Page 1
`
`2004 WL 2459623 (Physicians' Desk Reference)
`
`Physicians' Desk Reference
`Copyright (c) 2004 by Thomson PDR, Montvale N.J.
`Current through 2004 Printing
`Manufacturers' Index
`Brand and Generic Name Index
`Product Category Index
`
`CARDENE® I.V.
`(NICARDIPINE HYDROCHLORIDE) Rx ONLY
`
`ESP PHARMA
`
`Current through 2004 Printing
`
`DESCRIPTION
`
`Cardene (nicardipine HCl) is a calcium ion influx inhibitor (slow channel blocker or calcium channel blocker).
`Cardene I.V. for intravenous administration contains 2.5 mg/mL of nicardipine hydrochloride. Nicardipine hydrochloride
`is a dihydropyridine derivative with IUPAC (International Union of Pure and Applied Chemistry) chemical name
`(±)-2-(benzyl-methyl amino) ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate mono-
`hydrochloride and has the following structure:
`0048.Ica1860d81b8a11d8af1e3e00e2075f43
`Nicardipine hydrochloride is a greenish-yellow, odorless, crystalline powder that melts at about 169° C. It is freely sol-
`uble in chloroform, methanol, and glacial acetic acid, sparingly soluble in anhydrous ethanol, slightly soluble in n-
`butanol, water, 0.01 M potassium dihydrogen phosphate, acetone, and dioxane, very slightly soluble in ethyl acetate, and
`practically insoluble in benzene, ether, and hexane. It has a molecular weight of 515.99.
`Cardene I.V. is available as a sterile, non-pyrogenic, clear, yellow solution in 10 mL ampuls for intravenous infusion
`after dilution. Each mL contains 2.5 mg nicardipine hydrochloride in Water for Injection, USP with 48.00 mg Sorbitol,
`NF, buffered to pH 3.5 with 0.525 mg citric acid monohydrate, USP and 0.09 mg sodium hydroxide, NF. Additional cit-
`ric acid and/or sodium hydroxide may have been added to adjust pH.
`
`CLINICAL PHARMACOLOGY
`
`MECHANISM OF ACTION
`
`Nicardipine inhibits the transmembrane influx of calcium ions into cardiac muscle and smooth muscle without chan-
`ging serum calcium concentrations. The contractile processes of cardiac muscle and vascular smooth muscle are depend-
`ent upon the movement of extracellular calcium ions into these cells through specific ion channels. The effects of
`nicardipine are more selective to vascular smooth muscle than cardiac muscle. In animal models, nicardipine produced
`relaxation of coronary vascular smooth muscle at drug levels which cause little or no negative inotropic effect.
`
`PHARMACOKINETICS AND METABOLISM
`
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`Page 2
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`Following infusion, nicardipine plasma concentrations decline tri-exponentially, with a rapid early distribution phase
`([agr ]-half-life of 2.7 minutes), an intermediate phase ([bgr ]-half-life of 44.8 minutes), and a slow terminal phase ([ggr
`]-half-life of 14.4 hours) that can only be detected after long-term infusions. Total plasma clearance (Cl) is 0.4 L/hr·kg,
`and the apparent volume of distribution (Vd) using a non-compartment model is 8.3 L/kg. The pharmacokinetics of
`Cardene I.V. are linear over the dosage range of 0.5 to 40.0 mg/hr.
`Rapid dose-related increases in nicardipine plasma concentrations are seen during the first two hours after the start of
`an infusion of Cardene I.V. Plasma concentrations increase at a much slower rate after the first few hours, and approach
`steady state at 24 to 48 hours. On termination of the infusion, nicardipine concentrations decrease rapidly, with at least a
`50% decrease during the first two hours post-infusion. The effects of nicardipine on blood pressure significantly correlate
`with plasma concentrations.
`Nicardipine is highly protein bound (>95%) in human plasma over a wide concentration range.
