Accupri|®
`(Quinapril Hydrochloride Tablets)
`
`WARNING: FETAL TOXICITY
`
`death to the developing fetus. See Warnings: Fetal Toxicity
`
`- When pregnancy is detected, discontinue ACCUPRIL as soon as possible.
`- Drugs that act directly on the renin-angiotensin system can cause injury and
`
`DESCRIPTION
`
`ACCUPRILQ9 (quinapril hydrochloride) is the hydrochloride salt of quinapril, the ethyl ester of a
`non-sulfhydryl, angiotensin-converting enzyme (ACE) inhibitor, quinaprilat.
`
`Quinapril hydrochloride is chemically described as [3S-[2[R*(R*)], 3R*]]—2-[2-[[l-
`(ethoxycarbonyl)-3-phenylpropyl]am1no]- l -oxopropyl]- 1 ,2,3,4-tetrahydro-3-
`isoquinolinecarboxylic acid, monohydrochloride. Its empirical formula is C25H30N205 -HCl and
`its structural formula is:
`
`CH)
`,.c\H , NH\
`N
`(3
`6’
`,,
`cu,
`COOH
`
`/cu
`
`cu
`cooEr
`
`,_
`9cH.,,
`
`M.W_=4'/4.98
`
`HCI
`
`Quinapril hydrochloride is a white to off-white amorphous powder that is freely soluble in
`aqueous solvents.
`
`ACCUPRIL tablets contain 5 mg, 10 mg, 20 mg, or 40 mg of quinapril for oral administration.
`
`Each tablet also contains candelilla wax, crospovidone, gelatin, lactose, magnesium carbonate,
`magnesium stearate, synthetic red iron oxide, and titanium dioxide.
`
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action: Quinapril is deesterified to the principal metabolite, quinaprilat, which
`is an inhibitor of ACE activity in human subjects and animals. ACE is a peptidyl dipeptidase that
`
`catalyzes the conversion of angiotensin I to the vasoconstrictor, angiotensin II. The effect of
`
`quinapril in hypertension and in congestive heart failure (CHF) appears to result primarily from
`the inhibition of circulating and tissue ACE activity, thereby reducing angiotensin II formation.
`Quinapril inhibits the elevation in blood pressure caused by intravenously administered
`
`angiotensin I, but has no effect on the pressor response to angiotensin II, norepinephrine or
`epinephrine. Angiotensin II also stimulates the secretion of aldosterone from the adrenal cortex,
`thereby facilitating renal sodium and fluid reabsorption. Reduced aldosterone secretion by
`
`quinapril may result in a small increase in serum potassium. In controlled hypertension trials,
`
`Reference ID: 3506655
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2054 - 0001
`
`

`
`treatment with ACCUPRIL alone resulted in mean increases in potassium of 0.07‘ mmol/L (see
`
`PRECAUTIONS). Removal of angiotensin 11 negative feedback on renin secretion leads to
`increased plasma renin activity (PRA).
`
`While the principal mechanism of antihypertensive effect is thought to be through the renin-
`angiotensin-aldosterone system, quinapril exerts antihypertensive actions even in patients with
`
`low renin hypertension. ACCUPRIL was an effective antihypertensive in all races studied,
`although it was somewhat less effective in blacks (usually a predominantly low renin group) than
`in nonblacks. ACE is identical to kininase 11, an enzyme that degrades bradykinin, a potent
`
`peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of
`quinapril remains to be elucidated.
`
`Pharmacokinetics and Metabolism: Following oral administration, peak plasma quinapril
`concentrations are observed within one hour. Based on recovery of quinapril and its metabolites
`in urine, the extent of absorption is at least 60%. The rate and extent of quinapril absorption are
`diminished moderately (approximately 25-30%) when ACCUPRIL tablets are administered
`during a high—fat meal. Following absorption, quinapril is deesterified to its major active
`metabolite, quinaprilat (about 38% oforal dose), and to other minor inactive metabolites.
