PDR®
`
`5 1
`
`E D I r I o N
`
`2003
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`Executive Vice President, Directory Services: Paul M. Walsh
`
`Vice President, Sales and Marketing: Dikran N. Barsamian
`Director, PDR Pharmaceutical Sales: Anthony Sorce
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`Copyright © 2003 and published by Thomson PDR at Montvale, NJ 07645-1742. All rights reserved. None of the content of this publication
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`Officers of Thomson Healthizare: President and Chief Executive Officer: Richard Noble: Chief Financial Officer and Executive Vice President, Finance: Paul J. Hilger;
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`ISBN; 1-56363-445-7
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`Amgen Ex. 2018
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`Complex Innovations v. Amgen
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`Amgen Ex. 2018
`Complex Innovations v. Amgen
`IPR2016-00085
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`

`
`PRODUCT INFORMATION
`
`VICOPROFEN, like other drugs containing ibuprofen, is
`not free of side efl'ects The side effects ofthese drugs can
`cause discomfort and, rarely, there are more serious side ef-
`fects, such as gastrointestinal bleeding, which may result in
`hospitalization and even fatal outcomes Patients should be
`instructed to report any signs and symptoms ofgastrointes-
`tinal bleeding, blurred vision or other eye symptoms, skin
`rash, weight gain, or edema.
`Laboratory Tests
`A decrease in hemoglobin may occur during VICOPROFEN
`therapy, and elevations of liver enzymes may be seen in a
`small percentage of patients during VICOPROFEN therapy
`(see PRECAUTIONS - Hematological Eifects and PRECAU-
`TIONS - Hepatic Eifects).
`In patients with severe hepatic or renal disease, ,efi'ects of
`therapy should be monitored with liver and/or renal func-
`tion tests.
`_
`'
`Drug Interactions
`ACE-inhibitors: Reports suggest that NSAIDs may dimin-
`ish the antihypertensive effect ofACE-inhibitors. This inter-
`action should be given consideration in patients taking
`VICOPROFEN concomitantly with ACE-inhibitors.
`Antichalfnorgics: The concurrent use of anticholinergics
`with hydrocodone preparations may produce paralytic ileus.
`Antidepressants: The use of MAO inhibitors or tricyclic
`antidepressants with VICOPROFEN may increase the ef-
`fect of either the antidepressant or hydrocodone.
`Aspirin: As with other products containing NSAIDs, cen-
`comitant administration of VICOPROFEN and aspirin is
`not generally recommended because of the potential of in_-
`creased adverse effects
`CNS Depressants: Patients receiving other opioids, anti-
`histamines, antipsychoties, antianxiety agents, or other
`CNS depressants (including alcohol) concomitantly with
`VICOPROFEN may exhibit an additive CNS depression.
`When combined therapy is contemplated, the dose of one or
`both agents should be reduced.
`Furossmida:
`Ibuprofen has been shown to reduce the na-
`triuretic efl'ect offurosemide and thiazides in some patients
`This response has been attributed to inhibition of renal
`prostaglandm synthesis. During concomitant therapy with
`VICOPROFEN the patient should be observed closely for
`signs of renal failure (see PRECAUTIONS - Renal Effects),
`as well as diuretic eflicacy
`Lithium:
`Ibuprofen has been shown to elevate plasma lith-
`ium concentration and reduce renal lithium clearance. This
`effect has been attributed to inhibition of renal prostaglan-
`din synthesis by ibuprofen. Thus, when VICOPROFEN and
`lithium are administered concurrently, patients should be
`observed for signs of lithium toxicity
`Methoirexafe:
`Ibuprofen, as well as other NSAIDS, has
`been reported to competitively inhibit methotrexate accu-
`mulation in rabbit kidney slices. This may indicate that
`ibuprofen could enhance the toxicity of methotrexate. Cau-
`tion should be used when VICOPROFEN is administered
`concomitantly with methotrexate.
`Werferin: The elfects ofwarfarin and NSAIDB on GI bleed-
`ing are synergistic, such that users of both drugs together
`have a risk of serious GI bleeding higher than users of ei-
`ther drug alone.
`Carcinogenicity, Mutagenieity, and Impairment of Fertility
`The carcmogemc and mutagenic potential of VICOPROFEN
`has not been investigated. The ability of VICOPROFEN to
`impair fertility has not been assessed
`Pregnancy: Pregnancy Category C.
