ZIAC controls mild-to-moderate hypertension

in up to 80% of patients,t
ZIAC controls blood pressure for a full 24 hours
for true once-a-day dosing2 N
ZIAC minimizes traditional beta-blocker- and
HCTZ-associated metabolic effects (hypokalemia,
hyperuricemia, hypercholesterolemia, hyperglycemia)'
'The two most common side effects - dizziness and fatigue - occurred at rates
comparable to placebo.
'Clinical trial response rates were: 2.5 mg-61%; 5 mg-73%; 10 mg-80%. (bisoprolol fumarate-hydrochlorothiazide)
ZIAC is contraindicated in patients in cardiogenic shock, overt cardiac failure
(see WARNINGS section of full Prescribing Information), second- or third- 2.5,5, & 10 mg Tablets with 6.25 mg HCTZ
degree AV block, marked sinus bradycardia, anuria, and hypersensitivity to
either component of this product or to other sulfonamide-derived drugs.
Please see Brief Summary of Prescribing Information on adjacent page.
 ZIAC'" (BllOprolol Fumeratealld Hydroclliorottrllzldl) lIbl...

N2TAC; (bisoprolol fumarate-hydrochlorothiazide)

Body System/
Adverse Experience

Cardiovascular
%of Patients with Adverse Experiences'