`
`Following multiple oral dosing of ACCUPRIL, there is an effective accumulation half—life of
`quinaprilat of approximately 3 hours, and peak plasma quinaprilat concentrations are observed
`approximately 2 hours post—dose. Quinaprilat is eliminated primarily by renal excretion, up to
`
`96% of an TV dose, and has an elimination half—life in plasma of approximately 2 hours and a
`prolonged terminal phase with a half—life of 25 hours. The pharmacokinetics of quinapril and
`quinaprilat are linear over a single—dose range of 5-80 mg doses and 40-160 mg in multiple daily
`doses. Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound to
`proteins.
`
`In patients with renal insufficiency, the elimination half—life of quinaprilat increases as creatinine
`clearance decreases. There is a linear correlation between plasma quinaprilat clearance and
`creatinine clearance. In patients with end—stage renal disease, chronic hemodialysis or continuous
`ambulatory peritoneal dialysis has little effect on the elimination of quinapril and quinaprilat.
`
`Elimination of quinaprilat may be reduced in elderly patients (265 years) and in those with heart
`
`failure; this reduction is attributable to decrease in renal function (see DOSAGE AND
`ADMINISTRATION). Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis
`due to impaired deesterification of quinapril. Studies in rats indicate that quinapril and its
`metabolites do not cross the blood—brain barrier.
`
`Pharmacodynamics and Clinical Effects
`
`Hypertension: Single doses of 20 mg of ACCUPRIL provide over 80% inhibition of plasma
`
`ACE for 24 hours. Inhibition ofthe pressor response to angiotensin I is shorter—lived, with a 20
`mg dose giving 75% inhibition for about 4 hours, 50% inhibition for about 8 hours, and 20%
`inhibition at 24 hours. With chronic dosing, however, there is substantial inhibition of
`
`angiotensin II levels at 24 hours by doses of 20-80 mg.
`
`Administration of 10 to 80 mg of ACCUPRIL to patients with mild to severe hypertension results
`in a reduction of sitting and standing blood pressure to about the same extent with minimal effect
`
`Reference ID: 3506655
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2054 - 0002
`
`

`
`on heart rate. Symptomatic postural hypotension is infrequent although it can occur in patients
`
`who are salt—and/or volume—depleted (see WARNINGS). Antihypertensive activity commences
`within 1 hour with peak effects usually achieved by 2 to 4 hours after dosing. During chronic
`therapy, most of the blood pressure lowering effect of a given dose is obtained in 1-2 weeks. In
`
`multiple—dose studies, 10-80 mg per day in single or divided doses lowered systolic and diastolic
`
`blood pressure throughout the dosing interval, with a trough effect of about 5-] I/3-7 mm Hg.
`The trough effect represents about 50% of the peak effect. While the dose—response relationship
`is relatively flat, doses of 40-80 mg were somewhat more effective at trough than 10-20 mg, and
`twice daily dosing tended to give a somewhat lower trough blood pressure than once daily dosing
`with the same total dose. The antihypertensive effect of ACCUPRIL continues during long-term
`
`therapy, with no evidence of loss of effectiveness.
`
`Hemodynamic assessments in patients with hypertension indicate that blood pressure reduction
`produced by quinapril is accompanied by a reduction in total peripheral resistance and renal
`vascular resistance with little or no change in heart rate, cardiac index, renal blood flow,
`
`glomerular filtration rate, or filtration fraction.
`
`Use of ACCUPRIL with a thiazide diuretic gives a blood—pressure lowering effect greater than
`that seen with either agent alone.
`
`In patients with hypertension, ACCUPRIL 10-40 mg was similar in effectiveness to captopril,
`enalapril, propranolol, and thiazide diuretics.
`
`Therapeutic effects appear to be the same for elderly (265 years of age) and younger adult
`
`patients given the same daily dosages, with no increase in adverse events in elderly patients.