`Cardene I.V. has been shown to be rapidly and extensively metabolized by the liver. After coadministration of a radio-
`active intravenous dose of Cardene I.V. with an oral 30 mg dose given every 8 hours, 49% of the radioactivity was re-
`covered in the urine and 43% in the feces within 96 hours. None of the dose was recovered as unchanged nicardipine.
`Nicardipine does not induce or inhibit its own metabolism and does not induce or inhibit hepatic microsomal enzymes.
`The steady-state pharmacokinetics of nicardipine are similar in elderly hypertensive patients (>65 years) and young
`healthy adults.
`
`HEMODYNAMICS
`
`Cardene I.V. produces significant decreases in systemic vascular resistance. In a study of intra-arterially administered
`Cardene I.V., the degree of vasodilation and the resultant decrease in blood pressure were more prominent in hypertens-
`ive patients than in normotensive volunteers. Administration of Cardene I.V. to normotensive volunteers at dosages of
`0.25 to 3.0 mg/hr for eight hours produced changes of <5 mmHg in systolic blood pressure and <3 mmHg in diastolic
`blood pressure.
`An increase in heart rate is a normal response to vasodilation and decrease in blood pressure; in some patients these in-
`creases in heart rate may be pronounced. In placebo-controlled trials, the mean increases in heart rate were 7 ± 1 bpm in
`postoperative patients and 8 ± 1 bpm in patients with severe hypertension at the end of the maintenance period.
`Hemodynamic studies following intravenous dosing in patients with coronary artery disease and normal or moderately
`abnormal left ventricular function have shown significant increases in ejection fraction and cardiac output with no signi-
`ficant change, or a small decrease, in left ventricular end-diastolic pressure (LVEDP). There is evidence that Cardene in-
`creases blood flow. Coronary dilatation induced by Cardene I.V. improves perfusion and aerobic metabolism in areas
`with chronic ischemia, resulting in reduced lactate production and augmented oxygen consumption. In patients with
`coronary artery disease, Cardene I.V., administered after beta-blockade, significantly improved systolic and diastolic left
`ventricular function.
`In congestive heart failure patients with impaired left ventricular function, Cardene I.V. increased cardiac output both
`at rest and during exercise. Decreases in left ventricular end-diastolic pressure were also observed. However, in some pa-
`tients with severe left ventricular dysfunction, it may have a negative inotropic effect and could lead to worsened failure.
`&ldquo;Coronary steal&rdquo; has not been observed during treatment with Cardene I.V. (Coronary steal is the detri-
`mental redistribution of coronary blood flow in patients with coronary artery disease from underperfused areas toward
`better perfused areas.) Cardene I.V. has been shown to improve systolic shortening in both normal and hypokinetic seg-
`ments of myocardial muscle. Radionuclide angiography has confirmed that wall motion remained improved during in-
`creased oxygen demand. (Occasional patients have developed increased angina upon receiving Cardene capsules. Wheth-
`er this represents coronary steal in these patients, or is the result of increased heart rate and decreased diastolic pressure,
`is not clear.)
`
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`In patients with coronary artery disease, Cardene I.V. improves left ventricular diastolic distensibility during the early
`filing phase, probably due to a faster rate of myocardial relaxation in previously underperfused areas. There is little or no
`effect on normal myocardium, suggesting the improvement is mainly by indirect mechanisms such as afterload reduction
`and reduced ischemia. Cardene I.V. has no negative effect on myocardial relaxation at therapeutic doses. The clinical be-
`nefits of these properties have not yet been demonstrated.
`
`ELECTROPHYSIOLOGIC EFFECTS
`
`In general, no detrimental effects on the cardiac conduction system have been seen with Cardene I.V. During acute
`electrophysiologic studies, it increased heart rate and prolonged the corrected QT interval to a minor degree. It did not af-
`fect sinus node recovery or SA conduction times. The PA, AH, and HV intervals* or the function and effective refractory
`periods of the atrium were not prolonged. The relative and effective refractory periods of the His-Purkinje system were
`slightly shortened.
