic, the daily dose should not exceed 0.1 mg/kg
`Intern Med 1977;137:1059-1064.
`(about 6 mg for the average patient).
`16. Cameron S' Chlorambucil and leukemia. N Eng J Med
`Alternate schedules for the treatment of chronic lympho-
`1977; 296:1065.
`cytic leukemia employing intermittent, bi-weekly or once
`17. Lawler SD, Lele KP Chromosomal damage induced by
`monthly pulse doses of chlorambucil have been reported.36,37
`chlorambucil in chronic lymphocytic leukemia Scand J
`Intermittent schedules of chlorambucil begin with an initial
`Haematol 1972;9:603-612.
`single dose of 0 4 mg/kg. Doses are generally increased by 0.1
`18 Stevenson AC, Patel C Effects of chlorambucil on hu-
`mg/kg until control of lymphocytosis or toxicity is observed.
`man chromosomes Muiat Res 1973;18.333-351.
`Subsequent doses are modified to produce mild hematologic
`19. Guesry P, Lenoir G, Broyer M: Gonadal effects of chlor-
`toxicity. It is felt that the response rate of chronic lympho-
`ambucil given to prepubertal and pubertal boys for ne-
`cytic leukemia to the bi-weekly or once monthly schedule of
`phrotic syndrome. J Pediatr 1978;92:299-303.
`chlorambucil administration is similar or better to that pre-
`20. Richter P, Calamera JC, Morgenfeld MC, et al* Effect of
`viously reported with daily administration and that hemato-
`chlorambucil on spermatogenesis in the human with
`logic toxicity was less than or equal to that encountered in
`malignant lymphoma. Cancer 1970,25:1026-1030.
`studies using daily chlorambucil.
`21. Morgenfeld MC, Goldberg V, Parisier H, et al. Ovarian
`Radiation and cytotoxic drugs render the bone marrow more
`lesions due to cytostatic agents during the treatment of
`vulnerable to damage and chlorambucil should be used with
`Hodgkin’s disease Surg Gynecol Obstet 1972;
`particular caution within four weeks of a full course of radia-
`134-826-828.
`tion therapy or chemotherapy However, small doses of palli-
`22. Sobrinho LG, Levine RA, DeConti RC- Amenorrhea in
`ative radiation over isolated foci remote from the bone mar-
`patients with Hodgkin’s disease treated with antineo-
`row will not usually depress the neutrophil and platelet
`plastic agents. Am J Obstet Gynecol 1971;109T35-139
`count. In these cases chlorambucil may be given in the cus-
`23 Galton DAG, Israels LG, Nabarro JDN, et al: Clinical
`tomary dosage.
`trials of p-(Di-2-chloroethylamino)-phenylbutyric acid
`It is presently felt that short courses of treatment are safer
`(CB 1348) in malignant lymphoma. Br Med J
`than continuous maintenance therapy although both meth-
`1955;2T172-1176.
`ods have been effective It must be recognized that continu-
`24. Ciobanu N, Runowicz C, Gucalp R, et al: Reversible cen-
`ous therapy may give the appearance of "maintenance” in
`tral nervous system toxicity associated with high-dose
`patients who are actually in remission and have no immedi-
`chlorambucil in autologous bone marrow transplanta-
`ate need for further drug. If maintenance dosage is used, it
`tion for ovarian cancer. Cancer Treat Rep
`should not exceed 0.1 mg/kg daily and may well be as low as
`1987,71:1324-1325
`0 03 mg/kg daily. A typical maintenance dose is 2 mg to 4 mg
`25 Moore GE, Bross IDJ, Ausman R, et al: Effects of chlor-
`daily, or less, depending on the status of the blood counts. It
`ambucil (NSC-3088) in 374 Patients with advanced can-
`may, therefore, be desirable to withdraw the drug after max-
`cer. Cancer Chemother Rep 1968;52(pt l)'661-666.
`imal control has been achieved since intermittent therapy
`26 Galton DAG, Wiltshaw E, Szur L, et al' The use of chlor-
`reinstituted at time of relapse may be as effective as continu-
`ambucil and steroids in the treatment of chronic lym-
`ous treatment.