`
`Heart Failure: In a placebo—controlled trial involving patients with congestive heart failure
`treated with digitalis and diuretics, parenteral quinaprilat, the active metabolite of quinapril,
`reduced pulmonary capillary wedge pressure and systemic vascular resistance and increased
`
`cardiac output/index. Similar favorable hemodynamic effects were seen with oral quinapril in
`baseline—controlled trials, and such effects appeared to be maintained during chronic oral
`quinapril therapy. Quinapril reduced renal hepatic vascular resistance and increased renal and
`
`hepatic blood flow with glomerular filtration rate remaining unchanged.
`
`A significant dose response relationship for improvement in maximal exercise tolerance has been
`observed with ACCUPRIL therapy. Beneficial effects on the severity of heart failure as measured
`by New York Heart Association (NYHA) classification and Quality of Life and on symptoms of
`
`dyspnea, fatigue, and edema were evident after 6 months in a double—blind, placebo—controlled
`study. Favorable effects were maintained for up to two years of open label therapy. The effects of
`quinapril on long-term mortality in heart failure have not been evaluated.
`
`INDICATIONS AND USAGE
`
`Hypertension
`
`ACCUPRIL is indicated for the treatment of hypertension, to lower blood pressure. Lowering
`blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and
`myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive
`
`drugs from a wide variety of pharmacologic classes including the class to which this drug
`principally belongs. There are no controlled trials demonstrating risk reduction with ACCUPRIL.
`
`Reference ID: 3506655
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2054 - 0003
`
`

`
`Control of high blood pressure should be part ofcomprehensive cardiovascular risk management,
`
`including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking
`cessation, exercise, and limited sodium intake. Many patients will require more than one drug to
`achieve blood pressure goals. For specific advice on goals and management, see published
`
`guidelines, such as those of the National High Blood Pressure Education Program’s Joint
`
`National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood
`Pressure (INC).
`
`Numerous antihypcrtensive drugs, from a variety of pharmacologic classes and with different
`mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular
`
`morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some
`other pharmacologic property of the drugs, that is largely responsible for those benefits. The
`largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of
`stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen
`regularly.
`
`Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk
`increase per mmflg is greater at higher blood pressures, so that even modest reductions of severe
`hypertension can provide substantial benefit. Relative risk reduction from blood pressure
`
`reduction is similar across populations with varying absolute risk, so the absolute benefit is
`
`greater in patients who are at higher risk independent of their hypertension (for example, patients
`with diabetes or hyperlipidemia), and such patients would be expected to benefit from more
`aggressive treatment to a lower blood pressure goal.
`
`Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black
`
`patients, and many antihypertensive drugs have additional approved indications and effects (e.g.,
`on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of
`therapy.
`
`ACCUPRIL may be used alone or in combination with thiazide diuretics.
`
`Heart Failure
`
`ACCUPRIL is indicated in the management of heart failure as adjunctive therapy when added to
`
`conventional therapy including diuretics and/or digitalis.
`
`In using ACCUPRIL, consideration should be given to the fact that another angiotensin-
`
`converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with
`renal impairment or collagen vascular disease. Available data are insufficient to show that
`ACCUPRIL does not have a similar risk (see WARNINGS).
`
`Angioedema in black patients: Black patients receiving ACE inhibitor monotherapy have been
`
`reported to have a higher incidence of angioedema compared to non—blacks. It should also be
`noted that in controlled clinical trials ACE inhibitors have an effect on blood pressure that is less
`in black patients than in non—blacks.
`
`CONTRAINDICATIONS
`
`ACCUPRIL is contraindicated in patients who are hypersensitive to this product and in patients
`with a history of angioedema related to previous treatment with an ACE inhibitor.
`
`Reference ID: 3506655
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2054 - 0004
`
`

`
`Do not eo—administer ACCUPRIL with aliskiren in patients with diabetes
`
`WARNINGS
`
`Anaphylactoid and Possibly Related Reactions
`Presumably because angiotensin—converting inhibitors affect the metabolism ofeicosanoids and
`polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including
`
`ACCUPRIL) may be subject to a variety of adverse reactions, some of them serious.
`
`Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and
`larynx has been reported in patients treated with ACE inhibitors and has been seen in 0.1% of
`patients receiving ACCUPRIL.
