`
`PHYSIOANS’
`
`#
`# DESK
`_
`PEEEEENCE‘
`
`_
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1019, p. 001
`
`

`

`
` 5g;
`5.3
`
`
`
`
`
`
`
`
`
`
`PHVSICIANS’
`DESK
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`BIOCON PHARMA LTD (IPR2020-01263) EX. 1019, p. 002
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1019, p. 002
`
`

`

`2358/PFIZER INC
`
`Navane IM—Cont.
`
`For Intramuscular Use Only
`Dosage of Navane should be individually adjusted depend-
`ing on the chronicity and severity of the condition. In gen-
`eral, small doses should be used initially and gradually in-
`creased to the optimal eflective level, based on patient re-
`sponse.
`Usage in children under 12 years of age is not recomA
`mended.
`Where more rapid control and treatment of acute behavior
`is desirable, the intramuscular form of Navane may be in-
`dicated. It is also of benefit where the very nature of the
`patient’s symptomatology, whether acute or chronic, renders
`oral administration impractical or even impossible.
`For treatment of acute symptomatology or in patients un-
`able or unwilling to take oral medication, the usual dose is
`4 mg of Navane Intramuscular For Injection administered
`2 to 4 times daily. Dosage may be increased or decreased
`depending on response. Most patients are controlled on a
`total daily dosage of 16 to 20 mg. The maximum recom-
`mended dosage is 30 mg/day. An oral form should supplant
`the injectable form as soon as possible. It may be necessary
`to adjust the dosage when changing from the intramuscular
`to oral dosage forms. Dosage recommendations for Navane
`Capsules and Concentrate can be found in the Navane oral
`package insert.
`'
`OVERDOSAGE
`Manifestations include muscular twitching, drowsiness,
`and dizziness. Symptoms of gross overdosage may include
`CNS depression, rigidity, weakness, torticollis, tremor, sali—
`vation, dysphagia, hypotension, disturbances of gait, or
`coma.
`Treatment: Essentially symptomatic and supportive. Keep
`patient under careful observation and maintain an open air-
`way, since involvement of the extrapyramidal system may
`produce dysphagia and respiratory difficulty in severe over—
`dosage. If hypotension occurs, the standard measures for
`managing circulatory shock should be used (LY. fluids and/
`or vasoconstrictors).
`If a vasoconstrictor is needed, levarterenol and phenyleph-
`rine are the most suitable drugs. Other pressor agents, in-
`cluding epinephrine, are not recommended, since phenothi-
`azine derivatives may reverse the usual pressor elevating
`action of these agents and cause further lowering of blood
`pressure.
`If CNS depression is marked, symptomatic treatment is in-
`dicated. Extrapyramidal symptoms may be treated with an-
`tiparkinson drugs.
`There are no data on the use of peritoneal or hemodialysis,
`but they are known to be of little value in phenothiazine
`intoxication.
`HOW SUPPLIED
`Navane (thiothixene hydrochloride) Intramuscular For In—
`jection is available in amber glass vials in packages of 10
`vials (NDC 0049-5765-83). When reconstituted with 2.2 ml
`of STERILE WATER FOR INJECTION, each ml contains
`thiothixene hydrochloride equivalent to 5 mg of thiothixene,
`and 59.6 mg of mannitol. The reconstituted solution of Na-
`vane Intramuscular For Injection may be stored for 48
`hours at room temperature before discarding. 70-4177<00—4
`Revised January 1988
`
`
`NORVASC®
`[nor ’vask]
`(amlodipine besylate)
`Tablets
`
`Br
`
`\
`DESCRIPTION
`NORVASC® is the besylate salt of amlodipine, a long-acting
`calcium channel blocker.
`NORVASC is chemically described as (R.S.) 3-ethyl-5-meth- /
`yl-2-(2-amino—ethoxymethyl)—4‘(2-chlorophenyl)-1,4-dihy-
`dro-6-methyl-3,5~pyridinedicarboxylate benzenesulphonate.