All Adverse Experiences

Placebo'
(n=I44)
%
82.5-40/H6.25'
(n = 252)
%
~
%
Drug-related
Adverse Experiences
Placebo' B2.5-101H8.25'
(n=2~)
%
2.5,5, & to mg Tablets with 6.25 mg HClZ bradycardia 0.7 1.1 0.7 0.9
arrhythmia 1.4 0.4 0.0 0.0
References: peripheral ischemia 0.9 0.7 0.9 0.4
1. DeQuattro V, Weir MR. Bisoprolol fumaratelhydrochlorothiazide 6.25 mg: a new, low-dose chest pain 0.7 1.8 0.7 0.9
option for first-line antihypertensive therapy. Adv Ther. 1993;10:197-206. Respiratory
2. Lewin AJ, Lueg MC, Targum 5, et al. A clinICal tflal evaluating the 24-hour effects of bisopro- bronchospasm 0.0 0.0 0.0 0.0
~i~~t~s
lol/hydrochlorothlazlde 5 mg/6.25 mg combination," patients with mild to moderate 1.0 2.2 0.7 1.5
hypertension. Clin Cardiol. 1993;16:732-736. 2.0 0.7 0.7 0.9
URI 2.3 2.1 0.0 0.0
Body as a Whole
Briel Summary asthenia 0.0 0.0 0.0 0.0
fati~ue 2.7 4.6 1.7 3.0
ZIAC '" (BllOprolol Fumarlla and Hydrochlorothiazide) llIblell perlrheral edema 0.7 1.1 0.7 0.9
FOR FULL PRESCRIBING INFORMATION, PLEASE CONSULT PACKAGE INSERT. Centra Nervous System
dizziness 1.8 5.1 1.8 3.2
DESCRIPTION headache 4.7 4.5 2.7 0.4
ZIAC (bisoprolollumarate and hydrochlorothiazide) is indicated for the treatment of hypertension. It combines Musculoskeletal
two antihypertensive agents in a once-daily dosage: a synthetiC beta,-selective (cardioselective) adrenoceptor muscle cramps 0.7 1.2 0.7 1.1
myalgia 1.4 2.4 0.0 0.0
blocking agent (bisoprolol fumarate) and abenzothiadiazlne diuretic (hydrochlorothiazide). Psychiatric
CLINICAL PHARMACOLOGY Insomma 2.4 1.1 2.0 1.2
somnolence 0.7 1.1 0.7 0.9
At doses'" 20 mg bisoprolol fumarate inhibits beta,-adrenoreceptors located in bronchial and vascular muscu- loss of libido 1.2
lature. To retain relative selectivity, it is Important to use the lowest effective dose. 0.4 1.2 0.4
impotence 0.7 1.1 0.7 1.1
CONTRAINDICAnONS GastrOintestinal
Cardiogenic shock, overt cardiac failure (see WARNINGS), second or third degree AV block, marked sinus diarrhea 1.4 4.3 1.2 1.1
bradycardia, anuria, and hypersensitivity to either component of this product or to other sunonamide-derived nausea 0.9 1.1 0.9 0.9
dyspepsia 0.7 1.2 0.7 0.9
drugs. •Avera~es adjusted to combine across studies.
WARNINGS 'Combined across studies.
Cardl.c F.llure: Beta-blocking agents should be avoided in patients with overt congestive failure. Other adverse experiences that have been reported with the Individual components are listed below
Patlenll WIIhDut a Hillary of Cardllc Failure: Continued depression of the myocardium with beta-blockers can Blloprolol Fumlrlle:.ln clinical trials worldwide, a variety of other AEs, in addition to those listed above, have
precipitate cardiac failure. At the first signs or symptoms of heart failure, discontinuation of ZIAC should be been reported. While In many cases It IS not known whether a causal relationship exists between bisoprolol and
conSidered. these AEs, they are listed to alert the physici~n to apossible relationship. Central Nervous System: Unsteadiness,
Abrupt CeUltlon olTherapy: Abrupt cessation of beta-blockers should be avoided. Even in patients without overt vertigo, syncope, paresthesia, hyperesthesl8, sleep dlsturbancelvlVld dreams, depreSSion, anxiety/resHessness,
coronary artery disease, it may be advisable to taper therapy with ZIAC over approximately 1week with the patient decreased concentraliO.n/memoty. cardiovascular: PalpitallOns and other rhythm disturbances, cold extremities,
under careful observation. Ifwithdrawal symptoms occur, beta-blocking agent therapy should be reinstituted. at claudlcaliO.n, hypotenSion, orthostatl.c hypotenSion, chest pain, congestive heart failure. Gastrointestinal: Gas-
least temporarily. tric/epigastric/abdominal pam, peptic ulcer, g~strltls, vomlling,.constipation, dry mouth. Musculoskeletal:
Peripheral Vllculer 01.....: Beta-blockers should be used with caution in patients with peripheral vascular Arthralgia, musclellomtpaln, back/neck pain, tw~chlnWtremor. Skm: Rash, acne, eczema, pSOriasis skin irrita-
disease. tion, pruritus, purpura, flushing, swe.ating, alopecia, dermatitis, exfoliative denmatitis (vety rare~). S(J6CiaI
Broneho.p.llie 01..1..: PATIENTS WITH BRONCHOSPASTIC PULMONARY DISEASE SHOULD, IN GENERAL, Senses: Vlsual.d.lsturbances,. ocular pain/pressure, abnonmallacrimation, tinnitus, decreased hearing, earache,
NOT RECEIVE BETA-BLOCKERS. taste abnormahtl~s. Melabollc: Gout. ReSPiratory: Asthma, bronchitis, dyspnea, pharyngitis, sinusitis. Genito-
Anallhllia .nd Mljor Surgery: If used perioperatively, particular care should be taken when anesthetic agents ~~ni~Zd:~~rome s disease (very rarely), CYStitiS, renal colic, polyuria. General: Maialse, edema, weight gain,
~n
that depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used.
Dlab,te..nd H~poglycemla: Beta-blockers may mask some of the manifestations o.f hypoglycemia, particularly addition, a variety of adverse effects have been reported with Other beta-adrenergiC blocking agents and
tachycardia. Patllnts sublectto spontaneous hypoglycemia, or diabetiC pallents recllvlng Insulin or oral hypogly- should be conSidered potential adverse effects: cantral Nervous System: Reversible mental depression progress-
cemic apents, should be cautioned. Also, latent diabetes mellitus may become manifest and diabetic patients Ing to catatoma, hallUCinations, an acute reversible s~ndrome characterized by disorientation to time and place,
given thlazides may require adjustment of their insulin dose. emOliO.nallablhf\:, silght~ clouded sensOrium. Allergic: Fever, combined with aching and sore throat laryngo-
TtlyrOlGlleo.ls: Beta-adrenergiC blockade may mask clinical signs of hyperthyroidism. Abrupt withdrawal of beta- spasm, and respiratory distress. HemstolOjlc: Agranulocytosis,thrombocytopenia. Gastrointesti,nal' Mesenteric
blockade may be followed by an exacerballOn Of the symptoms of hyperthyroidism or may precipitate thyroid arterial thrombosis and ischemic colitis. Mrscellaneous: The oculomucocutaneous syndrome associated with the
storm. beta.-blocker practolol has not been reported with bisoprolol fumarate during investigational use or extensive
Renal 011....: Cumulative effects of the thiazides may develop in patients with impaired renal function. In such forllgn marketing experience.
patients, thiazides may precipitate azotemia. In subjects with creatinine clearance less than 40 mUmin, the Hydroclliorothlaztde: The following adverse experiences, in addition to those listed in the above table have been
plasma half-lite of bisoprolol fumarate IS Increased up to threelold, as compared to healthy subjects. reported with hyd~ochlorothiazide (generally with doses of 25 mg or greater). General: Weakness. Central Ner-
HePllle 01.....: ZIAC should be used with caution in patients with impaired hepatic function or progressive liver vous sr,stem:vertlOo, parestheSia, resHessness. cardiovascular: OrthostatiC hypotension (may be potentiated by
disease. alcoho , barbitu~ates, or narcotics) .. GastrointesUmil: Anorexia, gastriC irritallon, cramping, constipation, jaun-
dice (IntrahepatiC cholesta.tl.c laundlce), panCreatitiS, cholecystitis, slaladenilis, dry mouth. Musculoskeletal:
PRECAUnONS Muscle spasm. Hypersensitive Reachons:. Purpura, photosenSitivity, rash, urticaria, necrotizing angiitis (vascu-
Genaral: Electrolyte and Ruid Balance Sfatus: Peri.odic determination of serum electrolytes should be performed, hMand cutaneous vascuhtls), fever, respiratory distress Including pneumonitis and pulmona'¥. edema, anaphy-
and patients should be observed for signs of flUid or electrolyte disturbances. Thiazides have been shown to lactiC reactions. Special Senses: TranSient blurred vision, xanthopsia. Metabolic: Gout. Genttourinary' Sexual
increase the urinary excretion of magnesium; this may result In hypomagnesemia. Hypokalemia may develop. dysfunction, renal failure, renal dysfunction, interstitial nephritiS. .
Hypokalemia and hypomagnesemia can provoke ventricular arrhythmias or sensitize or exaggerate the response LABORATORY ABNORMALlnES
of the heart to the toXIC effects of dlgitahs. OliullOnal hyponatremia may occur in edematous patients In hot
weather; appropriate therapy is water restriction rather than salt administration, except in rare instances when the ZlAC: Because olthe low dose. of hydrochlorothiazide in ZIAC, adverse metabolic effects with BlH6.25 mg are less
hyponatremia IS lite-threatening. In actual salt depletion, appropriate replacement is the therapy of choice. frequent and of smaller magmtude than with HCTZ 25 mg.
Parathyroid Disease: Calcium excretion is decreased by thiazldes, and pathologic changes In the parathyroid . Treatment with both beta-blockers and thiazide diuretics is associated with increases in uric acid. Mean
glands, with hypercal~mia and hypophosphatemia, have been observed in a few patients on prolonged thiazide mcreas~s !n serum trigl¥cerides were observed in patients treated with bisoprolol fumarate and hydro-
therapy. HyperuncemlB: HyperUricemia or acute gout may be preCIpitated In certain patllnts receiving thiazide ~~~:~~:~de 6.25 mg. otal cholesterol was generally unaffected, but small decreases in HDL cholesterol
diuretics. Bisoprolol fumarate, alone orin combination with HCTZ, has been associated with increases in uricacid.
Drug Interactions: ZIAC ~ay potentiate the action of other antihypertensive agents used concomitantly. ZIAC Other laboratoty abnonmalities that have been reported with the individual components are listed below.
should not be combmed With other beta-blockmg agents. In patients recllvmg concurrenltherapy with clonidine Biloprolol Fumarlle: In chmcal trials, the most frequently reported laboratory change was an increase In serum
if therapy is to be discontinued, it is suggested that ZIAC be discontinued for several days before the withdrawal of triglycerides, but this was not aconsistent finding.
clonidine. Sporadic liver test abnormalities have been reported. In the U.S. controlled trials experience with bisoprolol
ZIAC should be used with caution when myocardial depressants or inhibitors of AV conduction or anti- fumarate treatmentfor 4to 12 weeks, the incidence of concomitant elevations in SGOT and SGPT of between 1to 2
arrhythmic agents are used concurrently. ~~~afrmal was 3.9%, compared to 2.5% for placebo. No patient had concomitant elevations greater than twice
Blsoprolol Fumarate: Concurrent use of rifampin increases the metabolic clearance of bisoprolol fumarate.
shortening its elimination half-life. Pharmacokinetic studies document no Clinically relevant interactions with In the long-term, uncontrolled experience with bisoprolol fumarate treatment for 6-18 months the incidence of
other agents given concomitantly, Including thiazide diuretics, digoxin and cimetidlne. There was no effect of one or more concomitant elevations in SGOT and SGPT of between 1-2 times normal was 6.2%. 'The incidence of
bisoprolol fumarate on prothrombin times in patients on stalile doses of warfarin. multiple occurrence was 1.9%. For concomitant elevations in SGOT and SGPT of greater than twice normal the
While taking beta-blockers, patients with a history of severe anaphylactiC reaction may be more reactive to incidence was 1.5%. The incidence of muiliple occurrences was 0.3%. In many cases these elevations Ware
repeated challenge, either accidental, diagnostic, or therapeutic and may be unresponsive to the usual doses of attributed to underlying disorders, or resolved during continued treatment with bisoprolol fumarate.
epinephrine used to treat allergiC reactions. Other laboratory changes incl.uded small increases in uric acid, creetinlne, BUN, serum potaSSium, gl~cose,
Hydrochlorothiazide: T.he following drugs may interact with thiazide diuretics. Alcohol, barbiturates, or narcot- and phosphorus and dec~eases In wac and platelets. There have been. occasional reports of eosinophilia. These
ics-potentiation of orthostatic hypotension may occur. Dosage adjustment of the antidiabetic drugs (oral agents were generally not of chmcallmportance and rarely resuiled In dlscontmuatlon of bisoprolol fumarate.
and Insulin) may be required. Other antihypertensive drugs-additive effect or potentiation. Cholestyramine and As WIth other beta-blockers, ANA conversions have also been reported on bisoprolol fumarate. About 15% of
colestipol resinS-Single doses ofcholestyramine and colestipol resins bind the hydrochlorothiazide and reduce its patients In long-tenm studies converted to apositive titer, although about one-third of these patients subsequently
absorption in the gastrointestinal tract by up to 85 and 43 percent, respectively. CorticosterOids, ACTH-intensi- reconverted to a negative titer while on continued therapy.
fied electrolyte depletion, particularly hypokalemia. Possible decreased response to pressor amines but not suf- Hydrochlorothiazide: Hypergl~cemia, glycosuria, hyperuricemia, hypokalemia and other electrolyte imbaiances
f.icienlto preclude their use. Possible increased responsiveness to muscle relaxants, nondepolarizing. Generally, (see PRECAUTIONS), hyperl!pldemla, hypercalcemia, leukofllRla, agranulocytosis, thrombocytopenia, aplastiC
lithium should not be given With diuretiCS. OIUretlC agents reduce the renal clearance of hthlum and add a high risk anemia, and hemo~,c anemia have been associated with HeTZ therarr,.
of lithium toxiCity. The administration of a nonsteroidal anti-inflammatory agent can reduce the diuretic, in~~~a~i~~AGE A 0 ADMINISTRAnON section in package insert or complete dosing and precautionary
natriuretic, and antihypertensive effects of loop, potassium-sparin~ and thiazide diuretics.
In patients receiving thiazides, sensitivity reactions may occur With or without a history of allergy or bronchial ADVANTUS PHARMACEUTICALS and
asthma. Photosensitivity reactions and possibleexacerbation or activation of systemic lupus erythematosus have 4fl!l!'!BClP
LEDERLE LABORATORIES DIVISION
been reported in patients receiving thiazides. The antihypertensive effects of thiazides may be enhanced in the - _ _-- American Cyanamid Company
post-sympathectomy patient. Pearl River, NY 10965
Laboratory rellinferactions: Based on reports involving thiazides, ZIAC may decrease serum levels of protein- REV. 3/93
bound iodme without signs of thyroid disturbance. Because it includes a thiazide, ZIAC should be discontinued Under license of E. MERCK, Darmsladt Genmany L-32073-93
before carrying out tests for parathyroid function (see PRECAUTIONS-Parathyroid Disease).
ADVERSE REACnONS
Copromoted by
ZIAC: Bisoprololfumarate/H6.25 mg is well tolerated in most patients. Most adverse effects (AEs) have been mild LEDEILE LABOIATORlfS ~~ n...... ...._.r:.--..£.I_
and transient. In more than 65,000 patients treated worldwide with bisoprolol fumarate, occurrences of broncho- .JtI!nrpnp ADivision of American Cyanamid (ompony
_______ Wayn., New Jersey 07470 rm8ceu 8S
rlf.A.llDOL'-IIMl1UIf:J
PHARMACEUTICALS
spasm have been rare. Discontinuation rates for AEs were similar for B1H6.25 mg and placebo-treated patients.
In the United States, 252 patients received bisoprolol fumarate (2.5, 5, 10, or 40 mg)1H6.25 mg and 144 Under license 01 E. MERCK, Darmstadt, Germany
patients received placebo in two controlled trials. In Study I, bisoprolol fumarate 51H6.25 mg was administered
for 4 weeks. In Study 2, bisoprolol fumarate 2.5, 10 or 401H6.25 mg was administered for 12 weeks. All adverse
experiences, whether drug-related or not, and drug-related adverse experiences in patients treated with
B2.5-101H6.25 mg, reported during comparable, 4 week treatment periods by at least 2% of bisoprolol fumarate/
H6.25 mg-treated patients (plus additional selected adverse experiences) are presented in the following table: © 1994 Lederle Laboratories February 1994 8728-3R
 The First in a New Chemical Class
of Non-benzodiazepine Sleep Agents
• ¢ $
m 2:.