`
`HEPATIC FUNCTION
`
`Because nicardipine is extensively metabolized by the liver, plasma concentrations are influenced by changes in hepat-
`ic function. In a clinical study with Cardene capsules in patients with severe liver disease, plasma concentrations were el-
`evated and the half-life was prolonged (see &ldquo;PRECAUTIONSSS&rdquo;). Similar results were obtained in pa-
`tients with hepatic disease when Cardene I.V. (nicardipine hydrochloride) was adminstered for 24 hours at 0.6 mg/hr.
`
`RENAL FUNCTION
`
`When Cardene I.V. was given to mild to moderate hypertensive patients with moderate degrees of renal impairment,
`significant reduction in glomerular filtration rate (GFR) and effective renal plasma flow (RPF) was observed. No signi-
`ficant differences in liver blood flow were observed in these patients. A significantly lower systemic clearance and high-
`er area under the curve (AUC) were observed.
`When Cardene capsules (20 mg or 30 mg TID) were given to hypertensive patients with impaired renal function, mean
`plasma concentrations, AUC, and Cmax were approximately two-fold higher than in healthy controls. There is a transient
`increase in electrolyte excretion, including sodium (see &ldquo; PRECAUTIONS &rdquo;).
`Acute bolus administration of Cardene I.V. (2.5 mg) in healthy volunteers decreased mean arterial pressure and renal
`vascular resistance; glomerular filtration rate (GFR), renal plasma flow (RPF), and the filtration fraction were un-
`changed. In healthy patients undergoing abdominal surgery, Cardene I.V. (10 mg over 20 minutes) increased GFR with
`no change in RPF when compared with placebo. In hypertensive type II diabetic patients with nephropathy, Cardene cap-
`sules (20 mg TID) did not change RPF and GFR, but reduced renal vascular resistance.
`
`PULMONARY FUNCTION
`
`In two well-controlled studies of patients with obstructive airway disease treated with Cardene capsules, no evidence
`of increased bronchospasm was seen. In one of the studies, Cardene capsules improved forced expiratory volume 1
`second (FEV1) and forced vital capacity (FVC) in comparison with metoprolol. Adverse experiences reported in a lim-
`ited number of patients with asthma, reactive airway disease, or obstructive airway disease are similar to all patients
`treated with Cardene capsules.
`
`In patients with mild to moderate chronic stable essential hypertension, Cardene I.V. (0.5 to 4.0 mg/hr) produced dose-
`
`EFFECTS IN HYPERTENSION
`
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`dependent decreases in blood pressure, although only the decreases at 4.0 mg/hr were statistically different from placebo.
`At the end of a 48-hour infusion at 4.0 mg/hr, the decreases were 26.0 mmHg (17%) in systolic blood pressure at 20.7
`mmHg (20%) in diastolic blood pressure. In other settings (e.g., patients with severe or postoperative hypertension),
`Cardene I.V. (5 to 15 mg/hr) produced dose-dependent decreases in blood pressure. Higher infusion rates produced thera-
`peutic responses more rapidly. The mean time to therapeutic response for severe hypertension, defined as diastolic blood
`pressure <= 95 mmHg or >= 25 mmHg decrease and systolic blood pressure <=160 mmHg, was 77 ± 5.2 minutes. The
`average maintenance dose was 8.0 mg/hr. The mean time to therapeutic response for postoperative hypertension, defined
`as >=15% reduction in diastolic or systolic blood pressure, was 11.5 ± 0.8 minutes. The average maintenance dose was
`3.0 mg/hr.
`
`INDICATION AND USAGE
`
`Cardene I.V. is indicated for the short-term treatment of hypertension when oral therapy is not feasible or not desir-
`able.
`For prolonged control of blood pressure, patients should be transferred to oral medication as soon as their clinical con-
`dition permits (see &ldquo;DOSAGE AND ADMINISTRATION&rdquo;).