`Its empirical formula is CZOHZSCIN205-C6HSO3S, and its
`structural formula is:
`
`Cl
`0
`
`H c
`3 \o
`H36
`
`CH3
`
`l
`
`0
`
`I
`
`NH
`
`01NH2
`
`CGHGOSS
`Amlodipine besylate is a white crystalline powder with a
`molecular weight of 567.1. It is slightly soluble in water and
`sparingly soluble in ethanol. NORVASC (amlodipine besy-
`late) tablets are formulated as white tablets equivalent to
`2.5, 5 and 10 mg of amlodipine for oral administration. In
`addition to the active ingredient, amlodipine besylate, each
`
`
`
`ADVERSE REACTIONS
`NOTE: Not all of the following adverse reactions have been
`reported with Navane. However, since Navane has certain
`chemical and pharmacologic similarities to the phenothia-
`zines, all of the known side effects and toxicity associated
`with phenothiazine therapy should be borne in mind when
`Navane is used.
`Cardiovascular Effects: Tachycardia, hypotension, light-
`headedness, and syncope. In the event hypotension occurs,
`epinephrine should not be used as a pressor agent since a
`paradoxical further lowering of blood pressure may result.
`Nonspecific EKG changes have been observed in some pa-
`tients receiving Navane. These changes are usually revers»
`ible and frequently disappear on continued Navane therapy.
`The clinical significance of these changes is not known.
`CNS Effects: Drowsiness, usually mild, may occur although
`it usually subsides with continuation of Navane therapy.
`The incidence of sedation appears similar to that of the pi—
`perazine group of phenothiazines, but less than that of cer-
`tain aliphatic phenothiazines. Restlessness, agitation and
`insomnia have been noted with Navane. Seizures and par-
`adoxical exacerbation of psychotic symptoms have occurred
`with Navane infrequently.
`Hyperreflexia has been reported in infants delivered from
`mothers having received structurally related drugs.
`In addition, phenothiazine derivatives have been associated
`with cerebral edema and cerebrospinal fluid abnormalities.
`Extrapyramidal symptoms, such as pseudo-parkinsonism,
`akathisia, and dystonia have been reported. Management of
`these extrapyramidal symptoms depends upon the type and
`severity. Rapid relief of acute symptoms may require the
`use of an injectable antiparkinson agent. More slowly
`emerging symptoms may be managed by reducing the dos-
`age of Navane and/or administering an oral antiparkinson
`agent.
`Persistent Tardive Dyskinesia: As with all antipsychotic
`agents tardive dyskinesia may appear in some patients on
`long term therapy or may occur after drug therapy has been
`discontinued. The syndrome is characterized by rhythmical
`involuntary movements of the tongue, face, mouth or jaw
`(e.g., protrusion of tongue, pufl‘ing of cheeks, puckering of
`mouth, chewing movements). Sometimes these may be ac-
`companied by involuntary movements of extremities.
`Since early detection of tardive dyskinesia is important, pa-
`tients should be monitored on an ongoing basis. It has been
`reported that fine vermicular movement of the tongue may
`be an early sign of the syndrome. If this or any other pre-
`sentation of the syndrome is observed, the clinician should
`consider possible discontinuation of neuroleptic medication.
`(See WARNINGS section.)
`Hepatic Effects: Elevations of serum transaminase and al-
`kaline phosphatase, usually transient, have been infre-
`quently observed in some patients. No clinically confirmed
`cases ofjaundice attributable to Navane (thiothixene hydro-
`chloride) have been reported.
`Hematologic Eifects: As is true with certain other psycho-
`tropic drugs, leukopenia and leucocytosis, which are usually
`transient, can occur occasionally with Navane. Other anti—
`psychotic drugs have been associated with agranulocytosis,
`eosinophilia, hemolytic anemia, thrombocytopenia and pan-
`cytopenia.