M IEN z
Z.

(ZOlP DEM TARTRATE) G 5-MG & lO-MG TABLETS

• AMBIEN-an imidazopyridine, chemically With AMBIEN, Patients Awaken

unrelated to benzodiazepines or any other Refreshed and Alert
sleep agent
• A short half-life - mean 2.5 hours, with no
• Extensive clinical experience-over 500 active metabolites
million doses prescribed throughout Europe'
• No evidence of significant daytime sedation
With AMBIEN, Patients Fall Asleep or psychomotor impairment,,2,5,6
Fast and Get a Full Night's Sleep Although AMBIEN is generally not associated with next·day effects,
until your patients know how they will react to this sleep agent, they
should not engage in activities requiring mental alertness or motor
AMBIEN Generally Preserves Normal coordination after taking AMBIEN (eg, driving or operating haz·
ardous machinery). Potential impairment of the performance of such
Sleep Physiology2.s activities may occur the day following ingestion of AMBIEN

Mean Percentage of Time in Each Sleep Stagel

1 2

Natural
Sleep
No statistically significant difference from natural sleep (at baseline) for all
sleep stages, in a double·blind, controlled study of 12 healthy volunteers.'
The clinical significance is unknown.

Please see references and brief summary of prescribing

SEARLE information on last page of this advertisement.

01993 Sfarle
A Favorable Safety Profile Indicated For Short-Term
• No rebound insomnia in studies of up to 35 Management of Insomnia
nights at recommended doses 1'" • Prescriptions for AMBIEN should not exceed a
• No evidence of tolerance in sleep latency in 1-month supply. Hypnotics should generally
studies of up to 35 nights 1,3 be limited to 7to 10 days of use, and reevalu-
ation of the patient is recommended if they
• A low incidence of adverse events are taken for more than 2 to 3 weeks.
In short-term treatment (up to 10 nights) with AMBIEN at doses
$; 10 mg, the adverse events seen at statistically significant differences Recommended Dosage:
from placebo were: drowsiness (2%), dizziness (1 %), and diarrhea
(1 %); and in longer-term treatment (28 to 35 nights): dizziness (5%)
and drugged feelings (3%), For normal adults: .;.~ one 10-rng tablet
• Because of additive effects, AMBIEN should For elderly/debilitated patients: . " one 5-rng tablet '
not be combined with alcohol. Dosage adjust-
Patients should take AMBIEN right before going to bed and when~
ments may be necessary when AMBIEN is ready for sleep.
coadministered with eNS depressants.
• In patients with hepatic dysfunction,
dosage should be reduced and appropriate
monitoring instituted.

AMBIENN
The First in a New Chemical Class of Sleep Agents (ZOlPIDEM TARTRATE)@5·MG & lCJ.MG TABLETS
 References: 1. Data on file, Searle. 2. Merlolli l, Roehrs T, Koshorek G. et al. The dose effects of zolpidem on the sleep of healthy normals. J elin
I'!ychopharmacol. 1989;9:9-14.3. Vogel GW, Scharf M, Walsh J, et al. Effects of chronically administered zolpidem on the sleep of health insomniacs.
Sleep Research. 1989;18:80. Abstract. 4. Scharf MB, Mayleben OW, Kaffeman M, et al. Dose response effects of zolpidem in normal geriatric subjects.
Ambien™ @ J elin I'!ychiatry. 1991;52:77-83. 5. Walsh JK, Schweitzer PK, Sugerman Jl, et al. Transient insomnia associated with a Hour phase advance of sleep time
and treatment with zolpidem. J elin I'!ychopharmacol. 1990; 10: 184-189. 6. Oswald I, Adam K. A new look at short-acting hypnotics. In: Sauvanet JP,
(zolpidem tartrate) langer SZ. Morselli Pl, eds.lmidazopyridines in Sleep Disorders. New York, NY: Raven Press; 1988:253-259.
BRIEF SUMMARY
INDICATIDNS AND UIADE comparable to those seen in histOrical controls and the tumor findings are lnet...... allho....II·Eme'1lIlllAdft,.. flI... ~_1 I.
Ambian (zolpidem tartrate) is indicated for the short-term treatment of insomnia. thought to be a spontaneous occurrence. lang-linn PI_-Controll.d Ctlnlcol Trtl" (ConI'd)
Hypnotics should generally be limited to 7 to 10 days of use, and reevaluation M"",."..: Zolpidem did not have mutagenic activity in several tests including (Perc.ntage of pati.nts reporting)
of the patient is recommended If they are to be taken for more than 2 to 3 the Ames test. genotoxicity in mouse lymphoma cells in vitro, chromosomal Zolpid.m
weeks. aberrations in cultured human lymphocytes, unscheduled DNA synthesis In rat Body Syst.m/ (:S10 mg) Plac.bo
Amb,en should not be prescribed in Quantities exceeding a 1-month supply hepatocytes in vitro, and the micronucleus test in mice. Adverse Event- (N-152) (N-161)
(se. Warnings). ' ' ' ' ' _ ., lin/lily: In a rat reproduction sludy. the high dose (100 mg
base/kg) of zolpidem resulted In irregular estrus cycles and prolonged precoital Musculoskel.tal System
CONTRAINDICATIONS intervalS, but there was no effect on male or female fertility after daily oral Myalgia
None known. doses of 4 to 100 mg base/kg or 5 to 130 times the recommended human Arthralgia
WARNINGS dose in mg/m2. No effects on any other fertility parameters were noted. Respiratory System
Since sleep disturbances may be the presenting manifestation of a physical Pr.gOl • ., Upper respiratory infection 6
and/or psychiatriC disorder, symptomatic treatment of Insomnia should be Category B. Studies to assess the effects of zolpidem on human reproduction Sinusitis 2
initiated only after a careful evaluation of the patient. The failure of insomma and development have not been conducted. Pharyngitis I
to remit after 7 to 10 days of treatment may indicate the presence 01 a Teratology studies were conducted in rats and rabbits. Rhinitis 3
primary psychiatric andlor medIcal iUness which should be evaluated. Worsening In rats. adv.rse maternal and fetal effects occurred at 20 and 100 mg base/ Skin and App.ndages
of insomnia or the emeroence of new thinking or behaVior abnormalities may kg and includ.d dose-relat.d matemal lethargy and ataxia and a dose-related Rash
be the consequence of an unrecognized psychiatric or physical disorder. Such trend to incomplete ossification of fetal skull bones. Urog.nital Sysl.m
findings have emerged during the course of treatment with sedative/hypnotic In rabbits, dose-related maternal sedation and decreased weight gain occurred Urinary tract infection
drugs. including Ambien. Because some of the important adverse effects of at all doses test.d. AI the high dose. 16 mg baseikQ. there was an Inc..... 'Events reported by at least 1% of pati.nts tr..l.d w~h Ambi.n.
Amblen appear to be dose related (see PrrcautiOfls and Oosaae and Admin- in postimplantation fetal loss and underosslfication of sternebrae in viable
istration). it is important to use the smallest possible effective dose. especially fetuses There is evidence from dose comparison trials suggesting a dose relationship
in the elderly. This drug should be used during pi'egnancy only n clearly need.d. for many of the adverse events aSSOCiated with zolpidem use, particularly for
A variety of abnormal thinking and behavior changes have been reported to
occur in asSOCiation with the use of sedative/hypnotics. Some of these changes
M.,,",.,.,..,. ",..,,: Studies to assess the effects on children whose
mothers took zOlpidem during pregnancy have not been conducted. However,
certain CNS and gastrOintestinal adverse events.
Adverse events are further classified and enumerated In order of decreasing
may be characterized by decreased inhibition (eg, aggressiveness and extro- frequency using the following definitions: frequent adverse events are defined
children born of mothers taking sedative/hypnotic drugs may be at some risk as those occurring In greater than 1/100 subjects: infrequent adverse events
version that seemed out of character), similar to effects produced by alcohol for withdrawal symptom. lrom the drug during the postnatal p.riod. In addition.
and other CNS depressants. Other reported behavioral changes have included are those occurring in 1/100 to 1/1,000 patients: rare events are those
n.onatal flaccidity has been reported In infants bom of mOlhere who received occurring in less than 1/1.000 patl.nlS.
bizarre behavior, agitation, hallucinations, and depersonalization. Amnesia and sedative/hypno1ic drugs during pregnaney.
other neuropsychiatric symptoms may occur unpredictably. In primarily de- frI.....nt abdominal pain, amnesia, ataxia, confusion, depression, diarrhea,
lIbDf Ind dellv.,,: Ambien has no eslabllsh.d use In labor and deliv.ry. diplopia, dizziness, dreaming abnormal, drowsiness, drugged feeling, dry mouth,
pressed patients, worsening of depression, including suicidal thinking, has been N...IIg mOltl...: Studi .. in lactating moth.rs indicat. that _en 0.004
reported In association with the use of sedative/hypnotics. dyspepsia. euphoria. fatlgu,. headache. insomnia. lethargy. lighlheadedness.
and 0.019% of the total administered dose is .xcreted into milk. bu1 the .ff.ct myalgia, nausea, upper respiratory infection, vertigo, vision abnormal, vomiting.
It can rarely be determined with certainty whether a particular 'Instance of
of lolpidem on the infant is unknown. Infrequlnt: agitation, allergy, anorexia, anxiety. arthralgia, arthritis, asthenia.
the abnormal behaviors listed above are drug Induced, spontaneous in origin, The use of Ambien in nursing mothers is not recommended.
or a result of an underlying psychiatriC or physical disorder. Nonetheless, the back pain, bronchitis, cerebrovascular disorder. chest pain. constipation, cough~
Safety and effectiveness in children below the age of 18 have not been Ing. cyst~is. decr..sed cogn~ion. d.tach.d. difficulty concentrating. dysarthria.
emergence of any new behavioral sign or symptom of concern requires careful established.
and immediate evaluation. dysphagia. dyspn... ed.ma. .molional lability. eye irritation. falling. lever.
Following the rapid dose decrease or abrupt discontinuation of sedative/ ADVERSE REACTIONS flatulence, gastroenteritis, hallucination, hiccup, hyperglycemia, hypertension,
hypnotics, there have been reports of signs and symptoms similar to those _1.ltd willi dlaco.Un••lIon 01 Irlllmtnt Approximat.ly 4% 01 1.701 hypoaesthesia, infection, influenza·lile symptoms, malaise, menstrual disorder,
associat.d w~h withdrawal from other CNS-depressant drugs (see Drug Abuse pati.nts who rec.ived zolpid.m at all doses (1.25 to 90 mg) In U.S. prem_ng migraine, nervousness, pallor, palpitation, paresthesia, pharyngitis, postural
and Depend."ce). clinical trials discontinued treatment because of an adverse clinical event. hypotension, pruritus, rash, rhinitis, scleritis, SGPT increased, sinusitis, sleep
Ambien. like other sedative/hypnotic drugs. has CNS-d.pressant effects. Events most commonly associated with discontinuation from U.S. trials were disorder. sleeping (after daytime dosing). stupor. sweating increas.d. tachycar-
Due to the rapid onset of action, Ambien should only be ingested immediately daytime drowsiness (0.5%). dizziness (0.4%). h.adache (0.5%). nausea (0.6%). dia, taste perversion, tinnttus, tooth disorder, trauma, tremor, urinary inconttn·
prior to going to bed. Patients should be cautioned against engaging in and vomiting (0.5%). ence, urinary tract infection, vaginitis.
hazardous occupations requiring complete mental alertness or motor coordi- Approximat.ly 6% of 1.320 pati.nts who r..,.iv.d zolpidem at all doses (5 Rill: abdominal body sensation, abscess, acne, acute renal failure, aggressive
nation such as operating machinery or driving a motor vehicle after Ingesting to 50 mg) in similar foreign trials discontinued treatment becalJse of an adverse reaction, allergic reaction. allergy aggravated, anaphylactic shock. anemia.
the drug. including potential impairment of the performance of such activities event. Events most commonly associated with discontinuation from these trials appetite Increased, arrhythmia, arteritiS, arthrosis, bilirubinemia, breast fibroad~