`
`In two similarly sized U.S. postmarketing trials that, combined, enrolled over 3,000 black
`patients and over 19,000 non—blacks, angioedema was reported in 0.30% and 0.55% ofblacks (in
`study 1 and 2 respectively) and 0.39% and 0.17% of non-blacks.
`
`Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of
`the face, tongue, or glottis occurs, treatment with ACCUPRIL should be discontinued
`immediately, the patient treated in accordance with accepted medical care, and carefully observed
`
`until the swelling disappears. In instances where swelling is confined to the face and lips, the
`
`condition generally resolves without treatment; antihistamines may be useful in relieving
`
`symptoms. Where there is involvement of the tongue, glottis, or larynx likely to cause
`
`airway obstruction, emergency therapy including, but not limited to, subcutaneous
`epinephrine solution l:l000 (0.3 to 0.5 mL) should be promptly administered (see
`ADVERSE REACTIONS).
`
`Patients taking concomitant mTOR inhibitor (cg. tcmsirolimus) therapy may be at increased risk
`for angioedema.
`
`Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE
`inhibitors. These patients presented with abdominal pain (with or without nausea or Vomiting); in
`
`some cases there was no prior history of facial angioedema and C-1 esterase levels were normal.
`The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at
`surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should
`be included in the differential diagnosis ofpatients on ACE inhibitors presenting with abdominal
`pain.
`
`Patients with a history of angioedema: Patients with a history of angioedema unrelated to
`ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor
`
`(see also CONTRAINDICATIONS).
`
`Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing
`treatment with hymenoptera venom while receiving ACE inhibitors sustained life—threatening
`anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors
`
`were temporarily withheld, but they reappeared upon inadvertent rechallenge.
`
`Anaphylactoid reactions during membrane exposure: Anaphylactoid reactions have been
`reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE
`
`Reference ID: 3506655
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2054 - 0005
`
`

`
`inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low—density
`
`lipoprotein apheresis with dextran sulfate absorption.
`
`Hepatic Failure: Rarely, ACE inhibitors have been associated with a syndrome that starts with
`cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The
`mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop
`
`jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and
`receive appropriate medical follow-up.
`
`Hypotension: Excessive hypotension is rare in patients with uncomplicated hypertension treated
`with ACCUPRIL alone. Patients with heart failure given ACCUPRIL commonly have some
`
`reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic
`hypotension usually is not necessary when dosing instructions are followed. Caution should be
`observed when initiating therapy in patients with heart failure (see DOSAGE AND
`
`ADMINISTRATION). In controlled studies, syncope was observed in 0.4% of patients
`(N=3203); this incidence was similar to that observed for captopril (1%) and enalapril (0.8%).
`
`Patients at risk of excessive hypotension, sometimes associated with oliguria and/or progressive
`azotemia, and rarely with acute renal failure and/or death, include patients with the following
`
`conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent
`intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt
`depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with
`
`heart failure), reduce the diuretic dose or cautiously increase salt intake (except in patients with
`
`heart failure) before initiating therapy with ACCUPRIL in patients at risk for excessive
`
`hypotension who are able to tolerate such adjustments.
`
`In patients at risk of excessive hypotension, therapy with ACCUPRIL should be started under
`
`close medical supervision. Such patients should be followed closely for the first two weeks of
`treatment and whenever the dose of ACCUPRIL and/or diuretic is increased. Similar
`
`considerations may apply to patients with ischemic heart or cerebrovascular disease in whom an
`
`excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular
`accident.
`
`If excessive hypotension occurs, the patient should be placed in the supine position and, if
`necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is
`not a contraindication to further doses of ACCUPRIL, which usually can be given without
`difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose
`reduction or discontinuation of ACCUPRIL or concomitant diuretic may be necessary.