`
`CONTRAINDICATIONS
`
`Cardene I.V. is contraindicated in patients with known hypersensitivity to the drug. Cardene I.V. is also contraindic-
`ated in patients with advanced aortic stenosis because part of the effect of Cardene I.V. is secondary to reduced afterload.
`Reduction of diastolic pressure in these patients may worsen rather than improve myocardial oxygen balance.
`
`WARNINGS
`
`BETA-BLOCKER WITHDRAWAL
`
`Nicardipine is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker with-
`drawal; any such withdrawal should be by gradual reduction dose of beta-blocker.
`
`RAPID DECREASES IN BLOOD PRESSURE
`
`No clinical events have been reported suggestive of a too rapid decreases in blood pressure with Cardene I.V.
`However, as with any antihypertensive agent, blood pressure lowering should be accomplished over as long a time as is
`compatible with the patient[rsquo ]s clinical status.
`
`USE IN PATIENTS WITH ANGINA
`
`Increases in frequency, duration, or severity of angina have been seen in chronic oral therapy with Cardene capsules.
`Induction or exacerbation of angina has been seen in less than 1% of coronary artery disease patients treated with
`Cardene I.V. The mechanism of this effect has not been established.
`
`USE IN PATIENTS WITH CONGESTIVE HEART FAILURE
`
`Cardene I.V. reduced afterload without impairing myocardial contractility in preliminary hemodynamic studies of CHF
`patients. However, in vitro and in some patients, a negative inotropic effect has been observed. Therefore, caution should
`be exercised when using Cardene I.V., particularly in combination with a beta-blocker, in patients with CHF or signific-
`ant left ventricular dysfunction.
`
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`USE IN PATIENTS WITH PHEOCHROMOCYTOMA
`
`Only limited clinical experience exists in use of Cardene I.V. for patients with hypertension associated with pheo-
`chromocytoma. Caution should therefore be exercised when using the drug in these patients.
`
`PERIPHERAL VEIN INFUSION SITE
`
`To minimize the risk of peripheral venous irritation, it is recommended that the site of infusion of Cardene I.V., be
`changed every 12 hours.
`
`PRECAUTIONS
`
`GENERAL
`
`Blood Pressure:
`
`Because Cardene I.V. decreases peripheral resistance, monitoring of blood pressure during administration is required.
`Cardene I.V., like other calcium channel blockers, may occasionally produce symptomatic hypotension. Caution is ad-
`vised to avoid systemic hypotension when administering the drug to patients who have sustained an acute cerebral infarc-
`tion or hemorrhage.
`
`Use in Patients with Impaired Hepatic Function:
`
`Since nicardipine is metabolized in the liver, the drug should be used with caution in patients with impaired liver func-
`tion or reduced hepatic blood flow. The use of lower dosages should be considered.
`Nicardipine administered intravenously has been reported to increase hepatic venous pressure gradient by 4 mmHg in
`cirrhotic patients at high doses (5 mg/20 min). Cardene I.V. should therefore be used with caution in patients with portal
`hypertension.
`
`Use in Patients with Impaired Renal Function:
`
`When Cardene I.V. was given to mild to moderate hypertensive patients with moderate renal impairment, a signific-
`antly lower systemic clearance and higher AUC was observed. These results are consistent with those seen after oral ad-
`ministration of nicardipine. Careful dose titration is advised when treating renal impaired patients.
`
`DRUG INTERACTIONS
`
`Since Cardene I.V. may be administered to patients already being treated with other medications, including other anti-
`hypertensive agents, careful monitoring of these patients is necessary to detect and promptly treat any undesired effects
`from concomitant administration.
`
`BETA-BLOCKERS
`
`In most patients, Cardene I.V. can safely be used concomitantly with beta-blockers. However, caution should be exer-
`cised when using Cardene I.V. in combination with a beta-blocker in congestive heart failure patients (see &ldquo;
`WARNINGS&rdquo;).