1rI_
that may occur the day following ingestion of Ambl.n. Ambien showed additive were daytime drowsiness (1.6%). amnesia (0.6%). dizzin.ss (0.6%). headache enosis, breast neoplasm, breast pain female, bronchospasm, bullous eruption,
• ffects when combined wittl ~cohol and should not be taken with alcohol. (0.6%). and nausea (0.6%) . BUN increased, circulatory failure, corneal ulceration, delusion, dementia,
Patients should also be cautioned about possible combined effects with other
CNS-depressant drugs. Dosage adjustments may be necessary wnen Ambien
IS administered with such agents because of the potentially additive effects.
M..,..."".."" otumrI ,m,.•...""
loclrll... In ..ntroIltd ..1....11rI...
tn.1I: During short-
depersonalization, dermatitis, dysphasia. dysuria, edema periorbital, ententls,
.plstaxls.•ructalion. esophagospasm. ESR Incr....d. extrasystoles. eye ""In.
fac••d.ma. feeling strange. Ilushing. luruneulosis. gastritis. glaucoma. goul.
PRECAUTIONS :~~~e~m:~~.J0~~.~~hi~.~:h~~~::~: ~~~'~h~Pu~ ~~ ~~~~"m~~ hemorrhoids, hepatic function abnormal, herpes simplex, herpes zoster, hot
Go....1 seen at statistically significant differences from placebo-treated patients were flashes. hypercholesteremia. hypem.moglobinemia. hyp.rlipld.mia. hypen.n-
Un IrIIlllIIhrIy w'or rlltl/n."d /Milt.,,: Impaired motor and/or cognitiv. drOWSiness (reported by 2% of zolpld.m pati.nts). dizzin.ss (f %). and diarrhea slon aggravated. hypol.nslOn. hypotonia. hypoxia. hysleria. illusion. Impolene••
performance after repeated exposure or unusual sensitivity to sedative/hypnotic (1 %). During longer-t.rm treatmenl (28 to 35 nights) w~h zolpid.m at doses injection Site inflammation, intestinal obstruction, intoxicated feeling. lacrimation
drugs IS a concern in the treatment of elderly and/or debilitated patients. up to 10 mg, the most commonly observed adverse events associated with abnormal. laryngitis. leg cramps. I.ukop.nia. libido d.cre...d. Iymphad.nop-
Therefore, the recommended Ambien dosage is 5 mg in such patients (see the use of zolpldem and seen at statistically significant differences from athy, macrocytic anemia, manic reaction, micturition frequency, muscle weak-