`Teratogeriic Effects: VTCOPROFEN, administered to rab-
`hits at 95 mg/kg (5.72 and 1 9 times the maximum clinical
`dose based on body weight and surface area, respectively), a
`maternally toxic dose, resulted in an increase in the per-
`centage of litters and fetuses with any IDEJOI‘ abnormality
`and an increase in the number of litters and fetuses with
`one or more nonossified metacarpals (a minor abnormality).
`VICOPROFEN, administered to rats at 166 mg/kg (10.0 and
`1.66 times the maximum clinical dose based on body weight
`and surface area, respectively), a mstemally toxic dose, did
`not result in any reproductive toxicity There are'no ade-
`qunte and well-controlled studies in pregnant women.
`VICOPROFEN should be used during pregnancy only if the
`potential benefit yustifies the potential risk to the fetus.
`Nonteratoganic Effects: Because of the known effects of
`nonsteroidal anti-inflammatory dnigs on the fetal cardio-
`vascular system (closure of the ductus arteriosus), use dur-
`ing pregnancy (particularly late pregnancy) should be
`avoided. Babies born to mothers who have been taking opi-
`oid.s regularly prior to delivery will be physically dependent.
`The withdrawal signs include irritability and excessive cry-
`ing, tremors, hyperactive reflexes, increased respiratory
`rate, increased stools, sneezing, yawning, vomiting, and fo-
`ver The i.ntensity of the syndrome does not always correlate
`with the duration of maternal opioid use or dose. There is no
`consensus on the best method ofmanaging withdrawal
`Labor and Delivery
`.
`As with other drugs known to inhibit proatnglandin synthe-
`sis. an increased incidence of dystocia and delayed pa.rturi-
`tion occurred in rats. Administration of VICOPROFEN is
`not recommended during labor and delivery
`Nursing Mothers
`-
`It is not known whether hydrocodone is excreted in human
`milk. In limited studies, an assay capable of detecting
`1 mcg/mL did not demonstrate ibuprofen in the milk of lac-
`tating mothers. However, because of the limited nature of
`the studies, and the possible adverse efiects cf prostaglan-
`din-inhibiting drugs on neonates, VICOPROFEN is not rec-
`ommended for use in nursing mothers.
`
`Pediatric Use
`The safety and effectiveness of VICOPROFEN in pediatric
`patients below the age of 16 have not been established.
`Geriatric Use
`In controlled clinical trials there was no difference in toler-
`abihty between patients < 65 years of age and those 2 65,
`apart from an increased tendency of the elderly to develop
`constipation However, because the elderly may be more
`sensitive to the renal and gastrointestinal efiects of nonste-
`roidal anti-inflammatory agents as well as possible in-
`creased‘ risk of respiratory depression with opioids, extra
`caution and reduced dosages should be used when treating
`the elderly with VICOPROFEN.
`ADVERSE REACTIONS
`VICOPROFEN was administered to approximately 300
`pain patients in a safety study that employed dosages and a
`duration of treatment sufiicient to encompass the recom-
`mended usage (see DOSAGE AND ADMINISTRATION).
`Adverse event rates generally increased with increasing
`daily dose. The event rates reported below are from approx-
`imately 150 patients who were in a group that received one
`tablet of VICOPROFEN an average of three to four times
`daily. The overall incidence rates of adverse experiences in
`the trials were fairly similar for this patient group ‘and
`those who received the comparison treatment, acetamino-
`phen 600 mg with codeine 60 mg.
`The following lists adverse events that occurred with an in-
`cidence of 1% or greater in clinical trials of VICOPROFEN,
`without regard to the causal relationship of the events to
`the drug To distinguish different rates ofoccurrence in clin-
`ical studies, the adverse events are listed as follows:
`'
`name of adverse event = less than 3%
`adverse events marked with an asterisk * = 3% to 9%
`adverse event rates over 9% are in parentheses.
`‘
`Body as a Whole: Abdominal pain‘; Asthenia‘; Fever, Flu
`syndrome; Headache (27%); Infection‘; Pain.