`
`CIMETIDINE
`
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`Cimetidine has been shown to increase nicardipine plasma concentrations with Cardene capsule administration. Pa-
`tients receiving the two drugs concomitantly should be carefully monitored. Data with other histamine-2 antagonists are
`not available.
`
`DIGOXIN
`
`Studies have shown that Cardene capsules usually do not alter digoxin plasma concentrations. However, as a precau-
`tion, digoxin levels should be evaluated when concomitant therapy with Cardene I.V. is initiated.
`
`FENTANYL ANESTHESIA
`
`Hypotension has been reported during fentanyl anesthesia with concomitant use of a beta-blocker and a calcium chan-
`nel blocker. Even though such interactions were not seen during clinical studies with Cardene I.V. (nicardipine hydro-
`chloride), an increased volume of circulating fluids might be required if such an interaction were to occur.
`
`CYCLOSPORINE
`
`Concomitant administration of Cardene capsules and cyclosporine results in elevated plasma cyclosporine levels.
`Plasma concentrations of cyclosporine should therefore be closely monitored during Cardene I.V. administration, and the
`dose of cyclosporine reduced accordingly.
`
`IN VITRO INTERACTION
`
`The plasma protein binding of nicardipine was not altered when therapeutic concentrations of furosemide, propranolol,
`dipyridamole, warfarin, quinidine, or naproxen were added to human plasma in vitro.
`
`CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
`
`Rats treated with nicardipine in the diet (at concentrations calculated to provide daily dosage levels of 5, 15, or 45 mg/
`kg/day) for two years showed a dose-dependent increase in thyroid hyperplasia and neoplasia (follicular adenoma/car-
`cinoma). One- and three-month studies in the rat have suggested that these results are linked to a nicardipine-induced re-
`duction in plasma thyroxine (T4) levels with a consequent increase in plasma levels of thyroid stimulating hormone
`(TSH). Chronic elevation of TSH is known to cause hyperstimulation of the thyroid. In rats on an iodine deficient diet,
`nicardipine administration for one month was associated with thyroid hyperplasia that was prevented by T4 supplementa-
`tion. Mice treated with nicardipine in the diet (at concentrations calculated to provide daily dosage levels of up to 100
`mg/kg/day) for up to 18 months showed no evidence of neoplasia of any tissue and no evidence of thyroid changes.
`There was no evidence of thyroid pathology in dogs treated with up to 25 mg nicardipine/kg/day for one year and no
`evidence of effects of nicardipine on thyroid function (plasma T4 and TSH) in man. There was no evidence of a muta-
`genic potential of nicardipine in a battery of genotoxicity tests conducted on microbial indicator organisms, in micronuc-
`leus tests in mice and hamsters, or in a sister chromatid exchange study in hamsters. No impairment of fertility was seen
`in male or female rats administered nicardipine at oral doses as high as 100 mg/kg/day (50 times the 40 mg TID maxim-
`um recommended dose in man, assuming a patient weight of 60 kg).
`
`Pregnancy Category C:
`
`Cardene® I.V. at doses up to 5 mg/kg/day to pregnant rats and up to 0.5 mg/kg/day to pregnant rabbits produced no
`embryotoxicity or teratogenicity. Embryotoxicity was seen at 10 mg/kg/day in rats and at 1 mg/kg/day in rabbits, but no
`teratogenicity was observed at these doses.
`
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`Nicardipine was embryocidal when administered orally to pregnant Japanese White rabbits, during organogenesis, at
`150 mg/kg/day (a dose associated with marked body weight gain suppression in the treated doe), but not at 50 mg/kg/day
`(25 times the maximum recommended dose in man). No adverse effects on the fetus were observed when New Zealand
`albino rabbits were treated, during organogenesis, with up to 100 mg nicardipine/kg/day (a dose associated with signific-
`ant mortality in the treated doe). In pregnant rats administered nicardipine orally at up to 100 mg/kg/day (50 times the
`maximum recommended human dose) there was no evidence of embryolethality or teratogenicity. However, dystocia, re-
`duced birth weights, reduced neonatal survival, and reduced neonatal weight gain were noted. There are no adequate and
`well-controlled studies in pregnant women. Cardene should be used during pregnancy only if the potential benefit justi-
`fies the potential risk to the fetus.