/h, I. /M- """ .... _nt

00sBge and Administration) to decrease the possibility of side effects. These
patients should be closely monitored.
III..": Clinical experi.nce with Ambi.n in
patients with concomitant systemic illness is limited. Caution is advisable in
using Amblen in patients with diseases or conditions that could affect
plac.bo-treat.d patients were dizziness (5%) and drugged feelings (3%).
1 _... aI h.hn••Hme..... AllYl... flip"',.", II
Shorl·llnn PI.cob..eo_ltd CII....I Trt...
(Perc.nlag. 01 ""tlents reporting)
ness, myocardial infarction, neuralgia, neuritis, neuropathy, neurosis, otitis
extema. o1ills m.dia. pain. pan~ aftack. paresis. personality disorder. phleb~I••
photopsia, photosensttivlty reaction, pneumonia, polyuria, pulmonary edema,
pulmonary .mbollsm. purpura. py.lonephritis. rectal h.morrhag •• renal p~n.
reSlI.ss I.gs. rigors. saliva att.red. sciatica. SGDT increased. somnambulism.
metabOlism or hemodynamic responses. Although preliminary studies did not Zolpid.m suicide attempt. syncope. t.ndln"i •• t.n.smus. t.tany. thinking abnormal. Ihlrst.
reveal respiratory depressant effects at hypnotic doses of Ambien in normals, Body Syst.m/ (:s10 mg) Plac.bo tolerance increased, tooth carles, urinary retention, urticaria, varicose veins,
precautions should be observed if Amblen is prescribed to patients with Adverse Event- (N=685) (N=-473) v,ntrlcular tachycardia. weight d.creas•• yawning.
compromised respiratory function, since sedative/hypnotics have the capacity DRUG ABUSE AND DEPENDENCE
to depress respiratory drive. Data In end-stage renal flilure patients repeatedly Central and Peripheral Nervous System C."lroIltd lublll...: Sch.dule IV.
treated with Ambien did not demonstrate drug accumulation or alterations in H.adache All••• Ind .............: Studies of abuse pot.ntlal in former drug abusers
pharmacokinetic parameters. No dosage adjustment in renally impaired patients Drowsiness found that the effects of slngl. dos.. of zolpidem tartrate 40 mg were similar.
is required: however, these patients should be closely monitored (see Phar- Dizziness but not Identical. to dlaz.""m 20 mg. whil. zolpid.m tartrate 10 mg was
macokinetics). A study in subjects with hepatiC impairment did reveal prolonged Gastrointestinal System difficult to distinguish from placebo.
elimination in this group; therefore, treatment should be initiated with 5 mg in Nausea S.dativ./hypnolics have produced withd ..waI signs and symptoms fOllowing
patients with hepatic compromise, and they should be closely monitored. Diarrhea abrupl dlscontinualion. Th.se reported symptoms range from mild dysphoria
U.. I" ~ As with other sedative/hypnotic drugs. Amblen should be Musculoslllietal System and insomnia to a withdrawal syndrome that may includ. abdominal and
administered with caution to patients exhibiting signs or symptoms of depres- Myalgia muscl. cramps. vomiting. sweating. tremors. and convulsion•. Th. U.S. clln~al
sion. Suicidal tendencies may be present in such patients and protective trial ."",rlonce from zolpid.m does not raveal any cl.ar evld.nce for withdrawal
measures may be reqUired. Intentional overdosage is more common in this -Events reported by at least 1% of Ambien patients are included.
syndrom•. Nev.rtheless. the 1011 owing adverse ev.nts Included in DSM-III-R
group of patients: therefore, the least amount of drug that is feasible should criteria for uncomplicat.d sedatlv./hypnotic withdllWal were repOrted at an
be prescribed for the patient at anyone time. 1••ld.... 01 h,....II-Eme'1l.nl All..... flIp,",- In Incidence of :s1% during U.S, clinical trials fOllowing placebo subst~ution
I,.",..""" ,,111'*: lit Patient information is printed in the complete
prescribing information and is available in pads for distribution to patients.
lang-linn PI...bo-Co_ltd CII.lcol 1)1.11
(Perc.ntag. of patients reporting)
occurring within 48 hours following last zolpidem treatment: fatigue, nause••
flushing, lightheadedness, uncontrolled crying, emesis, stomach cramps, paniC
lIbor11ary Ie"': There are no specific laboratory tests recommended. Zolpidem attack, nervousness, and abdominal discomfort.
D..gl....._ Body Syst.m/ (:S10 mg) Placebo Individuals w~h a history of addiction to. or abuse 01. drugs or alcohol ...
CNS~'rtI". dru,,: Ambien was evaluated in healthy volunteers in single-dose Adverse Event- (N-152) (N-161) at risk of haMuation and d.pend.nce; they should be under careful surveillance
Interaction studies for several eNS drugs. A study involving haloperidol and when receiving any hypnotic.
zolpidem revealed no effect of haloperidol on the pharmacokinetics or phar- Autonomic Nervous System OVERDOIADE
macodynamics of zolpidem. Imipramine in combination with zolpidem produced Dry mouth Ilglll Ind aympIomo: In Europ..n postmarketlng reports 01 overdose with
no pharmacokinetlc interactIon other than a 20% decrease In peak levels of Body as a Whol. zoipidem alone, Impairment of consciousness has ranged from somnolence to
imipramine, but there was an additive effect of decreased alertness. Similarly, Allergy light coma, with one case each of cardiovascular and respiratory compromise.
chlorpromazine in combination with zolpidem produced no pharmacokinetic Back palO Individuals have fully recovered from zOlpidem tartrate overdoses up to 400
interaction. but there was an additive effect of decreased alertness and Influenza·lile symptoms mg (40 times the maximum recommended dose). Overdose cases involving
psychomotor performance. The lack of a drug interaction following single-dose Chest pain muttipl. CNS-d.pressanl ag.nts. including zolpldem. have resutted In mOre
administration does not predict a lack following chronic administration. Fatigue severe symptomatology, including fatal outcomes.
An additive effect on psychomotor performance between alcohol and zolpidem Cardiovascular System ........._ 1 _ Gen ...1 symptomatic and supponive m.asures
was demonstrated. Palpitation should be used along w~h immedi ..e gastric lavage where appropriate.
Since the systematic evaluations of Ambien in combination with other CNS- C.ntral and Periph.ral N.rvous Syst.m Intravenous fluids should be administered as needed. Flumazenil may be useful.
active drugs have b&en limited, careful consideration should be given to the Headach. 19 22 Raspiralion. pulse. blood pressure. and other appropriale signs should be
pharmacology of any CNS-active drug to be used w~h zolpidem. Any drug Drowsiness 8 5 mon~ored and gen.ral supportlv. m.as......mployed. Sedating drugs should
With CNS-depressant .ffects could pot.ntially .nhance the CNS-depressant Dizziness 5 1 be withheld following zolpid.m overdosag•. Zolpldem is not dialyzable.
effects of zOlpidem l.thargy 3 1 The possibility of multiple drug ingestion should be considered.
0IIIIr ....: A study involving cimetidine/zolpidem and ranitidine/zolpidem Drugged ... ling 3 Caution: Federal law prohibits dispensing without prescription.
combinations revealed no effect of either drug on the pharmacokinetics or llghthead.dness 2
Depression 2 5/27/93
pharmacodynamics of zolpidem. Zolpidem had no effect on digoxin kinetics ManUlactured and distributed by
and did not affect prothrombin time when given with warfarin In normal Abnonnal dreams 1 G.D. Searl. & Co.
subjects. Zolpidem's sedative/hypnotic effect was reversed by flumazenil; Amnesia 1 ChiC8g0. IL 60680
however, no Significant alterations in zolpidem phannacokinetics were found. Anxiety 1 byagreemtmlwilh
Drug'........." 1..1 1..........0: Zolpid.m is not known to int.rfere Wllh Nervousness 1 Lorex Ph'rrTllcsuticals
commonly emploved clinical laboratory tests. Sleep disorder 1 Skoki•• IL
C"reI."","II. mull......II. ImpllrmeAl aI flrIIllIy Gastrointestinal System
Nausea Addr.ss m.diCl/lnquiries /0:
C~: Zolpidem was administered to rats and mice for 2 years at G,O. Searl. & Co.
d~tary dosages of 4. 18. and 80 mg/kg/day. In mice. these doses are 26 10
Dyspepsia
Diarrhea M.dlcal & Sci.",lnc Informal/on Depertmtmt
520 times or 2 to 35 times the maximum 10-mg human dose on a mg/kg or Abdominal pain 4901 Searl. Parkwly
mg/m 2 basis, respectively. In rats these doses are 43 to 876 tImes or 6 to Constipation Skokie. IL 60077
115 times the maximum 10-mg human dose on a mg/kg or mg/m 2 basis,
Anorexia 80x 5110
respectively. No evidence of carCinogenic potential was observed in mice. Renal
liposarcomas were seen In 4/100 rats (3 males, 1 female) receiving 80 mg/
kO/day and a renal lipoma was observed in on. mal. rat at Ih. 18 mg/kg/
Vomiting
Immunologic System SE4RLE Chicago, IL 60680·5110
day dose. Incidence rates of lipoma and liposarcoma for zolpidem were Inf!ction Ambl.n is a trademark of Synthelabo. C93AB8570T
 INFORMATION FOR READERS
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 INFORMATION FOR AUTHORS
The Journal ofthe American Board of related to the practice or education of ceptable. Address all submissions to
Family Practice welcomes for editorial family physicians in various countries John P. Geyman, M.D., Editor, the
review manuscripts that contribute to around the world (usual length 1200- Journal ofthe American Board ofFamily
family practice as a clinical scientific 1800 words). Practice, Department of Family Medi-
discipline. High priority is given to re- cine (HQ-30), School of Medicine,
ports of clinically relevant studies that Reflections in Family Practice. Pa- University of Washington, Seattle,
have practical implications for im- p'ers in narrative or essay format that WA 98195. A covering letter should
Illuminate qualitative aspects of family
proved patient care. Manuscripts are practice, including such areas as ethi- identify the person (with the address
considered in relation to the extent to cal issues, the physician-patient rela- and telephone number) responsible for
which they represent original work, tionship, or the diverse roles of the negotiations concerning the manu-
their significance to the advancement family physician. script; the letter should make it clear
of family medicine, and their interest that the final manuscript has been seen
to the practicing family physician. Editorial. Focused opinion or com- and approved by all authors. If authors
Some papers that are accepted by the mentary that bears on an issue rele- acknowledge by name persons who
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dIscussion in the Journal, usually not
The Journal expects authors to take
Original Articles. Reports of origi- to exceed 500 words. public responsibility for their manu-
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ically relevant study. John P. Geyman, Editor, the Journal of and review of the paper. Authors are
expected to stand behind the validity of
Medical Practice. Scholarly articles the American Board of Famil), Practice,
Deeartment of Family Medicine their data and, if asked by the Editor, to
that relate directly to clinical topics (H<J-30), School of Medicine, Uni-
useful in everyday family practice, versity submit the actual data for editorial re-
of Washington, Seattle, WA view with the manuscript. In most in-
whether dealing with diagnostic or 98195.
therapeutic roles of the family physi- stances authorship should be limited to
cian or reporting studies of what 8 authors or fewer, all meeting the
The following guidelines are in ac- above criteria for authorship. Excep-
family phYSIcians do in practice. cordance with the "Uniform Require- tions to these guidelines, especially
ments for Manuscripts Submitted to those involving multisite collaborative
Clinical Review. In-depth reviews Biomedical Journals." The current
of sl?ecific clinical problems, disease (fourth) edition was published in the research projects, should be discussed
entioes, or treatment modalities; com- February 7, 1991, issue of the New on a case-by-case basis with the Editor.
prehensive and critical analysis of the EnglondJournalofMedicine. The Journal also expects authors to
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Manuscripts containing original connection with the submitted article.
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Care. Summaries of major clinical other equity interests, patent-licensing
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organizations, with critical commen- substance, tables, or figures has been or ciations that might involve conflict of
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Family Practice and the Health the TournaI. This restriction does not submission. Such information will be
Care System. Articles reporting stud- appfy to abstracts or press reports pub- held in confidence while the paper is
ies ana scholarly commentary on lished in connection with scientific under review and will not influence the
changing trends and patterns of care meetings. Copies of any possibly du- editorial decision. If the manuscript is
in family practice, prtmary care, and plicative manuscripts should be sub- accepted, the Editor will discuss with
the health care system. mitted to the Editor along with the the authors how best to disclose the
manuscript that is to be considered by relevant information. Questions about
Special Articles. Articles in other the Journal. The Journal strongly dis- this policy should be directed to the
areas that may relate to the role of courages the submission of more than Editor.
the family physician! education for one article dealing with related aspects
family practice, or other subjects im- of the same study. In almost all cases, a
portant to family practice as a clinical MANUSCRIPTS
specialty. single study is best reported in a single Titles IIndAutbors' Names
paper. WIth the manuscript, provide a page
Brief Reports. Short reports of pi- Submit an original and 3 copies of giving the title of the paper; a running
lot stuwes or case reports with a teach- the complete manuscript, including foot of fewer than 40 letter spaces; the
ing point of clinical relevance (usual text pages, legends, tables, references, name(s) of the author(s), including
length 1000-1500 words). and glossy prints of figures. Only typed first name(s) and academic degree(s);
copy, on standard-sized typewriter the name of the department and insti-
Family Practice - World Perspec- paper and double-spaced throughout, tution in which the work was done; and
tive. Papers reporting developments with margins of at least 2.5 em, is ac- the name and address of the author to