`Cardiovascular: Palpitations; Vasodilation
`Central Nervous System: Anxiety‘; Confusion; Dizziness
`(14%); Hypértonia; Insomnia‘; Nervousness*; Paresthesia;
`Somnolence (22%); Thinking abnormalities.-
`Digestive: Anorexia; Constipation (22%); Diarrhea‘; Dry
`mouth‘, Dyspepsia (12%); Flatulence‘, Gastritis; Melena;
`Mouth ulcers; Nausea (21%); Thirst; Vomiting’.
`Metabolic and Nutritional Disorders: Edema‘.
`Respiratory: Dyspnea; Hiccups; Pharyngitis; Rhinitis.
`Skin and Appandages: Pru.ritus*, Sweating‘
`Special Senses: Tinnitus.
`Urogenital: Urinary frequency.
`Incidence less than 1%
`Body as a Whole: Allergic reaction.
`Cardiovascular: Arrhythmia, Hypotension; Tachycardia.
`Central Nervous System: Agitation; Abnormal dreams;
`Decreased libido, Depression, Euphoria; Mood changes;
`Neuralgia; Slurred speech; Tremor, Vertigo.
`Digestive:
`Chalky stool; “Clenching teeth"; Dysphagia;
`Esophageal spasm; Esophagitis; Gastroenteritis, Glossitis,
`Liver enzyme elevation.
`,
`Metabolic and Nutritional: Weight decrease
`Musculoskeletal: Arthralgia; Myalgia.
`Respiratory: Asthma; Bronchitis; Hoarseness, Increased
`cough, Pulmonary congestion; Pneumonia; Shallow breath-
`ing; Sinusitis.
`Skin and Appendages: Rash; Urticaria.
`Special Senses: Altered vision; Bad taste; Dry eyes.
`Urogenital: Cystitis,_Glycosuria, Impotence; Urinary in-
`continence; Urinary retention.
`DRUG ABUSE AND DEPENDENCE
`Controlled Substance: VICOPROFEN Tablets are a
`Schedule III controlled substance
`Abuse: Psychic dependence, physical dependence, and tol-
`erance may develop upon repeated administration of opi-
`oids; therefore, VICOPROFEN Tablets should be prescribed
`and administered with the same degree of caution appropri-
`ate to use of other oral narcotic medications.
`Dependence: Physical dependence, the condition I.l1 which
`continued administration of the drug is required to prevent
`the appearance of a withdrawal syndrome; assumes clini-
`cally significant proportions only alter several weeks of
`continued opioid use, although a mild degree of physical de-
`pendence may develop after a few days of opioid therapy.
`'lbIerance, in which increasingly large doses are required in
`order to produce the same degree ofanalgesia, is marufestecl
`initially by a shortened duration of analgesic effect, and
`subsequently by decreases in the intensity of analgesia. The
`rate of development of tolerance varies among patients
`However, psychic dependence is unlikely to develop when
`VICOPROFEN Tablets are used for a short time for the
`treatment of acute pain.
`OVERDOSAGE
`Following an acute overdosage, toxicity may result from
`hydrocodone and/or ibuprofen.
`Signs and Symptoms:
`overdose with
`Hydracodone
`component: Serious
`hydrocodone is characterized by respiratory depression (a
`decrease in respiratory rate and/or tidal volume, Cbeyne-
`Stokes respiration, cyanosis) extreme somnolence progres-
`sing to stupor or coma, skeletal muscle flaccidity, cold and
`clammy skin, and sometimes bradycardia and hypotensioii.
`In severe overdosage, apnea, circulatory collapse, cardiac
`arrest and death may occur
`Ibuprofen component: Symptoms include gastrointestinal
`irntation with erosion and hemorrhage or perforation, lud-
`
`ABBOTT/515
`
`ney damage, liver damage, heart damage, hemolytic ane-
`mia, agranulocytosis, thrombocyiopenia, aplastic anemia,
`and meningitis Other symptoms may include headache,
`dizziness, tinnitus, confusion, blurred vision, mental dis-
`turbances, skin rash, stomatitis, edema, reduced retinal
`sensitivity, corneal deposits, and hyperkalemia.
`Treatment:
`Primary attention should be given to the re-establishment
`of adequate respiratory exchange throiigh provision of a pa-
`tent airway and the institution of assisted or controlled ven-
`tilation Naloxone, a narcotic antagonist, can reverse respi-
`ratory depression and coma associated with opioid overdose
`or unusual sensitivity to opioids, including hydrocodone.