`
`NURSING MOTHERS
`
`Studies in rats have shown significant concentrations of nicardipine in maternal milk. For this reason, it is recommen-
`ded that women who wish to breastfeed should not be given this drug.
`
`PEDIATRIC USE
`
`Safety and efficacy in patients under the age of 18 have not been established.
`
`USE IN THE ELDERLY
`
`No significant difference has been observed in the antihypertensive effect of Cardene I.V. in elderly patients (>= 65
`years) compared with other adult patients in clinical studies.
`
`Adverse Experiences
`
`Two hundred forty-four patients participated in two multicenter, double-blind, placebo-controlled trials of Cardene I.V.
`Adverse experiences were generally not serious and most were expected consequences of vasodilation. Adverse experi-
`ences occasionally required dosage adjustment. Therapy was discontinued in approximately 12% of patients, mainly due
`to hypotension, headache, and tachycardia.
`
`Percent of Patients with Adverse Experiences During the Double-Blind Portion of Controlled Trials
`
`Adverse Experience
`Body as a Whole
`Headache
`Asthenia
`Abdominal pain
`Chest pain
`Cardiovascular
`Hypotension
`Tachycardia
`ECG abnormality
`Postural hypotension
`Ventricular extrasystoles
`
`Cardene (n=144)
`
`Placebo (n=100)
`
`14.6
`0.7
`0.7
`0.7
`
`5.6
`3.5
`1.4
`1.4
`1.4
`
`2.0
`0.0
`0.0
`0.0
`
`1.0
`0.0
`0.0
`0.0
`0.0
`
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`0.0
`0.0
`0.0
`0.0
`0.0
`0.0
`0.0
`
`1.0
`
`0.0
`0.0
`
`0.0
`
`0.0
`0.0
`0.0
`0.0
`
`0.0
`
`0.0
`
`0.0
`0.0
`
`Extrasystoles
`Hemopericardium
`Hypertension
`Supraventricular tachycardia
`Syncope
`Vasodilation
`Ventricular tachycardia
`Digestive
`Nausea/vomiting
`Injection Site
`Injection site reaction
`Injection site pain
`Metabolic and Nutritional
`Hypokalemia
`Nervous
`Dizziness
`Hypesthesia
`Intracranial hemorrhage
`Paresthesia
`Respiratory
`Dyspnea
`Skin and Appendages
`Sweating
`Urogenital
`Polyuria
`Hematuria
`
`RARE EVENTS
`
`0.7
`0.7
`0.7
`0.7
`0.7
`0.7
`0.7
`
`4.9
`
`1.4
`0.7
`
`0.7
`
`1.4
`0.7
`0.7
`0.7
`
`0.7
`
`1.4
`
`1.4
`0.7
`
`The following rare events have been reported in clinical trials or in the literature in association with the use of intra-
`venously administered nicardipine.
`Body as a Whole: fever, neck pain
`Cardiovascular: angina pectoris, atrioventricular block, ST segment depression, inverted T wave, deep-vein throm-
`bophlebitis
`Digestive: dyspepsia
`Hemic and Lymphatic: thrombocytopenia
`Metabolic and Nutritional: hypophosphatemia, peripheral edema
`Nervous: confusion, hypertonia
`Respiratory: respiratory disorder
`
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`Special Senses: conjunctivitis, ear disorder, tinnitus
`Urogenital: urinary frequency
`Sinus node dysfunction and myocardial infarction, which may be due to disease progression, have been seen in patients
`on chronic therapy with orally administered nicardipine.