JABFP March-April1994 Vol. 7 No.2

whom reprint requests should be ad- histamine is the causative toxin of ure has been reduced to fit the width of
dressed. All funding sources support- scombroid-fish poisoning. N Engl J a single column.
ing the work should be routinely Med 1991; 324:716-20. The back of each figure should in-
acknowledged on the title page, as clude the sequence number, the name
should all institutional or corporate Organization as Author of the author, and the proper orienta-
affiliations of the authors. Two to four Clinical Experience Network tion (e.g., "top"). Do not mount the
key words should be submitted with (CEN). A large-scale, office-based figure on cardboard. Photomicro-
the manuscripts to be used for pur- study evaluates the use of a new class of graphs should be cropped to a width of
poses of classification by subject. Use nonsedating antihistamines. A report 8 cm, and electron photomicrographs
terms from the Medical Subject Head- from CEN. J Am Board Fam Pract should have internal scale markers.
ings from Index Medicuswhen possible. 1990; 3:241-58. If photographs of patients are used,
either the subjects should not be iden-
Abstracts Book tifiable or their pictures must be ac-
Use another page to provide an ab- Rakel RE. Textbook of family prac- companied by written permission to
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This abstract should be factual, not de- 1990. available from the Editor.
scriptive, with its content appropriate Legends for illustrations should be
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cles reporting results of studies, a four- Haynes RC Jr. Agents affecting cal- rate sheet and should not appear on the
paragraph format should be used la- cification: calcium, parathyroid hor- illustrations.
beled Background, Methods, Results, mone, calcitonin, vitamin 0, and other Color illustrations are used from
and Conclusions. These should briefly compounds. In: Gilman AG, Rall Tw, time to time. Send both transparencies
describe, respectively, the object of the Nies AS, Taylor P, editors. Goodman and prints for this purpose.
study, the methods used, the major re- and Gilman's the pharmacological
sults, and the author(s) conclusions. basis of therapeutics. 8th ed. New Permissions
Abstracts are not necessary for Brief York: Pergamon Press, 1990. Every effort (short of changing the
Reports or World Perspective papers. patient data) should be made by the au-
Government Agency thors to protect the anonymity of pa-
Abbreviations SchwartzJL. Review and evaluation tients (and relatives) in any published
Except for units of measurement, of smoking cessation methods: the work. If identification is unavoidable,
abbreviations are discouraged. Con- United States and Canada, 1978-1985. informed consent should be obtained
sult the Council of Biowgy Editors Style Bethesda, MD: Department of Health and attached with the submitted letter;
Manual (Fifth edition. Bethesda, MD: and Human Services, 1987. (Nlli pub- in the case of minors or incompetent
Council of Biology Editors, 1983) for lication no. 87-2940.) patients, consent should be obtained
lists of standard abbreviations. The from relatives or guardians.
first time an abbreviation appears, it Personal Communications Materials taken from other sources
should be preceded by the words for Numbered references to personal must be accompanied by a written
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Drug Names
and manuscripts either "in prepara- . publisher giving permission to the
Generic names should, in general, tion" or "submitted for publication" Journal for reproduction. Obtain per-
be used. If an author so desires, brand are unaccertable (see "Permissions"). mission in writing from at least one
names may be inserted in parentheses. If essentia , such material may be in- author of lapers still in press, of
corporated in the appropriate place in unpublishe data, and of personal
the text. communications.
Inclusive Language
Sex bias should be avoided and gen- RlMEW AND ACTION
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possible. Type tables in double spacing on torial staff and are usually sent to out-
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References each. For footnotes, use the following
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ATTENTION ******** 3-DIGIT-080
0028 @34])76/88 ABFP
BEVERLY J. CLARK MD
DIPLOMATES OF THE ABFP 24 LEXI GTON ST
AKRON 0 44309
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 We Agree, And We F
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Ulnar Fracture Brace™
In 1987, Galveston Manufacturing introduced the Galveston Metacarpal Brace™.
After over seven years of clinical use, the brace has proven successful in treating
metacarpal shaft fractures. Galveston Manufacturing has continued serving the
medical community, bringing you the latest quality fracture management products
at affordable prices. 50 far this year we've introduced three new products to our
line; the THUMZ'UP® functional thumb splint, the ORFIZIP® casting system
and the PLA5T-O-FIT® thermoplastic bandage system.
For ordering information or a product catalog, simply call1-BOO-634-3309.
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GALVESTON
MANUFACTURING
"Simple Solutions In Functional Bracing"
 IX® Works Jointly
IN 0.025%) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __
Aunique topical analgesic cream, ZOSTRIX has amechanism of action that complements NSAIDs .
NSAlDs inhibit prostaglandin synthesis, while capsaicin, the acffve ingredient in ZOSTRIX, depletes
substance P, aneurotransmitter of pain.
When ZOSTRIX cream is added to NSAID therapyl:

If t t t t t.J.t t t
- 7 out of 10 arthriffs paffents get addiffonal pain relief

If f f f f f ! . !_*1
- 9 out of 10 paffents experience improved mobility

TRIX® Works Direc~y

N0.025%) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _0 _....,
ZOSTRIX delivers pain·relieving acffon directly to the joint that hurts. 1,2 Anew clinical study shows that
applicaffon of capsaicin cream reduces the levels of substance Pand other biochemical mediators in the
synovial fluid of arthriffc joints. 3

IX® Works Safely and Economically

(IN 0.025%),_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __
ZOSTRIX is free from systemic side effects, and has no known drug interactions. The most common
side effect-transient burning at the site of applicaffon-usually resolves within afew days of use.
When used properly, ZOSTRIX is inexpensive pain therapy. In fact, when treaffng asingle knee joint,
a 20-gm tube can last up to amonth.