`Therefore, an appropriate dose of naloxone hydrochloride
`should be administered intravenously with simultaneous ef-
`forts at respiratory resuscitation. Since the duration of ac-
`tion of hydrocodone may exceed that of the naloxone, the
`patient should be kept under continuous surveillance and
`repeated doses of the antagonist should be administered as
`needed to maintain adequate respiration. Supportive meas-
`ures should be employed as indicated. Gastric emptying
`may be useful in removing unabsorbed drug. In cases where
`consciousness is impaired it may be inadvisable to perform
`gastric lavage If gastric lavage is performed, little drug will
`likely be recovered if more than an hour has elapsed since
`ingestion. Ibuprofen IS acidic and is excreted in the urine;
`therefore, it may be beneficial to administer alkali and in-
`duce diuresis. In addition to supportive measures the use of
`oral activated charcoal may help to reduce the absorption
`and reabsorption of ibuprofen. Dialysis is not likely to be
`effective for removal of ibuprofen because it is very highly
`bound to plasma proteins.
`DOSAGE AND ADM]N'lS'I'R.ATION
`For the short-term (generally less than 10 days) manage-
`ment
`of
`acute
`pain,
`the
`recommended
`dose
`of
`VICOPROFEN is one tablet every 4 to 6 hours, as neces-
`sa.ry. Dosage should not exceed 5 tablets in a 24-hour period.
`It should be kept in mind that tolerance to hydrocodone can
`develop with continued use and that the incidence of unto-
`ward efiects is dose related.
`The lowest CITBCIGIVO dose or the longest dosing interval
`should be sought for each patient, especially in the elderly.
`Afler observing the initial
`response to therapy with
`VICOPROFEN, the dose and frequency of dosing should be
`adjusted to suit the individual patient’s need, without ex-
`ceeding the totsl daily dose recommended.
`HOW SUPPLIED
`VICOPROFEN® tablets are available as’
`White film-coated round convex tablets, engraved with “VP”
`over 3 on one side and plain on the other side
`Bottles of 100-NDC 0074-2277-I4
`Bottles of 500-N'DC 0074-2277-54
`Hospital Unit Dosage Package-100 tablets
`(4X25 tablets)-NDC 0074-2277-I2
`Storage: Store at 25"C (77°F); excursions permitted to
`15°-30°C (59°-86°F).
`lsee, USP Controlled Room Tempera-
`ture].
`Dispense iii a tight, light-resistant container.
`A Schedule @ Narcotic
`©Abbott
`Revised: August, 2001
`Ref.‘ 03-5136
`'
`ABBOTT LABORATORIES
`NORTH CHICAGO, IL 60064, U.S.A PRINTED IN U.S.A'
`Shown in Product Identification Guide, page 304
`
`ZEMPLARW
`Iparicalcitol injection)
`Fliptop VIII
`DESCRIPTION
`ZempIarT"' (paricalcitol injection) is a synthetically manu-
`factured vitamin D analog It is available as a steiile, clear,
`colorless, aqueous solution for intravenous injection. Each
`mL contains paricalcitol, 5 mcg; propylene glycol, 30% (v/v);
`and alcohol, 20% (v/v).
`Paricalcitol is a white powder chemically designated as 19-
`nor-111,3B,25-trihydi-oxy-9,10-secoergosta-5(Z),7(E),22(E)-
`tnene and has the following structural formula‘
`
`on
`Ho"”
`Molecular formula is C?-,H“O_-,.
`Molecular weight is 416 65.
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`Paricalcitol is a synthetic vitamin D analog Vitamin D and
`paricalcitol have been shown to reduce parathyroid hor-
`mone (PTH) levels.
`
`Continued on next page
`
`Consult 2 D 03 FDR“ supplements and ‘future editions for revisions
`
`

`
`516/ABBOTT
`
`PHYSICIANS’ DESK REFEFlENCE®
`
`Zemplar—Corif:.