`
`Neutropenia/Agranulocytosisz Another ACE inhibitor, captopril, has been shown to cause
`agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension,
`but more frequently in patients with renal impairment, especially if they also have a collagen
`vascular disease, such as systemic lupus erythematosus or scleroderma. Agranulocytosis did
`
`occur during ACCUPRIL treatment in one patient with a history of neutropenia during previous
`captopril therapy. Available data from clinical trials of ACCUPRIL are insufficient to show that,
`in patients without prior reactions to other ACE inhibitors, ACCUPRIL does not cause
`
`agranulocytosis at similar rates. As with other ACE inhibitors, periodic monitoring ofwhite
`blood cell counts in patients with collagen vascular disease and/or renal disease should be
`considered.
`
`Reference ID: 3506655
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2054 - 0006
`
`

`
`Fetal Toxicity
`Pregnancy Category D
`
`Use of drugs that act on the renin—angiotensin system during the second and third trimesters of
`pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.
`Resulting oligohydrarnnios can be associated with fetal lung hypoplasia and skeletal
`
`deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension,
`renal failure, and death. When pregnancy is detected, discontinue ACCUPRIL as soon as
`possible. These adverse outcomes are usually associated with use of these drugs in the second
`
`and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after
`
`exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the
`
`renin—angiotensin system from other antihypertensive agents. Appropriate management of
`
`maternal hypertension during pregnancy is important to optimize outcomes for both mother and
`fetus.
`
`in the unusual case that there is no appropriate alternative to therapy with drugs affecting the
`renin—angiotensin system for a particular patient, apprise the mother of the potential risk to the
`fetus. Perform serial ultrasound examinations to assess the intra—amniotic environment. If
`
`oligohydramnios is observed, discontinue ACCUPRIL, unless it is considered life-saving for the
`mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and
`
`physicians should be aware, however, that oligohydrarnnios may not appear until after the fetus
`has sustained irreversible injury. Closely observe infants with histories of in mam exposure to
`ACCUPRIL for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS, Pediatric Use).
`
`No tcratogenic effects of ACCUPRTL were seen in studies of pregnant rats and rabbits. On a
`mg/kg basis, the doses used were up to 180 times (in rats) and one time (in rabbits) the maximum
`recommended human dose.
`
`PRECAUTIONS
`
`General
`
`Impaired renal function: As a consequence ofinhibiting the renin-angiotensin-aldosterone
`system, changes in renal function may be anticipated in susceptible individuals. In patients with
`
`severe heart failure whose renal function may depend on the activity ofthe renin—angiotensin—
`aldosterone system, treatment with ACE inhibitors, including ACCUPRIL, may be associated
`with oliguria and/or progressive azotemia and rarely acute renal failure and/or death.
`
`In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis,
`
`increases in blood urea nitrogen and serum creatinine have been observed in some patients
`following ACE inhibitor therapy. These increases were almost always reversible upon
`discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function
`should be monitored during the first few weeks of therapy.
`
`Some patients with hypertension or heart failure with no apparent preexisting renal vascular
`disease have developed increases in blood urea and serum creatinine, usually minor and transient,
`especially when ACCUPRIL has been given concomitantly with a diuretic. This is more likely to
`occur in patients with preexisting renal impairment. Dosage reduction and/or discontinuation of
`any diuretic and/or ACCUPRIL may be required.
`
`Reference ID: 3506655
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2054 - 0007
`
`

`
`Evaluation of patients with hypertension or heart failure should always include assessment
`of renal function (see DOSAGE AND ADMINISTRATION).
`
`Hyperkalemia and potassium—sparing diuretics: In clinical trials, hyperkalemia (serum
`
`potassium 25.8 mmol/L) occurred in approximately 2% of patients receiving ACCUPRIL. In
`most cases, elevated serum potassium levels were isolated values which resolved despite
`continued therapy. Less than 0.1% of patients discontinued therapy due to hyperkalemia. Risk
`
`factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and
`
`the concomitant use of potassium—sparing diuretics, potassium supplements, and/or potassium-
`
`containing salt substitutes, which should be used cautiously, if at all, with ACCUPRIL (sec
`
`PRECAUTIONS, Drug Interactions).