OSTRIX®
PSAICIN 0.025%
ADJUNCTIVE PAIN RELIEF FDR ALL YOUR ARTHRITIS PATIENTS

R,II"nell: Marketed~
1. Deal CLbSChnltzer TJ. Lipstein E. et al. Treatment of arthritis with topical capsaicin: a double-blind
trial [au set analysis of data]. Clln Ther. 1991;13:383-395.
2. McCarthy GM. McCarty OJ. Effect of topical capsaicin in the therapy of painful osteoarthritis of the GenOerm Corporation U.
hands. J Rheumatol. 1992;19:604-607.
3. Lotz M. Weisman M. Yaksh T. Hagaman C. Flynn P. Effects of topical capsaicin (0.075%) on substance
P and prostaglandin E, in synovial fluid: a double-blind study. Arthritis Rheum. 1992;35(9):8235.
Lincolnshire.IL 60069

© 1993 GenOerm Corporation Z6037

....-.
GENDERM" ICI10II
3/93
 ReflrlftClS: drug-related esophageal or gastric pathology was observed in the rats or were dose-related. The incidence of discontinuations due to these adVilrse
I. TII/J fifth Report of the Joint National Committee on Detection Evaluation, wrth chronic administration in mice and dogs. The latter species, like man, experiences are shown in parentheses.
and Treatment of High Blood PresSUIB. Bethesda, MO: National Heart, has no anatomical structure comparable to the esophageal groDYi!.
lung and Blood Instrtute; 1993. NIH Publication No. 93-1088. AllYerse Placebo J,SJIII 5!nI 1!!.nII ~
Felodipine was not carcinogenic when fed to mice at doses of up to 138.6 EfflCl h121 N=11 h12 h123 hI
mg/kg/day (28 times' the maximum recommended human dose on a mg/m'
BRIEF SUMMARY Peripheral
basis) for periods of up to 80 weeks in males and 99 weeks in females. Edema 2.5 (1.6) 1.4 (0.0) 13.9 (2.8) 19.5 (2.4) 36.0 (10.0)
TABLETS Felodipine did not display any mutagenic activity in vitro in the Ames Palpitation 0.8 (0.8) 1.4(0.0) 0.0(0.0) 2.4 (0.8) 12.0 (8.0)
PLENDIL~ microbial mutagenicity test or in the mouse lymphoma forward mutation Headache 12.4 (0.0) 11.3 (1.4) 11.1 (0.0) 18.7 (4.1) 28.0 (18.0)
(FElDDIPfNE) assay. No clastogenit potential was seen in vivo in the mouse micronucle- Flushing 0.0(0.0) 4.2 (0.0) 2.8 (00) 8.1 (0.8) 20.0 (8.0)
us test at oral doses up to 2500 mg/kg (506 times' the maximum recom-
EXTENDED-RELEASE TABLETS
mended human dose on a mg/m' basis) or in vitro in a human lymphocyte In addition, adverse experiences that occurred in 0.5 up to 1.5 percent of
IlIDlCAnONS AIID USAGE chromosome aberration assay. patients who lBCeived PlENDllO(Felodipine) in all controlled clinical stud-
PlENOll* is indicated for the treatment of hypertension. PlENDll may be Afertility study in which male and femalp rats were administered doses ies (listed in order of decreasing severity within each category) and serioos
used alone or com:omitantiy with other antihypertensive agents. of 3.8, 9.6 or 26.9 mg/kg/day showed no significant effect of felodipine on adverse events that occurred at a lower rate or were found during market-
reproductiVil periormance. ing experience (those lower rate events are in italics) were: Body as ,
CONTRAINDICATIONS Whole. Facial edema, warm sensation; Cardiovascular: Tachycardia,
PlENDll is contraindicated in patients who are hypersensitiVil to this
Prepaney
Prtttwrcy Cm,ory C myocardial infarction, hypotension, syncope, angina pectoris, arrhythmia;
product. Digestive: Vomiting, dry mouth, flatulence; Hematologic: Anemia;
Teratogenic Effects: Studies in pregnant rabbits administered doses of
PRECAUTIONS 0.46, 1.2, 2.3 and 4.6 mg/kg/day (from 0.4 to 4times' the maximum recom- Musculoskeletal: Arthralgia, arm pain, knee pain, leg pain, foot pain, hip
General mended human dose on amg/m' basis) showed digital anomalies consisting pain, myalgia; NervousIPsychiatric: Depression, anxiety disorders, insom-
I/nIOItinkHI: Felodipine, like other calcium antagonists, may occasion- of reduction in size and degree of ossrtication of the terminal phalanges in nia, irrrtability, nervousness, somnolence; Respiratory: Bronchitis, influen-
ally plBCipitate significant hypotension and rarely syncope. It may lead to the fetuses. The frequency and severrty of the changes appeared dose-relat- za, sinusitis, dyspnea, epistaxis, respiratory infection, sneezing; Skin:
reflex tachycardia which in susceptible individuals may plBCiprtate angina ed and were noted even at the lowest dose. These changes have been shown Contusion, erythema, urticaria; Urogenital: Decreased libido, impotence,
pectoris. (See ADVERSE REACTIONS.) to occur wrth other members of the dihydropyridine class and are possibly a urinary frequency, urinary urgency, dysuria.
Hurt FIIhtrr: Although acute hemodynamic studies in a small number resu~ of compromised uterine blood flow. Similar fetal anomalies were not Felodipine, as an immediate release formulation, has also been studied
of patients with NYHA Class II or III heart failure treated with felodipine observed in rats given felodipine. as monotherapy in 680 patients with hypertension in U.S. and DYerseas
haVil not demonstrated negatiVil inotropic effects, safety in patients wrth In a teratology study in cynomolgus monkeys no reduction in the size of controlled clinical studies. Other adverse experiences not listed above and
heart failure has not been established. Caution therefore should be exer- the terminal phalanges was observed but an abnormal position of the dis- with an incidence of 0.5 percent or greater include: Body as a Whole:
cised when using PLENDIl in patients wrth heart failure or compromised tal phalanges was noted in aboot 40 percent of the fetuses.. Fatigue; Digestive: Gastrointestinal pain; Musculoskeletal: Arthritis, local
Vilntricular function, particularly in combination with a beta blocker. weakness, neck pain, shoulder pain, ankle pain; NervousIPsychiatric:
Nonteratogenic Effects: Aprolongation of parturition wrth difficu~ labor Tremor; Respiratory: Rhinitis; Skin: Hyperhidrosis, pruritus; Special
EIdIrly I'ItiIrItJ or I'I1f1llls IIIIfIltrrplirrd Li'fIII FrmcIfon: Patients over and an increased frequency of fetal and early postnatal deaths were
65 years of age or patients wrth impaired liVilr function may haVil elevated Senses: Blurred viSion, tinnitus; Urogenital: Nocturia.
observed in rats administered doses of 9.6 mg/kg/day (4 times' the maxi-
plasma concentrations of felodipine and may therefore respond to lower mum human dose on a mg/m' basis) and above. B/lIf/rIIl/yJllrp/n/I: Gingival hyperplasia, usually mild, occurred in
doses of PLINDIl. These patients shoold haVil their blood pressure moni- <0.5 percent of patients in controlled studies. This condition may be
Significant enlargement of the mammary glands in excess of the normal avoided or may regress with improVild dental hygiene. (See PRECAUTIONS,
tored closely during dosage adjustment of PlENDll and should rare~ enlargement for pregnant rabbrts was found with doses greater than or
require doses above 10 mg. (See CUNICAl PHARMACOLOGY and DOSAGE Information for Patients.)
equal to 1.2 mg/kg/day (equal to the maximum human dose on a mg/m'
AND ADMINISTRATION sections of complete Prescribing Information.) basis). This effect occurred only in pregnant rabbits and regressed during CHnklll.llHlrltory T.I/ Flntllnts
I'Itfp/Im/ ErIfmI: Peripheral edema, general~ mild and not associated lactation. Similar changes in the mammary glands were not observed in SInnn EIIcIrDIytt$: No significant effects on serum electrolytes were
with generalized fluid retention, was the most common adverse event in the rats or monkeys. observed during short- and long-term therapy.
clinical trials. The incidence of peripheral edema was both dose- and age- Sef/lm 8h1cD1I: No significant effects on fasting serum glucose were
There are no adequate and well-controlled studies in pregnant women. If Observed in patients treated wrth PLENDIl in the U.S. controlled study.
dependent. Frequency of peripheral edema ranged from aboot 10 pen;ent in felodipine is used during pregnancy, or if the patient becomes pregnant
patients under 50 years of age taking 5 mg daily to about 30 pen;ent in while taking this drug, she should be apprised of the potential hazard to Li'fIII EnzymlS: One of two episodes of elevated serum transaminases
those over 60 years of age taking 20 mg daily. This adverse effect genera~ the fetus, possible digital anomalies of the infant, and the potential effects decreased once drug was discontinued in clinical studies; no follow-up was