`Pharmacoliinotics
`Distribution
`The phai-inaoolsinetics of paiicalcitol have been studied in
`patients with chronic renal failure (CRF) requiring hemodi-
`alysis. Zemplarm is administered as an intravenous bolus
`injection. Within two hours after administering doses rang-
`ing Erom 0.04 to 0.24 mcglkg, concentrations of paricalcitol
`decreased rapidly; thereafier, concentrations of paricalcitol
`declined log-linearly with a mean half-life of about 15 hours.
`No accumulation of paricalcitol was observed with multiple
`dosing.
`-
`Elimination
`In healthy subjects, plasma radioactivity after a single
`0.16 mog/kg intravenous bolus dose of “H-paricalcitol (n=4)
`was attributed to parent drug. Paricalcitol was eliminated
`primarily by hepatobiliary excretion, as 74% of the radioac-
`tive dose was recovered in feces and only 16% was found in
`urine.
`-
`Metabolism
`.
`Several unknown metabolites were detected in both the
`urine and feces, with no detectable paricalcitol in the urine.
`These metabolites have not been characterized and have
`not been identified Together, these metabolites contributed
`51% of the urinary radioactivity and 59% of the fecal radio-
`activity. In uilro plasma protein binding of paiicalcitol was
`extensive (>99.9%) and nonsaturable over the concentra-
`tion range of 1 to 100 ng1mL.
`
`Parioalcitol Pliarmncokinetic Characteristics in CHF '
`Patients (0.26 mcgllig dose)
`Parameter
`n Values (Mean : SD)
`
`Cm, (5 min. alter bolus)
`AUC.,..,
`‘
`CL ’
`‘
`V__
`
`6
`5
`5
`5
`
`1850 1' 664 (pg/mL)
`27332 1 5230 (pg°hr/mL)
`0.72 t 0.24 (L/hr)
`6 t 2 (L)
`
`Laboratory Tbsts
`In placebo-controlled studies, paricalcitol reduced serum to-
`tal alkaline phosphatase levels.
`Special Populations
`,
`Parlcalcitol pharmacokinetics have not been investigated in
`special populations (geriatric, pediatric, hepatic insufli-
`ciency), or for drug~drug interactions. Pharmacokinetics
`were not gender-dependent.
`Clinical Studies
`In three 12-week, placebo-controlled, phase 3 studies in
`chronic renal failure patients on dialysis,
`the dose of
`Zemplarm was started at 0.04 mcg/kg 3 times per week.
`The dose was increased by 0.04 mcg/kg every 2 weeks until
`intact parathyroid hormone (IPTH) levels were decreased at
`least 30% from baseline or a fifih escalation brought the
`dose to 0.24 mcg/kg, or iPI‘H fell to less than 100 pglmL, or
`the Ca X P product was greater than 75 within any 2 week
`period, or serum calcium became greater than 11.5 mg/dL at
`any time
`'
`Patients treated with Zemplarm achieved a mean iPTI-I re-
`duction of 30% within 6 weeks. In these studies, there was
`no significant difference in the incidence of hypercaloemia
`or hyperphosphatemia between Zemplarm and placebo-
`treatad patients. The results from these studies are as
`follows:
`[See table above]
`A long-term, open-label safety study of» 164 CRF patients
`(mean dose of 7.5 mcg three times per week), demonstrated
`that mean serum Ca, P, and Ca X P remained within clini-
`cally appropriate ranges with P'l‘H reduction (mean de-
`crease of319 pg/mL at 13 months).
`
`esfififlfififififififififiiild
`
`mw-1
`
`in
`
`II
`
`I:
`
`I:
`
`l1NlDlCA'l‘ll0NS AND USAGE
`Zemplarm is indicated for the prevention and treatment of
`secondary hyperparathyroidism associated with chronic re-
`nal failure. Studies in patients with chronic renal failure
`show that Zemplaz-V“ suppresses PI'H levels with no signif-
`icant difl’erence in the incidence of hypercalcemia or hyper-
`phosphatemia when compared to placebo. However, the
`serum phosphorus, calcium and calcium X phosphorus
`product (Ca X P) may increase when Zen-iplo.r‘”" is admin-
`istered.
`
`PTH (pg/mL)
`
`Alkaline Phosphatase (Ul/L)
`
`Cali.-ium (mg/dL)
`
`Phosphoriis (mg/dL)
`
`Calcium x
`Phosphorus Product
`
`Group
`We. of PIS.)