`Allergic Reactions: Rash, pruritus, urticaria, and rare cases
`of anaphylaxis have been reported with Navane. Undue ex-
`posure to sunlight should be avoided. Although not experi—
`enced with Navane, exfoliative dermatitis, contact dermati—
`tis (in nursing personnel), have been reported with certain
`phenothiazines.
`Endocrine Disorders: Lactation, moderate breast enlarge-
`ment and amenorrhea have occurred in a small percentage
`of females receiving Navane. If persistent, this may neces-
`sitate a reduction in dosage or the discontinuation of ther-
`apy. Phenothiazines have been associated with false posi-
`tive pregnancy tests, gynecomastia, hypoglycemia, hyper-
`glycemia, and glycosuria.
`Autonomic Efl'ects: Dry mouth, blurred vision, nasal conges-
`tion, constipation, increased sweating, increased salivation,
`and impotence have occurred infrequently with Navane
`therapy. Phenothiazines have been associated with miosis,
`mydriasis, and adynamic ileus.
`Other Adverse Reactions: Hyperpyrexia, anorexia, nausea,
`vomiting, diarrhea, increase in appetite and weight, weak-
`ness or fatigue, polydipsia and peripheral edema.
`Although not reported with Navane, evidence indicates
`there is a relationship between phenothiazine therapy and
`the occurrence of a systemic lupus erythematosus-like syn-
`drome.
`Neuroleptic Malignant Syndrome (NMS): Please refer to the
`text regarding NMS in the WARNINGS section.
`NOTE: Sudden deaths have occasionally been reported in
`patients who have received certain phenothiazine deriva-
`tives. In some cases the cause of death was apparently car—
`diac arrest or asphyxia due to failure of the cough reflex. In
`others, the cause could not be determined nor could it be
`established that death was due to phenothiazine ad-
`ministration.
`DOSAGE AND ADMINISTRATION
`Preparation
`Navane (thiothixene hydrochloride) Intramuscular For In-
`jection must be reconstituted with 2.2 ml of sterile water for
`injection.
`Information will be superseded by supplements and SUBd-QQQ'N PHARMA LTD (IPR2020-0 1263) EX. 1 0 l 9, p. 003
`
`
`
`' PHYSICIANSLDESK REFERENCEQ
`
`tablet contains the following inactive ingredients: micro-
`crystalline cellulose, dibasic calcium phosphate anhydrous,
`sodium starch glycolate, and magnesium stearate.
`CLINICAL PHARMACOLOGY
`Mechanism of Action: NORVASC is a dihydropyridine cal-
`cium antagonist (calcium ion antagonist or slow-channel
`blocker) that inhibits the transmembrane influx of calcium
`ions into vascular smooth muscle and cardiac muscle. Ex-
`perimental data suggest that NORVASC binds to both dihy-
`dropyridine and nondihydropyridine binding sites. The con-
`tractile processes of cardiac muscle and vascular smooth
`muscle are dependent upon the movement of extracellular
`calcium ions into these cells through specific ion channels.
`NORVASC inhibits calcium ion influx across cell mem-
`branes selectively, with a greater effect on vascular smooth
`muscle cells than on cardiac muscle cells. Negative inotropic
`efi'ects can be detected in vitro but such effects have not
`been seen in intact animals at therapeutic doses. Serum cal-
`cium concentration is not affected by NORVASC. Within the
`physiologic pH range, NORVASC is an ionized compound
`(pKa=8.6), and its kinetic interaction with the calcium
`channel receptor is characterized by a gradual rate of asso-
`ciation and dissociation with the receptor binding site, re-
`sulting in a gradual onset of effect.
`NORVASC is a peripheral arterial vasodilator that acts di-
`rectly on vascular smooth muscle to cause a reduction in pe-
`ripheral vascular resistance and reduction in blood pres-
`sure.