`phocytic leukemia. Br J Haematol 1961,7.73-98
`Procedures for proper handling and disposal of anti-cancer
`27. Rudd P, Fries JF, Epstein WV: Irreversible bone mar-
`drugs should be considered. Several guidelines on this sub-
`row failure with chlorambucil. J Rheumatol
`ject have been published.38-'14
`1975;2:421-429.
`There is no general agreement that all of the procedures
`28 Wolfson S, Olney MB- Accidental ingestion of a toxic
`recommended in the guidelines are necessary or appropri-
`dose of chlorambucil: Report of a case in a child. JAMA
`ate
`y 1957;165:239-240
`HOW SUPPLIED
`29. Bryne TN, Moseley TAE, Finer MA: Myoclonic seizures
`White sugar-coated tablet containing 2 mg chlorambucil;
`following chlorambucil overdose. Ann Neurol
`bottle of 50 (NDC-0081-0635-35).
`1981;9:191-194
`Store at 15°-25°C (59<>-77BF) in a dry place
`30. LaDelfa I, Myers BR, Hoffstein V: Chlorambucil in-
`REFERENCES
`duced myoclonic seizures in an adult. J Chn Oncol
`1. Everett JL, Roberts JJ, Ross WCJ‘ Aryl-2-
`1985;3:1691-1692.
`31 Naysmith A, Robson RH Focal fits during
`halogenoalkylamines. Part XII. Some carboxylic deriva-
`tives of NN-Di-2-chloroethylanihne. J Chem Soc 1953,
`chlorambucil therapy. Postgrad Med J 1979;55:806-807.
`32. Blank DW, Nanji AA, Schreiber DH, et al: Acute renal
`3:2386-2392.
`2. Alberts DS, Chang SY, Chen H-SG, et al: Pharmacoki-
`failure and seizures associated with chlorambucil over-
`netics and metabolism of chlorambucil in man: A pre-
`dose J. Toxicol Clm Toxicol 1983,20.361-365.
`liminary report. Cancer Treat Rev, 1979;6 (suppl):9-17.
`33. Ammenti A, Reitter B, Muller-Wiefel DE: Chlorambucil
`3. McLean A, Woods RL, Catovsky D, et al. Pharmacoki-
`neurotoxicity: Report of two cases. Helv Paediatr Acta
`netics and metabolism of chlorambucil in patients with
`1980;35:281-287.
`malignant disease. Cancer Treat Rev, 1979;6(suppl)'33-
`34. Green AA, Naiman JL. Chlorambucil poisoning Am J
`42
`Dis Child 1968;116T90-191.
`35. Enck RE, Bennett JM* Inadvertent chlorambucil over-
`4 Ehrsson H, Lonroth U, Wallin 1, et al' Degradation of
`chlorambucil in aqueous solution: Influence of human
`dose in adults. NY State J Med 1977;77'1480-1481.
`albumin binding JPharm Pharmacol, 1981:33 313-315.
`36. Knospe WH, Loeb V Jr, Huguley CM: Bi-weekly chlor-
`ambucil treatment of chronic lymphocytic leukemia.
`5. Shotton D, Monie IW- Possible teratogenic effect of
`Cancer 1974;33'555-562.
`chlorambucil on a human fetus. JAMA 1963;186 74-75.
`
`Always consult Supplement
`
`37. Sawitsky A, Rai KR, Glidewell O, et al: Comparison of
`daily versus intermittent chlorambucil and prednisone
`therapy in the treatment of patients with chronic lym-
`phocytic leukemia. Blood 1977;50:1049-1059.
`38. Recommendations for the safe handling of parenteral
`antineoplastic drugs. US Dept of Health and Human
`Services publications No. (NIH) 83-2621 Government
`Printing Office, 1983.
`39. Council on Scientific Affairs: Guidelines for handling
`parenteral antineoplastic drugs. AMA COUNCIL RE-
`PORT JAMA 1985;253:1590-1592.
`40. National Study Commission on Cytotoxic Exposure'
`Recommendations for Handling Cytotoxic Agents.