`
`Zemplarm (ii=40)
`placebo (n=38)
`
`zempim-W <n=31)
`placebo (ii=34)
`Zemplar” (11:40)
`placebo (n=38)
`
`2emplar” (n=40)
`placebo (n=38)
`Zemplar” (n=40)
`
`placebo (ii=38)
`
`Baseline Mean
`(Range)
`783 (291-2076)
`745 (320-1671)
`150 (40-600)
`
`169 (56-911)
`9.3 (7.2—10.4)
`9.1 (7.8-10.7)
`5.8 (3.7—10 2)
`6.0 (2.8—8.8)
`54 (32-106)
`
`54 (26-77)
`
`Mean [SE] Change
`From Baseline to
`Final Evaluation
`
`~379 (43.7)
`-69.6 (44.8)
`—41.5 (10.6)
`
`+2.6 (10.1)
`+0 47 (0.1)
`+0.02 (0.1)
`+0.47 (0.3)
`-0.47 (0.3)
`+7.9 (2.2)
`
`-3.9 (2.3)
`
`CONTlR.A.[NDICATIONS
`Zemplai-T“ should not be given to patients with evidence
`of vitamin D toxicity, hypercalcemia, or hypersensitivity
`to any ingredient in this product (see PRECAUTIONS.
`General).
`-
`’
`wsnnnms .
`Acute overdose ofZemplarl" may cause hypercalcemia, and
`require emergency attention. During dose adjustment,
`serum calcium and phosphorus levels should be monitored
`closely (e.g., twice weekly). Ifclinically significant hyperbol-
`cemia develops, the dose should be reduced or interrupted.
`Chronic administration of Zemplar” may place patients at
`risk of hypercalceniia, elevated Ca X Pproduct, and meta-
`static calcification. Signs and symptoms of vitamin D intox-
`ication associated with hypercalcemia include-
`Early
`Weakness, headache, somnolence, nausea, vomiting, dry
`mouth, constipation, muscle pain, bone pain, and metallic
`taste.
`Late
`-
`Anorexia, weight loss, conjunctivitis (calcific), pancreati-
`tis, photziphobia, rhinorrhea, pruritus, hypertliermia, de-
`creased libido, elevated BUN, hypercholesteroleniia, ele-
`vated AST and ALT, ectopic calcification, hypertension,
`cardiac arrhythmias, somnolenoe, death, and rarely, overt
`psychosis.
`Treatment of patients with clinically significant hypercalce-
`mia consists of immediate dose reduction or interruption of
`Templar“ therapy and includes a low calcium diet, with-
`drawal of calcium supplements, patient mobilization, atten-
`tion to fluid and electrolyte imbalances, assessment of
`electrocardiogi-aphic abnormalities (critical in patients re-
`ceiving digitalis), and hemudialysis or peritoneal dialysis
`against a calcium-free dialysate, as warranted. Serum cal-
`cium levels should be monitored frequently until normocal-
`oemia ensues.
`Phosphate or vitamin D-related compounds should not be
`taken concomitantly with Zemplarl“.
`PlR.lECAU'I‘ll0NS
`General: Digitalis toxicity is potentiated by hypercalcemia
`of any cause, so caution should be applied when digitalis
`compounds are prescribed concomitantly with Zemplarm,
`Adynamic bone lesions may develop if PTH levels are sup-
`pressed to abnormal levels
`Information for tha_Paliont: The patient should be in-
`structed that, to ensure efiectiveness ufZemplar“‘ therapy,
`it is important to adhere to a dietary regimen of calcium
`supplementation and phosphorus restriction. Appropriate
`types of phosphate-bindmg compounds may be needed to
`control serum phosphorus levels in patients with chronic re-
`oal failure (CRF), but excessive use ofaluminum containing
`compounds should be avoided. Patients should also be care-
`fully informed about the symptoms of elevated calcium.
`Essential Laboratory Taste: During the initial phase of
`medication, serum calcium and phosphorus should be deter-
`mined frequently (e.g., twice weekly). Once dosage has been
`established, serum calcium and phosphorus should be mea-
`sured at least monthly. Measurements of serum or plasma
`PTH are recommended every 3 months. An intact PTH
`(iP'l'H) assay is recommended for reliable detection of bio-
`logically active PTH in patients with CRF. During dose ad-
`justment of Zempla.r“", laboratory tests may be required
`more Frequently.