Iy occurs within 2-3 weeks of the initiation of treatment. of felodipine on labor and delivery, and on the mammary glands of preg- available for the other patient.
IrIfrImIIIfonforl'ltilrltJ nant females.
Patients shoold be instructed to take PLINDIl whole and not to crush or OVERDOSAGE
/IIHlItrfMlrs Oral doses of 240 mg/kg and 264 mg/kg in male and female mice,
chew the tablets. They shoold be told that mild gingival hyperplasia (gum It is not known whether this drug is secreted in human milk and because
swelling) has been reported. Good dental hygiene decreases its incidence respectively and 2390 mg/kg and 2250 mg/kg in male and female rats,
of the potential for serioos adVilrse reactions from felodipine in the infant, respectively, caused significant lethalrty.
and severity.
adecision should be made whether to discontinue nursing or to discontin- In a suicide attempt, one patient took 150 mg felodipine together wrth
NOTE: As wrth many other drugs, certain advice to patients being treated ue the drug, taking into account the importance of tfIe drug to the mother.
wrth PLINDIl is warranted. This information is intended to aid in the safe 15 tablets each of atenolol and spironolactone and 20 tablets of
Prdlltrtc /hi nitrazepam. The patient's blood pressure and heart rate were normal on
and effective use of this medication. It is not a disclosure of all possible Safety and effectiVilness in children have not been established.
ad¥else or intended effects. admission to hospital; he subsequently IBCDYered without significant
sequelae.
IInIt IrrtIrIctIorrI ADVERSE REACTIONS
Overdosage might be expected to cause excessive peripheral vasodila-
~.I4tms: Apharmacokinetic study of felodipine in conjunc- In controlled studies in the United States and overseas approximataly
tion wrth metoprolol demonstrated no significant effects on the pharmaco- 3000 patients were treated with felodipine as either the extended-release tion with marked hypotension and possibly bradycardia.
kinetics of leIodipine. The AUC and Cmll of metoprolol, however, were or the immediate-release formulation. If severe hypotension occurs, symptomatic treatment should be institut-
increased approximately 31 and 38 percent, respectively. In controlled clin- The most common clinical adverse experiences reported with ed. The patient should be placed supine with the legs elevated. The
ical trials, however, beta blockers including metoproiol were concurrently PlENDIlo (Felodipine) administered as monotherapy in all settings and administration of intravenous fluids may be useful to treat hypotension
administered with felodipine and were well tolerated. with all dosage forms of leIodipine were peripheral edema and headache. due to oVilrdosage with calcium antagonists. In case of accompanying
CIrntIfrIInt: In healthy subjects pharmacokinetic studies showed an Peripheral edema was generally mild, but it was age- and dose-related bradycardia, atropine (0.5-1 mg) should be administered intravenously.
approximately 50 percent increase in the area under the plasma concen- and resulted in discontinuation of therapy in about 4 pen;ent of the Sympathomimetic drugs may also be given if the physician feels they are
tration time curve (AUC) as well as the Cmax of felodipine when given con- enrolled patients. Discontinuation of therapy due to any clinical adVilrse warranted.
comitantly with cimetidine. ~ is anticipated that a clinically significant experience occurred in about 9 percent of the patients lBCeiving PlENDll, It has not been established whether felodipine can be removed from the
interaction may occur in some hypertensive patients. Therefore, it is IBC- principally for peripheral edema, headache, or flushing. circulation by hemodialysis.
ommended that low doses of PLINDIl be used when given concomitantly Adverse experiences that occurred with an incidence of 1.5 percent or greater DOSAGE AIID ADMINISTRAnON
with cimetidine. during monotherapy with PLENDil without regard to causalrty are compared to The 1BC0mmanded initial dose is 5 mg once a day. Therapy should be
/IIrUIII: When given concomitantly with felodipine the peak plasma con- placebo in tfIe table beIa.¥. adjusted individually according to patient response, generally at intervals
centration of digoxin was significantly increased. There was, however, no Percent 01 PatIents with AdYell8 Effects In Controlled of not less than two weeks. The usual dosage range is 5-10 mg once daily.
significant change in the AUC of digoxin. Trials of PLEIIDIL n Manotherapy The maximum recommended daily dose is 20 mg once a day. That dose in
Anliclllflllunts: In a pharmacokinetic study, maximum plasma concen- (Incidence 01 dlscontinuations shown In parentheses) clinical trials showed an increased blood pressure response but a large
trations of felodipine were considerably lower in epileptic patients on long- AdYeIl8 Effect PL£NDIL% Placebo % increase in the rate of peripheral edema and other vasodilatory adverse
term anticonvulsant therapy (e.g., phenytoin, carbamazepine, or phenobar- N= 130 N=283 eVilnts (see ADVERSE REACTIONS). Modification of the recommended
brtal) than in healthy volunteers. In such patients, the mean area under dosage is usually not required in patients with renal impairment.
the felodipine plasma concentration-time curve was also reduced to Peripheral Edema 22.3 (4.2) 3.5
PlENDll should be swallowed whole and not crushed or chewed.
approximately six percent of that observed in hearthy volunteers. Since a Headache 18.6 (2.1) 10.6
Flushing 6.4 (1.0) l.l /h. In IfII EIdfrIy ar I'ItWnts IIIIfIltrrpllrId Li'fIII FullCllon: Patients
clinically significant interaction may be anticipated, a~emative antihyper- OVilr 65 years of age or patients with impaired liver function, because they
tensive therapy should be considered in these patients. Diuiness 5.8 (0.8) 3.2
may develop higher plasma concentrations of felodipine, should have their
IItIrIr CIllClllllitlnt Tbm/lf.ln healthy subjects there were no clinically Upper Respiratory blood pressure monitored closely during dosage adjustment (see PRECAU-
significant interactions when felodipine was giViln concomitantly wrth Infection 5.5 (0.1) l.l TIONS). In general, doses aboVil 10 mg should not be considered in these
indomethacin or spironolactone. Asthenia 4.7 (o.!) 2.8 patients.
IIIIfrII:IfIlR IIIIfI FIIIIrI: See CUNICAl PHARMACOLOGY, I'rlatm8aidneti Cough 2.9 (0.0) 0.4
and Metabdism sectQ1 of oornplele Prescribing Infoonation. Paresthesia 2.5 (0.1) 1.8
~ I/idJtlRUlS.lmpl/nllfnt of FIrlIIIty Dyspepsia 2.3 (0.0) 1.4
In a two-year carcinogenicity study in rats fed felodipine at doses of 7.7, Chest Pain 2.1 (0.1) 1.4
23.1 or 69.3 mg/kg/day (up to 28 times' the maximum recommended Nausea 1.9 (0.8) l.l
human dose on a mg/m' basis), a dose related increase in the incidence of Muscle Cramps 1.9 (0.0) l.l
benign interstrtial cell tumors of the testes (Leydig cell tumors) was Palpitation 1.8 (0.5) 2.5
observed in treated male rats. These tumors were not observed in a simi-
Abdominal Pain 1.8 (0.3) l.l NMGROUP
lar study in mice at doses up to 138.6 mg/kg/day (28 times' the maximum of MERCK & co., INC.
recommended human dose on a mg/m' basis). Felodipine, at the doses
Constipation 1.6 (O.!) l.l
employed in the two-year rat study, has been shown to lower testicular Diarrhea 1.6 (0.1) l.l
testosterone and to produce acorresponding increase in serum luteinizing Pharyngitis 1.6 (0.0) 0.4
hormone in rats. The Leydig cell tumor development is possibly secondary Rhinorrhea 1.6 (0.0) 0.0 For more detailed information, consult your AstralMerck Specialist
to these hormonal effects which have not been observed in man. Back Pain 1.6 (0.0) l.l or see complete Prescribing Information.
Rash 1.5 (0.1) l.l AstraJ\1erck Group of Merck &Co., Inc.
In this same rat study a dose-related increase in the incidence of focal 725 Chestarbrook Boulevard, Wayne, PA 19087
squamoos cell hyperplasia compared to control was observed in the In the two dose response studies using PlENDll as monotherapy, the fol-
esophageal grooVil of male and female rats in all dose groups. No other lowing table describes the incidence (percent) of adverse experiences that PLINDll is a product of Astra!Merck Research
Copyright 01994 by Astra!Merck Group of Merck &Co., Inc.
-Registered trademark of AB Astra All rights reserved
'Based on patient weight of 50 kg 7650203 3000-0476193112-09/Ppl