`(Available from L.P. Jeffrey, Director of Pharmacy Ser-
`vices, Rhode Island Hospital, 593 Eddy St, Providence,
`RI 02902)
`41. Clinical Oncological Society of Australia: Guidelines
`and recommendations for safe handling of antineoplas-
`tic agents. Med J Australia 1983;1:426-428.
`42. Jones RB, Frank R, Mass T: Safe handling of chemo-
`therapeutic agents A report from the Mount Sinai Med-
`ical Center. CA-A Cancer J for Clin 1983;33258-263.
`43 American Society of Hospital Pharmacists technical
`assistance bulletin on handling cytotoxic drugs in hospi-
`tals. Am J Hosp Pharm 1985;42:131-137.
`44 Yodaiken RE, Bennett D: OSHA work-practice guide-
`lines for personnel dealing with cytotoxic (antineoplas-
`tic) drugs. AM J Hosp Pharm 1986;43T 193-1204
`Shown in Product Identification Section, page 407
`
`MANTADIL® CREAM IJ
`[man 'tah-dil" ]
`
`DESCRIPTION
`Mantadil® Cream contains the antihistamine chlorcycli-
`zine hydrochloride 2% and the corticosteroid hydrocortisone
`acetate 0.5%, with methylparaben 0.25% (added as a preser-
`vative) in a vanishing cream base The inactive ingredients
`are liquid and white petrolatum, emulsifying wax and puri-
`fied water
`Mantadil Cream is an ANTIPRURITIC-ANTI-INFLAMMA-
`TORY-ANESTHETIC for topical administration.
`Chlorcyclizine hydrochloride is known chemically as l-[(4-
`chlorophenyl)phenylmethyl]-4-methylpiperazine monohy-
`drochloride.
`Hydrocortisone acetate is the acetate ester of cortisol, known
`chemically as 21-(acetyloxy>ll/3,17-dihydroxypregn-4-ene-
`3,20-dione.
`The pH of this product is approximately 4.5.
`CLINICAL PHARMACOLOGY
`Chlorcyclizine hydrochloride is an Hi histamine-receptor
`antagonist that will occupy receptor sites in effector cells to
`the exclusion of histamine. It blocks most of the effects of
`histamine mediated by Hj receptors, including contraction
`of smooth muscle and increased capillary permeability. Ab-
`sorption of chlorcyclizine hydrochloride into the skin is rapid
`following topical application, whereas systemic absorption
`from the skin is minimal Chlorcyclizine hydrochloride pre-
`vents local edema and provides local anesthetic and antipru-
`ritic action in the skin.
`Hydrocortisone acetate administered topically suppresses
`most inflammatory and allergic responses in the skin. Fol-
`lowing topical application, it is absorbed rapidly into the
`skin, where it reduces local heat, redness, swelling, and ten-
`derness. A small part of the dose applied to broken skin is
`absorbed systemically and metabolized by the liver
`INDICATIONS AND USAGE
`Mantadil Cream is indicated for the treatment of pruritic
`skin eruptions and other dermatoses including: eczema (al-
`lergic, nuchal and nummular); dermatitis (atopic, lichenoid
`and seborrheic); contact dermatitis including poison ivy,
`poison oak and poison sumac; localized neurodermatitis;
`insect bites; sunburn, intertrigo; and anogenital pruritus.
`CONTRAINDICATIONS
`This preparation is contraindicated in patients who are hy-
`persensitive to any of its components; in tuberculosis of the
`skin, vaccinia, varicella, and herpes simplex. As with other
`topical products containing hydrocortisone, the cream
`should not be used m bacterial infections of the skin unless
`antibacterial therapy is concomitant.
`Not for ophthalmic use.
`WARNINGS
`Oral chlorcyclizine is teratogenic in animals. Long-term
`reproduction studies of topical chlorcyclizine Have not been
`conducted in humans.
`PRECAUTIONS
`General: If signs of irritation develop with use of this
`cream, treatment should be discontinued and appropriate
`therapy instituted.
`Any of the side effects reported following systemic use of
`corticosteroids, including adrenal suppression, may also
`occur following their topical use, especially in infants and
`
`NPC02237263
`
`NOVARTIS EXHIBIT 2168
`Par v Novartis, IPR 2016-00084
`Page 4 of 4