`Drug Interactions: Specific interaction studies were not
`performed. Digitalis toxicity is potentiated by hypercalce-
`mia of any cause, so caution should he applied when digita-
`lis
`compounds
`are
`prescribed concomitantly with
`Zemplarl“.
`Carcinogenesis, Mutagenasia,
`lmpairment of Fertility:
`Long-term studies in animals to evaluate the carcinogenic
`potential of paricalcitol have not been completed.
`Paricalcitol did not exhibit genetic toxicity in vitno with or
`without metabolic activatioii in the microbial niutagenesis
`assay (Ames Assay), mouse lymphoma niutageriesia assay
`(L5 l78Y), or a human lymphocyte cell chromosomal aberra-
`tion assay. There was also no evidence of genetic toxicity in
`an in viva mouse micmiiucleus assay. Zemplarm bad no ef-
`fect on fertility (male or female) in rats at intravenous doses
`
`up to 20 mcg/kgldose [equivalent to 13 times the highest rec-
`ommended human dose (0.24 meg/kg) based on surface area,
`mg/m2].
`Pregnancy: Pregnancy Category C. Paricalcitol has been
`shown to cause minimal decreases in fetal viability (5%)
`when administered daily to rabbits at a dose 0.5 times the
`0.24 mog/kg human dose (based on surface area, mg/mz) and
`when administered to rats at a dose 2 times the 0.24 meg/kg
`human dose (based on plasma levels of exposure). At the
`highest dose tested (20 mcg/kg 3 times per week'in rats, 13
`times the 0.24 mcgfkg human dose based on surface area),
`there was a significant increase of the mortality of newborn
`rats at doses that were maternally toxic (hypercalcemia).
`No other efiects on offspring development were observed.
`Par-icalcitol was not teratogenic at the doses tested.
`There are no adequate and well-controlled studies in preg-
`nant women. Zemplarm should be used during pregnancy
`only if the potential benefit justifies the potential risk to the
`fetus.
`Nursing Mothers:
`It is not known whether paricalcitol is
`excreted in human milk Because many drugs are excreted
`in human milk, caution should be exercised when
`Zeoipla.r“" is administered to a nursing Woman.
`Pediatric Use: Safety and eflicacy of Zemplar” in pediat-
`ric patients have not been established.
`‘
`Geriatric Use: Of the 40 patients receiving Zemplnrm in
`the three phase 3 placebo-controlled CRF studies,'l0 pa-
`tients were 65 years_or over. l.n these studies, no overall dif-
`ferences in eflicacy or safety were observedyhetween pa-
`tients 65 years or older and younger patients.
`ADVERSE REACTIONS
`Zemplarm has been evaluated for safety in clinical studies
`in 454 CRF patients. In four, placebo-controlled, double-
`blind, multicenter studies, discontinuation of therapy due to
`any adverse event occurred in 6.5% of 62 patients treated
`with Zemplar"“ (dosage titrated as tolerated, see CLINI-
`CAL PHARMACOLOGY, Clinical Studies) and 2.0% of 51
`patients treated with placebo for one to three months. Ad-
`verse events occurring with greater frequency in the
`Zemplai-"" group at a frequency of 2% or greater, regafdless
`of causality, are presented in the following table:
`Adverse Event Incidence Rates for All Treated Patients
`In All Placebo-Controlled Studies
`
`Adverse Event
`
`Overall
`
`Zempla_rT“
`(n=62)%
`71
`
`Placebo
`(n=5l)%
`78
`
`Body as a Whole
`Chills
`Feeling unwell
`Fever
`W
`Flu
`Sepsis
`cardiovascular System
`Palpitatioii
`Digestive System
`3
`Dry mouth
`5
`Gastrointestinal
`bleedingNausea
`18
`8
`Vomiting
`Metabolic and Nutritional Disorders
`Edema
`-
`7
`
`Nervous System
`Light-headedness
`Respiratory System
`Pneumonia
`
`A patient who reported the same medical term more than
`once was counted only once for that medical term.