`The precise mechanisms by which NORVASC relieves an-
`gina have not been fully delineated, but are thought to in»
`clude the following:
`Exertional Angina: In patients with exertional angina,
`NORVASC reduces the total peripheral resistance (after-
`load) against which the heart works and reduces the rate
`pressure product, and thus myocardial oxygen demand, at
`any given level of exercise.
`Vasospastic Angina: NORVASC has been demonstrated to
`block constriction and restore blood flow in coronary arter-
`ies and arterioles in response to calcium, potassium epi-
`nephrine, serotonin, and thromboxane A2 analog in experi-
`mental animal models and in human coronary vessels in vi-
`tro. This inhibition of coronary spasm is responsible for the
`effectiveness of NORVASC in vasospastic (Prinzmetal’s or
`variant) angina.
`Pharmacokinetics and Metabolism: After oral administra—
`tion of therapeutic doses of NORVASC, absorption produces
`peak plasma concentrations between 6 and 12 hours. Abso-
`lute bioavailability has been estimated to be between 64 and
`90%. The bioavailability of NORVASC is not altered by the
`presence of food.
`‘
`NORVASC is extensively (about 90%) converted to inactive
`metabolites via hepatic metabolism with 10% of the parent
`compound and 60% of the metabolites excreted in the urine.
`Ex vivo studies have shown that approximately 93% of the
`circulating drug is bound to plasma proteins in hyperten-
`sive patients. Elimination from the plasma is biphasic with
`'a terminal elimination half-life of about 30—50 hours.
`Steady-state plasma’levels of NORVASC are reached after 7
`to 8 days of consecutive daily dosing.
`The pharmacokinetics of NORVASC are not significantly in-
`fluenced by renal impairment. Patients with renal failure
`may therefore receive the usual initial dose.
`Elderly patients and patients with hepatic insufficiency
`have decreased clearance of amlodipine with a resulting in-
`crease in AUC of approximately 40—60%, and a lower initial
`dose may be required. A similar increase in AUC was ob-
`served in patients with moderate to severe heart failure.
`Pharmacodvnamics: Hemodynamics Following administra-
`tion of therapeutic doses to patients with hypertension,
`NORVASC produces vasodilation resulting in a reduction of
`supine and standing blood pessures. These decreases in
`blood pressure are not accompanied by a significant change
`in heart rate or plasma catecholamine levels with chronic
`dosing. Although the acute intravenous administration of
`amlodipine decreases arterial blood pressure and increases
`heart rate in hemodynamic studies of patients with chronic
`stable angina, chronic administration of oral amlodipine in
`clinical trials did not lead to clinically significant changes in
`heart rate or blood pressures in normotensive patients with
`angina.
`With chronic once daily oral administration, antihyperten-
`sive effectiveness is maintained for at least 24 hours.
`Plasma concentrations correlate with effect in both young
`and elderly patients. The magnitude of reduction in blood
`pressure with NORVASC is also correlated with the height
`of pretreatment elevation; thus, individuals with moderate
`hypertension (diastolic pressure 105—114 mmHg) had about
`a 50% greater response than patients with mild hyperten-
`sion (diastolic pressure 90—104 mmHg). Normotensive sub-
`jects experienced no clinically significant change in blood
`pressures (+1/ — 2 mmHg).
`In hypertensive patients with normal renal function, thera-
`peutic doses of NORVASC resulted in a decrease in renal
`vascular resistance and an increase in glomerular filtration
`rate and effective renal plasma flow without change in fil-
`tration fraction or proteinuria.
`As with other calcium channel blockers, hemodynamic mea-
`surements of cardiac function at rest and during exercise (or
`pacing) in patients with normal ventricular function treated
`with NORVASC have generally demonstrated a small in-
`crease in cardiac index without significant influence on
`dP/dt or on left ventricular end diastolic pressure or volume.