`
`OVERDOSAGE
`
`Several overdosages with orally administered nicardipine have been reported. One adult patient allegedly ingested 600
`mg of nicardipine [standard (immediate release) capsules], and another patient, 2160 mg of the sustained release formu-
`lation of nicardipine. Symptoms included marked hypotension, bradycardia, palpitations, flushing, drowsiness, confusion
`and slurred speech. All symptoms resolved without sequelae. An overdosage occurred in a one-year-old child who inges-
`ted half of the powder in a 30 mg nicardipine standard capsule. The child remained asymptomatic.
`Based on results obtained in laboratory animals,
`lethal overdose may cause systemic hypotension, bradycardia
`(following initial tachycardia) and progressive atrioventricular conduction block. Reversible hepatic function abnormalit-
`ies and sporadic focal hepatic necrosis were noted in some animal species receiving very large doses of nicardipine.
`For treatment of overdosage, standard measures including monitoring of cardiac and respiratory functions should be
`implemented. The patient should be positioned so as to avoid cerebral anoxia.
`Frequent blood pressure determinations are essential. Vasopressors are clinically indicated for patients exhibiting pro-
`found hypotension. Intravenous calcium gluconate may help reverse the effects of calcium entry blockade.
`
`DOSAGE AND ADMINISTRATION
`
`Cardene I.V. (nicardipine hydrochloride) is intended for intravenous use. DOSAGE MUST BE INDIVIDUALIZED
`depending upon the severity of hypertension and the response of the patient during dosing. Blood pressure should be
`monitored both during and after the infusion; too rapid or excessive reduction in either systolic or diastolic blood pres-
`sure during parenteral treatment should be avoided.
`
`WARNING: AMPULS MUST BE DILUTED BEFORE INFUSION
`
`PREPARATION
`
`Dilution:
`
`Cardene I.V. is administered by slow continuous infusion at a CONCENTRATION OF 0.1 MG/ML. Each ampul (25
`mg) should be diluted with 240 mL of compatible intravenous fluid (see below), resulting in 250 mL of solution at a con-
`centration of 0.1 mg/mL.
`Cardene I.V. has been found to be compatible and stable in glass or polyvinyl chloride containers for 24 hours at con-
`trolled room temperature with:
`Dextrose (5%) Injection, USP
`Dextrose (5%) and Sodium Chloride (0.45%) Injection, USP
`Dextrose (5%) and Sodium Chloride (0.9%) Injection, USP
`Dextrose (5%) and 40 mEq Potassium, USP
`Sodium Chloride (0.45%) Injection, USP
`Sodium Chloride (0.9%) Injection, USP
`Cardene I.V. is NOT compatible with Sodium Bicarbonate (5%) Injection, USP or Lactated Ringer[rsquo ]s In-
`jection, USP.
`
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`THE DILUTED SOLUTION IS STABLE FOR 24 HOURS AT ROOM TEMPERATURE.
`
`Inspection:
`
`As with all parenteral drugs, Cardene I.V. should be inspected visually for particulate matter and discoloration prior to
`administration, whenever solution and container permit. Cardene I.V. is normally light yellow in color.
`
`DOSAGE
`
`As a Substitute for Oral Nicardipine Therapy
`
`The intravenous infusion rate required to produce an average plasma concentration equivalent to a given oral dose at
`steady state is shown in the following table:
`
`Oral Cardene Dose
`20 mg q8h
`30 mg q8h
`40 mg q8h
`
`Equivalent I.V. Infusion Rate
`0.5 mg/hr
`1.2 mg/hr
`2.2 mg/hr
`
`For Initiation of Therapy in a Drug Free Patient
`
`The time course of blood pressure decrease is dependent on the initial rate of infusion and the frequency of dosage ad-
`justment.