`
`Infomiotlon will be superseded by supplements and subsequent editions
`
`

`
`PRODUCT INFORMATION
`
`Safety parameters (changes in mean Ca, P, Ca X P) in an
`open-label safety study up to 13 months in duration support
`the long-term safety of Zemplarm in this patient popula-
`tion.
`OVERDOSAGE
`Overdosage of Zemplar“ may lead to hypercalcemia (see
`WARNINGS).
`
`DOSAGE AND ADMINISTRATION
`The currently accepted target. range for iPI‘H levels in CRF
`patients is no more than 1.5 to 3 times the non-uremic up-
`per limit of normal.
`The recommended initial dose of Zemplarm is 0.04 meg/kg
`to 0.1 mcg/kg (2.8 — 7 mcg) administered as a bolus dose no
`more frequently than every other day at any time during
`dialysis. Doses as high as 0.24 mcg/kg (16.8 meg) have been
`safely administered.
`If a satisfactory response is not observed, the dose may be
`increased by 2 to 4 mcg at 2- to 4-week intervals. During
`any dose adjustment period, serum calcium and phosphorus
`levels should be monitored more frequently, and ifan ele-
`vated calcium level or a Ca X P product greater than 75 is
`noted, the drug dosage should be immediately reduced or
`interrupted until these parameters are normalized. Then,
`Zemplarm should be reinitiated at a lower dose. Doses may
`need to be decreased as the PTH levels decrease in response
`to therapy. Thus, incremental dosing must. be individual-
`ized
`The following table is a suggested approach in dose titra-
`tion:
`
`Suggested Dosing Guidelines
`Zemp|ar"" Doss
`increase
`increase
`maintain
`decrease
`
`PTH Level
`the same or increasing
`decreasing by <30%
`decreasing by >30%, <60%
`decreasing by >-60%
`one and one-halfto three
`times upper limit of normal
`
`maintain
`
`Parenteral drug products should be inspected visually for
`particulate matter and discoloration prior to administration
`whenever solution and container permit.
`'
`Discard unused portion.
`HOW SUPPLIED
`Zemplarr“ (paricalcitol injection) 5 mcg/mL is supplied as 1
`and 2 mL single-dose Fhptop Vials.
`__
`.
`Total
`Volume]
`Content
`Container Concentration
`
`List No.
`
`1658
`
`1658
`
`1 mL/Fliptop
`Vial
`2 mLIFliptop
`Vial
`
`5 mcgImL
`5 mcgfmL
`
`5 mcg
`
`10 meg
`
`Store at 25°C (77"F). Excursions permitted to.15°—30'C
`(59‘-86°F)
`.
`U S. patents‘ 5,246,925; 5,587,497
`58-6026-R3-Rev February 2000
`©Abbott 2000
`ABBOTT LABORATORIES, NORTH CHICAGO, IL 60064,
`USA
`
`ZYFLO® FILMTAB®
`[zi-flol
`(zileuton tublotsl
`
`DESCRIPTION
`Zileuton is an orally active inhibitor of 5-lipoxygeoase, the
`enzyme that catalyzes the formation of leukotrienes from
`arachidomc acid Zileuton has the chemical name (:)-1-(l-
`Benzofblthien-2-ylethyl)-l-hydroxyurea and the following
`chemical structure
`
`Zileuton has the molecular formula Cl1H12N202S and a mo-
`lecular weight of 236.29 It is a racemic mixture (50:50) of
`Rh) and S(-) enantriomers. Zileuton is a practically odorless,
`white, crystalline powder that is soluble in methanol and
`ethanol, slightly soluble in acetouitrile, and practically in-
`soluble in water and hexane The melting point ranges from
`144 2"C to 145 2°C. ZYFLO tablets for oral administration
`is supplied in one dosage strength containing 600 mg of
`zileuton.
`Inactive Ingredients:
`crospovidone, hydroxypropyl cellu-
`lose, hydroxypropyl methylcellulose, magnesium stearate,
`
`microcrystalline cellulose, pregelatinized starch, propylene
`glycol, sodium starch glycolate, talc, and titanium dioxide.
`CLINIC_AL PHARMACOLOGY
`Mechanism of Action:
`Zileuton is a specific inhibitor _of 5-lipoxygenase and thus
`inhibits leukotnene (LTB,, LTC,, LTD‘, and LTE4) forma-
`tion. Both the R(+) and S(-) enantiomers