`In hemodynamic studies, NORVASC has not been associ-
`ated with a negative inotropic effect when administered in
`
`
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1019, p. 003
`
`

`

`PRODUCT INFORMATION
`
`he therapeutic dose range to intact animals and man, even
`when co—administered with beta-blockers to man. Similar
`findings, however, have been observed in normals or well-
`compensated patients with heart failure with agents pos~
`sessing significant negative inotropic effects.
`Studies in Patients with Congestive Heart Failure: NOR-
`VASC has been compared to placebo in four 8—12 week stud-
`ies of patients with NYHA class lI/IlI heart failure, involv—
`ing a total of 697 patients. In these studies, there was no
`evidence of worsened heart failure based on measures of ex-
`ercise tolerance, NYHA classification, symptoms, or LVEF.
`In a long-term (follow»up at least 6 months, mean 13.8
`months) placebo-controlled mortality/morbidity study of
`NORVASC 5—10 mg in 1153 patients with NYHA classes III
`(n=931) or IV (n=222) heart failure on stable doses ofdiuret-
`ics, digoxin, and ACE inhibitors, NORVASC had no effect on
`the primary endpoint of the study which was the combined
`endpoint of all-cause mortality and cardiac morbidity (as de-
`fined by life-threatening arrhythmia, acute myocardial in-
`farction, or hospitalization for worsened heart failure), or on
`NYHA classification, or symptoms of heart failure. Total
`combined all-cause mortality and cardiac morbidity events
`were 222/571 (39%) for patients on NORVASC and 246/583
`(42%) for patients on placebo; the cardiac morbid events
`represented about 25% of the endpoints in the study.
`Electrophysiologic Effects: NORVASC does not change sino-
`atrial nodal function or atrioventricular conduction in intact
`animals or man. In patients with chronic stable angina, in-
`travenous administration of 10 mg did not significantly al-
`ter A—H and H-V conduction and sinus node recovery time
`after pacing. Similar results were obtained in patients re—
`ceiving NORVASC and concomitant beta blockers. In clini-
`cal studies in which NORVASC was administered in combi-
`nation with beta-blockers to patients with either hyperten-
`sion or angina, no adverse effects on electrocardiographic
`parameters were observed. In clinical trials with angina pa-
`tients alone, NORVASC therapy did not alter electrocardio-
`graphic intervals or produce higher degrees of AV blocks.
`Effects in Hypertension: The antihypertensive efficacy of
`NORVASC has been demonstrated in a total of 15 double—
`blind, placebocontrolled, randomized studies involving 800
`patients on NORVASC and 538 on placebo. Once daily ad-
`ministration produced statistically significant placebo-cor-
`rected reductions in supine and standing blood pressures at
`24 hours postdose, averaging about 12/6 mmHg in the
`standing position and 13/7 mmHg in the supine position in
`patients with mild to moderate hypertension. Maintenance
`of the blood pressure effect over the 24-hour dosing interval
`was observed, with little difference in peak and trough ef~
`fect. Tolerance was not demonstrated in patients studied for
`up to 1 year. The 3 parallel, fixed dose, dose response stud-
`ies showed that the reduction in supine and standing blood
`pressures was dose~related within the recommended dosing
`range. Effects on diastolic pressure were similar in young
`and older patients. The effect on systolic pressure was
`greater in older patients, perhaps because of greater base-
`line systolic pressure. Effects were similar in black patients
`and in white patients.