`Cardene I.V. is administered by slow continuous infusion at a CONCENTRATION OF 0.1 MG/ML. With constant in-
`fusion, blood pressure begins to fall within minutes. It reaches about 50% of its ultimate decrease in about 45 minutes
`and does not reach final steady state for about 50 hours.
`When treating acute hypertensive episodes in patients with chronic hypertension, discontinuation of infusion is fol-
`lowed by a 50% offset of action in 30 ± 7 minutes but plasma levels of drug and gradually decreasing antihypertensive
`effects exist for about 50 hours.
`Titration: For gradual reduction in blood pressure, initiate therapy at 50 mL/hr (5.0 mg/hr). If desired blood pressure
`reduction is not achieved at this dose, the infusion rate may be increased by 25 mL/hr (2.5 mg/hr) every 15 minutes up to
`a maximum of 150 mL/hr (15.0 mg/hr), until desired blood pressure reduction is achieved.
`For more rapid blood pressure reduction, initiate therapy at 50 mL/hr (5.0 mg/hr). If desired blood pressure reduction
`is not achieved at this dose, the infusion rate may be increased by 25 mL/hr (2.5 mg/hr) every 5 minutes up to a maxim-
`um of 150 mL/hr (15.0 mg/hr), until desired blood pressure reduction is achieved. Following achievement of the blood
`pressure goal, the infusion rate should be decreased to 30 mL/hr (3 mg/hr).
`Maintenance: The rate of infusion should be adjusted as needed to maintain desired response.
`
`CONDITIONS REQUIRING INFUSION ADJUSTMENT
`
`Hypotension or Tachycardia:
`
`If there is concern of impending hypotension or tachycardia, the infusion should be discontinued. When blood pressure
`has stabilized, infusion of Cardene I.V. may be restarted at low doses such as 30 - 50 mL/hr (3.0 - 5.0 mg/hr) and adjus-
`ted to maintain desired blood pressure.
`
`© 2013 Thomson Reuters. No Claim to Orig. US Gov. Works.
`
`Sandoz Exhibit 1005 Page 10
`
`

`
`Page 11
`
`Infusion Site Changes:
`
`Cardene I.V. should be continued as long as blood pressure control is needed. The infusion site should be changed
`every 12 hours if administered via peripheral vein.
`
`Impaired Cardiac, Hepatic, or Renal Function:
`
`Caution is advised when titrating Cardene I.V. in patients with congestive heart failure or impaired hepatic or renal
`function (see &ldquo;PRECAUTIONSSS&rdquo;).
`
`TRANSFER TO ORAL ANTIHYPERTENSIVE AGENTS
`
`If treatment includes transfer to an oral antihypertensive agent other than CARDENE capsules, therapy should gener-
`ally be initiated upon discontinuation of Cardene I.V.
`If Cardene capsules are to be used, the first dose of a TID regimen should be administered 1 hour prior to discontinu-
`ation of the infusion.
`
`HOW SUPPLIED
`
`Cardene® I.V. (nicardipine hydrochloride) is available in packages of 10 ampuls of 10 mL as follows:
`25 mg (2.5 mg/mL), NDC 67286-0812-3.
`Store at controlled room temperature 20° to 25°C (68° to 77°F).
`Freezing does not adversely affect the product, but exposure to elevated temperatures should be avoided.
`Protect from light. Store ampuls in carton until used.
`U S Patent Nos.: 3,985,758; 4,880,823; and 5,164,405
`Cardene® is a registered trademark of Roche Palo Alto LLC
`Manufactured under license
`from Roche Palo Alto LLC by:
`Baxter Healthcare Corporation
`Deerfield, IL 60015 USA
`CI 4806-2
`Marketed by:
`ESP Pharma, Inc.
`Edison, NJ 08817
`CIV0021 Revised December 20, 2002
`
`END OF DOCUMENT
`
`© 2013 Thomson Reuters. No Claim to Orig. US Gov. Works.
`
`Sandoz Exhibit 1005 Page 11
`
`

`
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