`
`Cough: Presumably due to the inhibition ofthe degradation of endogenous bradykinin, persistent
`non—productive cough has been reported with all ACE inhibitors, always resolving after
`discontinuation of therapy. ACE inhibitor—induced cough should be considered in the differential
`diagnosis of cough.
`
`Surgery/anesthesia: In patients undergoing major surgery or during anesthesia with agents that
`
`produce hypotension, ACCUPRIL will block angiotensin II formation secondary to
`compensatory renin release. If hypotension occurs and is considered to be due to this mechanism,
`it can be corrected by volume expansion.
`
`Information for Patients
`
`Pregnancy: Female patients of childbearing age should be told about the consequences of
`exposure to ACCUPRIL during pregnancy. Discuss treatment options with women planning to
`become pregnant. Patients should be asked to report pregnancies to their physicians as soon as
`possible.
`
`Angioedema: Angioedema, including laryngeal edema can occur with treatment with ACE
`inhibitors, especially following the first dose. Patients should be so advised and told to report
`
`immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes,
`
`lips, tongue, difficulty in swallowing or breathing) and to stop taking the drug until they have
`
`consulted with their physician (see WARNINGS).
`
`Symptomatic hypotension: Patients should be cautioned that lightheadedness can occur,
`
`especially during the first few days of ACCUPRIL therapy, and that it should be reported to a
`
`physician. If actual syncope occurs, patients should be told to not take the drug until they have
`
`consulted with their physician (see WARNINGS).
`
`All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea,
`
`or vomiting can lead to an excessive fall in blood pressure because of reduction in fluid volume,
`
`with the same consequences oflightheadedness and possible syncope.
`
`Patients planning to undergo any surgery and/or anesthesia should be told to inform their
`physician that they are taking an ACE inhibitor.
`
`Hyperkalemia: Patients should be told not to use potassium supplements or salt substitutes
`
`containing potassium without consulting their physician (see PRECAUTIONS).
`
`Neutropenia: Patients should be told to report promptly any indication of infection (eg, sore
`throat, fever) which could be a sign of neutropenia.
`
`Reference ID: 3506655
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2054 - 0008
`
`

`
`NOTE: As with many other drugs, certain advice to patients being treated with ACCUPRIL is
`warranted. This information is intended to aid in the safe and effective use of this medication. lt
`
`is not a disclosure of all possible adverse or intended effects.
`
`Drug Interactions
`Concomitant diuretic therapy: As with other ACE inhibitors, patients on diuretics, especially
`
`those on recently instituted diuretic therapy, may occasionally experience an excessive reduction
`of blood pressure after initiation ofthcrapy with ACCUPRIL. The possibility of hypotensive
`effects with ACCUPRIL may be minimized by either discontinuing the diuretic or cautiously
`
`increasing salt intake prior to initiation of treatment with ACCUPRIL. Ifit is not possible to
`discontinue the diuretic, the starting dose of quinapril should be reduced (see DOSAGE AND
`ADMINISTRATION).
`
`Agents increasing serum potassium: Quinapril can attenuate potassium loss caused by
`
`thiazide diuretics and increase serum potassium when used alone. If concomitant therapy of
`ACCUPRIL with potassium—sparing diuretics (eg, spironolactone, triamterene, or amiloride),
`potassium supplements, or potassium—containing salt substitutes is indicated, they should be used
`with caution along with appropriate monitoring of serum potassium (see PRECAUTION S).
`
`Tetracycline and other drugs that interact with magnesium: Simultaneous administration of
`tetracycline with ACCUPRIL reduced the absorption of tetracycline by approximately 28% to
`37%, possibly due to the high magnesium content in ACCUPRIL tablets. This interaction should
`
`be considered if coprescribing ACCUPRIL and tetracycline or other drugs that interact with
`
`magnesium.
`
`Lithium: lncreased serum lithium levels and symptoms of lithium toxicity have been reported in
`patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be
`
`coadministered with caution and frequent monitoring of serum lithium levels is recommended. If
`
`a diuretic is also used, it may increase the risk oflithium toxicity.
`
`Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and hypotension)
`have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and
`
`concomitant ACE inhibitor therapy.