`Effects in Chronic Stable Angina: The effectiveness of
`5—10 mg/day of NORVASC in exercise-induced angina has
`been evaluated in 8 placebo-controlled, double-blind clinical
`trials of up to 6 weeks duration involving 1038 patients (684
`NORVASC, 354 placebo) with chronic stable angina. In 5 of
`the 8 studies significant increases in exercise time (bicycle
`or treadmill) were seen with the 10 mg dose. Increases in
`symptom-limited exercise time averaged 12.8% (63 sec) for
`NORVASC 10 mg, and averaged 7.9% (38 sec) for NORVASC
`5 mg. NORVASC 10 mg also increased time to 1 mm ST seg-
`ment deviation in several studies and decreased angina at-
`tack rate. The sustained efficacy of NORVASC in angina pa—
`tients has been demonstrated over long-term dosing. In pa-
`tients with angina there were no clinically significant
`reductions in blood pressures (4/1 mmHg) or changes in
`heart rate (+0.3 bpm),
`In a double-blind, placebo-
`Effects in Vasospastic Angina:
`controlled clinical trial of 4 weeks duration in 50 patients,
`NORVASC therapy decreased attacks by approximately
`4/week compared with a placebo decrease of approximately
`1/week (p<0.01). TWo of 23 NORVASC and 7 of 27 placebo
`patients discontinued from the study due to lack of clinical
`improvement.
`INDICATIONS AND USAGE
`1. Hypertension
`NORVASC is indicated for the treatment of hypertension. It
`may be used alone or in combination with other antihyper—
`tensive agents.
`2. Chronic Stable Angina
`NORVASC is indicated for the treatment of chronic stable
`angina. NORVASC may be used alone or in combination
`with other antianginal agents.
`3. Vasospastic Angina (Prinzmetal’s or Variant Angina)
`NORVASC is indicated, for the treatment of confirmed or
`suspected vasospastic angina. NORVASC may be used as
`monotherapy or in combination with other antianginal
`drugs.
`CONTRAINDICATIONS
`
`
`
`.
`
`cardial infarction on starting calcium channel blocker ther-
`apy or at the time of dosage increase. The mechanism of this
`effect has not been elucidated.
`PRECAUTIONS
`General: Since the vasodilation induced by NORVASC is
`gradual in onset, acute hypotension has rarely been re-
`ported after oral administration of NORVASC. Nonetheless,
`caution should be exercised when administering NORVASC
`as with any other peripheral vasodilator particularly in pa-
`tients with severe aortic stenosis.
`In general,
`Use in Patients with Congestive Heart Failure:
`calcium channel blockers should be used with caution in pa-
`tients with heart failure. NORVASC (5—10 mg per day) has
`been studied in a placebo-controlled trial of 1153 patients
`with NYHA Class III or IV heart failure (see CLINICAL
`PHARMACOLOGY ) on stable doses of ACE inhibitor, di-
`goxin, and diuretics. Follow-up was at least 6 months, with
`a mean of about 14 months. There was no overall adverse
`effect on survival or cardiac morbidity (as defined by life-
`threatening arrhythmia, acute myocardial infarction, or
`hospitalization for worsened heart failure). NORVASC has
`been compared to placebo in four 8-12 week studies of pa‘
`tients with NYHA class II/III heart failure, involving a total
`of 697 patients. In these studies, there was no evidence of
`worsened heart failure based on measures of exercise toler—
`ance, NYHA classification, symptoms, or LVEF.
`Beta-Blocker Withdrawal: NORVASC is not a beta-blocker
`and therefore gives no protection against the dangers of
`abrupt beta-blocker withdrawal; any such withdrawal
`should be by gradual reduction of the dose of beta-blocker.
`Patients with Hepatic Failure: Since NORVASC is exten-
`sively metabolized by the liver and the plasma elimination
`half-life (t 1/2) is 56 hours in patients with impaired hepatic
`function, caution should be exercised when administering
`NORVASC to patients with severe hepatic impairment.
`Drug Interactions:
`In vitro data in human plasma indicate
`that NORVASC has no effect on the protein binding of drugs
`tested (digoxin, phenytoin, warfarin, and indomethacin).
`Special studies have indicated that the co-administration of
`NORVASC with digoxin did not change serum digoxin levels
`or digoxin renal clearance in normal volunteers; that co-
`administration with cimetidine did not alter the pharmaco-
`kinetics of amlodipine; and that co-administration with
`warfarin did not change the warfarin prothrombin response
`time.
`In clinical trials, NORVASC has been safely administered
`with thiazide diuretics, beta-blockers, angiotensin-convert—
`ing enzyme inhibitors, long-acting nitrates, sublingual ni-
`troglycerin, digoxin, warfarin, non-steroidal anti-inflamma-
`tory drugs, antibiotics, and oral hypoglycemic drugs.
`Drug/Laboratory Test Interactions: None known.
`Carcinogenesis, Mutagenesis,
`impairment of Fertility:
`Rats and mice treated with amlodipine in the diet for two
`years, at concentrations calculated to provide daily dosage
`levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of
`carcinogenicity. The highest dose Ifor mice, similar to. and
`for rats twice* the maximum recommended clinical dose of
`10 mg on a mg/m2 basis) was close to the maximum toler-
`ated dose for mice but not for rats.
`Mutagenicity studies revealed no drug related effects at ei-
`ther the gene or chromosome levels.
`There was no effect on the fertility of rats treated with am-
`lodipine (males for 64 days and females 14 days prior to
`mating) at doses up to 10 mg/kg/day (8 times* the maximum
`recommended human dose of 10 mg on 2 mg/m2 basis).
`Pregnancy Category C: No evidence of teratogenicity or
`other embryo/fetal toxicity was found when pregnant rats or
`rabbits were treated orally with up to 10 mg/kg amlodipine
`(respectively 8 times* and 23 times* the maximum recom—
`mended human dose of 10 mg on a mg/m2 basis) during
`their respective periods of major organogenesis. However,
`litter size was significantly decreased (by about 50%) and
`the number of intrauterine deaths was significantly in-
`creased (about 5-fold) in rats administered 10 mg/kg anilo—
`dipine for 14 days before mating and throughout mating
`and gestation Amlodipine has been shown to prolong both
`the gestation period and the duration of labor in rats at this
`dose. There are no adequate and well-controlled studies in
`pregnant women. Amlodipine should be used during preg—
`nancy only if the potential benefit justifies the potential risk
`to the fetus.
`It is not known whether amlodipine is
`Nursing Mothers:
`excreted in human milk. In the absence of this information,
`itis recommended that nursing be discontinued While NOR-
`VASC is administered.
`Pediatric Use: Safety and effectiveness of NORVASC in
`children have not been established.
`*Based on patient weight of 50 kg.
`ADVERSE REACTIONS
`
`M t
`
`Adverse
`Event
`Edema
`Dizziness
`Flushing
`Palpitation
`
`2.5 mg
`N=275
`1.8
`1.1
`0.7
`0.7
`
`5.0 mg
`N=296
`3.0
`3.4
`1.4
`1.4
`
`PFlZE R IN C/2359
`
`10.0 mg
`N=268
`10.8
`3.4
`2.6
`4.5
`
`Placebo
`N=520
`0.6
`1.5
`0.0
`0.6
`
`
`
`Other adverse experiences which were not clearly dose re-
`lated but which were reported with an incidence greater
`than 1.0% in placebo-controlled clinical trials include the
`following:
`
`Placebo-Controlled Studies
`NORVASC (%)
`PLACEBO (%)
`(N=1730)
`(N: 1250)
`7.3
`7.8
`4.5
`2.8
`2.9
`1.9
`1.6
`0.3
`1.4
`0.6
`
`Headache
`Fatigue
`Nausea
`Abdominal Pain
`Somnolence
`
`For several adverse experiences that appear to be drug and
`dose related, there was a greater incidence in women than
`men associated with amlodipine treatment as shown in the
`following table:
`
`ADR
`
`Edema
`Flushing
`Palpitations
`Somnolence
`
`NORVASC
`M=%
`F=%
`(N=1218)
`(N=512)
`5.6
`14.6
`1.5
`4.5
`1.4
`3.3
`1.3
`1.6
`
`PLACEBO
`M=%
`F=%
`(N=914)
`(N=336)
`1.4
`5.1
`0.3
`0.9
`0.9
`0.9
`0.8
`0.3
`
`The following events occurred in 51% but >0.1% of patients
`in controlled clinical trials or under conditions of open trials
`or marketing experience where a causal relationship is un-
`certain; they are listed to alert the physician to a possible
`relationship:
`Cardiovascular: arrhythmia (including ventricular tachy-
`cardia and atrial fibrillation), bradycardia, chest pain, by»
`potension, peripheral ischeinia, syncope, tachycardia, pos-
`tural dizziness, postural hypotension.