`
`Non-steroidal anti-inflammatory agents including selective cyclooxygenase-2 inhibitors
`(COX-2 inhibitors): In patients who are elderly, volume—depleted (including those on diuretic
`therapy), or with compromised renal function, co—administration ofNSAIDs, including selective
`
`COX-2 inhibitors, with ACE inhibitors, including quinapril, may result in deterioration of renal
`fi1I1Ctl0I‘l, including possible acute renal failure. These effects are usually reversible. Monitor
`renal function periodically in patients receiving quinapril and NSAID therapy.
`
`The antihypertensive effect of ACE inhibitors, including quinapril may be attenuated by
`NSAIDS.
`
`Agents that inhibit mTOR: Patients taking concomitant mTOR inhibitor (e.g. temsirolimus)
`
`therapy may be at increased risk for angioedema.
`
`Other agents: Drug interaction studies of ACCUPRIL with other agents showed:
`
`0 Multiple dose therapy with propranolol or cimetidine has no effect on the pharmacokinetics
`
`of single doses of ACCUPRIL.
`
`Reference ID: 3506655
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2054 - 0009
`
`

`
`0 The anticoagulant effect of a single dose of warfarin (measured by prothrombin time) was not
`
`significantly changed by quinapril coadministration twice-daily.
`
`I ACCUPRIL treatment did not affect the pharmacokinetics of digoxin.
`
`0 No pharmacokinetic interaction was observed when single doses of ACCUPRIL and
`
`hydrochlorothiazide were administered concomitantly.
`
`0 Co—administration ofmultiple 10 mg doses of atorvastatin with 80 mg of ACCUPRIL
`
`resulted in no significant change in the steady—state pharmacokinetic parameters of
`atorvastatin.
`
`Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS
`
`with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks
`of hypotension, hyperkalemia, and changes in renal function (including acute renal failure)
`compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not
`obtain any additional benefit compared to monotherapy. in general, avoid combined use ofRAS
`inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on
`
`ACCUPRIL and other agents that affect the RAS.
`
`Do not co—administer aliskiren with ACCUPRIL in patients with diabetes. Avoid concomitant
`use of aliskiren with ACCUPRIL in patients with renal impairment (GFR<60 mL/min/1.73 m2).
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`Quinapril hydrochloride was not carcinogenic in mice or rats when given in doses up to 75 or
`
`100 mg/kg/day (50 to 60 times the maximum human daily dose, respectively, on an mg/kg basis
`and 3.8 to l0 times the maximum human daily dose when based on an mg/mg basis) for 104
`weeks. Female rats given the highest dose level had an increased incidence of mescntcric lymph
`node hemangiomas and skin/subcutaneous lipomas. Neither quinapril nor quinaprilat were
`mutagenic in the Ames bacterial assay with or without metabolic activation. Quinapril was also
`
`negative in the following genetic toxicology studies: in vitro mammalian cell point mutation,
`sister chromatid exchange in cultured mammalian cells, micronucleus test with mice, in vitro
`Chromosome aberration with V79 cultured lung cells, and in an in viva cytogenetic study with rat
`
`bone marrow. There were no adverse effects on fertility or reproduction in rats at doses up to 100
`mg/kg/day (60 and 10 times the maximum daily human dose when based on mg/kg and mg/mg,
`respectively).
`
`Nursing Mothers
`Because ACCUPRIL is secreted in human milk, caution should be exercised when this drug is
`
`administered to a nursing woman.
`
`Pediatric Use
`Neonates with a histo
`
`of in were ex osure to ACCUPRIL:
`
`If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal
`
`perfusion. Exchange transfusions or dialysis may be required as a means of reversing
`hypotension and/or substituting for disordered renal function. Removal of ACCUPRIL, which
`crosses the placenta, from the neonatal circulation is not significantly accelerated by these means.
`
`The safety and effectiveness of ACCUPRIL in pediatric patients have not been established.
`
`Reference ID: 3506655
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`10
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2054 - 0010
`
`

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`Geriatric Use
`
`Clinical studies ofACCUPR