`Central and Peripheral Nervous System: hypoesthesia, par-
`esthesia, tremor, vertigo.
`Gastrointestinal: anorexia, constipation, dyspepsia,** dys-
`phagia, diarrhea, flatulence, vomiting, gingival hyperplasia.
`General: asthenia,** back pain, hot flushes, malaise, pain,
`rigors, weight gain.
`Musculoskeletal System: arthralgia, arthrosis, muscle
`cramps,** myalgia,
`Psychiatric: sexual dysfunction (male** and female), insom-
`3 ma, nervousness, depression, abnormal dreams, anxiety, de-
`personalization.
`W System: dyspnea.“m
`Skin andW grunts.” rah." rfih euthana-
`zcus. rah maricpapufir.
`“These events .x‘turred " 1e
`trolled trials. but the mCZLiEECE
`
`tween 1% and 2‘? in all mulup
`
`Special Senses: abnormal vision. conjunciiw.
`eye pain, tinnitus.
`Urinary System: micturition frequency, micturition disor-
`der, nocturia.
`Autonomic Nervous System: dry mouth, sweating in-
`creased.
`Metabolic and Nutritional: thirst.
`Hemopoietic: purpura.
`The following events occurred in S0.1% of patients: cardiac
`failure, pulse irregularity, extrasystoles, skin discoloration,
`urticaria, skin dryness, alopecia, dermatitis, muscle weak-
`ness, twitching, ataxia, hypertonia, migraine, cold and
`clammy skin, apathy, agitation, amnesia, gastritis,
`in-
`creased appetite, loose stools, coughing, rhinitis, dysuria,
`polyuria, parosmia, taste perversion, abnormal visual ac-
`commodation, and xerophthalmia.
`Other reactions occurred sporadically and cannot be distin-
`guished from medications or concurrent disease states such
`as myocardial infarction and angina.
`NORVASC therapy has not been associated with clinically
`significant changes in routine laboratory tests. No clinically
`relevant changes were noted in serum potassium, serum
`glucose, total triglycerides, total cholesterol, HDL choles-
`terol, uric acid, blood urea nitrogen, or creatinine.
`The following postmarketing event has been reported infre-
`quently where a causal relationship is uncertain: gyneco-
`mastia.
`In postmarketing experience,
`jaundice and
`hepatic enzyme elevations (mostly consistent with choleste-
`sis) in some cases severe enough to require hospitalization
`have been reported in association with use of amlodipine,
`NORVASC has been used safely in patients with chronic oh-
`structive pulmonary disease, well-compensated congestive
`heart failure, peripheral vascular disease, diabetes melli—
`tus, and abnormal lipid profiles.
`OVERDOSAGE ‘
`Single oral doses of 40 mg/kg and 100 mg/kg in mice and
`rats, respectively, caused deaths. A single oral dose of 4
`mg/kg or higher in dogs caused a marked peripheral vaso-
`dilation and hypotension.
`Overdosage might be expected to cause excessive peripheral
`vasodilation with marked hypotension and possibly a reflex
`tachycardia. In humans, experience with intentional over-
`dosage of NORVASC is limited. Reports of intentional over-
`
`Continued on next page
`Gal-263) EKMMQL...“
`
`i
`
`NORVASC has been evaluated for safety in more than
`11,000 patients i