A1,
A2,
B,
C1,
C2,
D,
E,
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G-H,
I-K,
L,
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Q-R,
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U-V,
W-Z
Prevpac Warnings, Precautions, Pregnancy, Nursing, Abuse - Lansoprazole, Amoxicillin And Clarithromycin
Prevpac Warnings, Precautions, Pregnancy, Nursing, Abuse - Lansoprazole, Amoxicillin And Clarithromycin
WARNINGS
Amoxicillin:
Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have
been reported in patients on penicillin therapy. Although anaphylaxis is more
frequent following parenteral therapy, it has occurred in patients on oral penicillins.
These reactions are more apt to occur in individuals with a history of penicillin
hypersensitivity and/or a history of sensitivity to multiple allergens.
There have been well documented reports of individuals with a history of penicillin
hypersensitivity reactions who have experienced severe hypersensitivity reactions
when treated with a cephalosporin. Before initiating therapy with any penicillin,
careful inquiry should be made concerning previous hypersensitivity reactions
to penicillins, cephalosporins, and other allergens. If an allergic reaction
occurs, amoxicillin should be discontinued and the appropriate therapy instituted.
SERIOUS ANAPHYLACTOID REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH
EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING
INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED.
Clarithromycin:
CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL CIRCUMSTANCES
WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE. IF PREGNANCY OCCURS WHILE TAKING
CLARITHROMYCIN, THE PATIENT SHOULD BE APPRISED OF THE POTENTIAL HAZARD TO THE
FETUS. CLARITHROMYCIN HAS DEMONSTRATED ADVERSE EFFECTS OF PREGNANCY OUTCOME
AND/OR EMBRYO-FETAL DEVELOPMENT IN MONKEYS, RATS, MICE, AND RABBITS AT DOSES
THAT PRODUCED PLASMA LEVELS 2 TO 17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS
TREATED AT THE MAXIMUM RECOMMENDED HUMAN DOSES. (See PRECAUTIONS
-
Pregnancy .)
Pseudomembranous colitis has been reported with nearly all antibacterial
agents, including clarithromycin, and may range in severity from mild to life
threatening. Therefore, it is important to consider this diagnosis in patients
who present with diarrhea subsequent to the administration of antibacterial
agents.
Treatment with antibacterial agents alters the normal flora of the colon and
may permit overgrowth of clostridia. Studies indicate that a toxin produced
by Clostridium difficile is a primary cause of "antibiotic-associated
colitis."
After the diagnosis of pseudomembranous colitis has been established, therapeutic
measures should be initiated. Mild cases of pseudomembranous colitis usually
respond to discontinuation of the drug alone. In moderate to severe cases, consideration
should be given to management with fluids and electrolytes, protein supplementation,
and treatment with an antibacterial drug clinically effective against Clostridium
difficile colitis.
PRECAUTIONS
Clarithromycin is principally excreted via the liver and kidney. Clarithromycin
may be administered without dosage adjustment to patients with hepatic impairment
and normal renal function. However, in the presence of severe renal impairment
with or without coexisting hepatic impairment, decreased dosage or prolonged
dosing intervals may be appropriate.
The possibility of superinfections with mycotic organisms or bacterial pathogens
should be kept in mind during therapy. In such cases, discontinue PREVPAC and
substitute appropriate treatment.
Symptomatic response to therapy with PREVACID does not preclude the presence
of gastric malignancy.
Information for Patients: Each dose of PREVPAC contains four pills:
one pink and black capsule (PREVACID), two maroon and light-pink capsules (amoxicillin)
and one yellow tablet (clarithromycin). Each dose should be taken twice per
day before eating. Patients should be instructed to swallow each pill whole.
Drug Interactions
PREVACID:
PREVACID is metabolized through the cytochrome P 450 system, specifically
through the CYP3A and CYP2C19 isozymes. Studies have shown that PREVACID does
not have clinically significant interactions with other drugs metabolized by
the cytochrome P 450 system, such as warfarin, antipyrine, indomethacin,
ibuprofen, phenytoin, propranolol, prednisone, diazepam, clarithromycin, or
terfenadine in healthy subjects. These compounds are metabolized through various
cytochrome P 450 isozymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6,
and CYP3A. When PREVACID was administered concomitantly with theophylline (CYP1A2,
CYP3A), a minor increase (10%) in the clearance of theophylline was seen. Because
of the small magnitude and the direction of the effect on theophylline clearance,
this interaction is unlikely to be of clinical concern. Nonetheless, individual
patients may require additional titration of their theophylline dosage when
PREVACID is started or stopped to ensure clinically effective blood levels.
PREVACID has also been shown to have no clinically significant interaction
with amoxicillin.
In a single-dose crossover study examining PREVACID 30 mg and omeprazole 20
mg each administered alone and concomitantly with sucralfate 1 gram, absorption
of the proton pump inhibitors was delayed and their bioavailability was reduced
by 17% and 16%, respectively, when administered concomitantly with sucralfate.
Therefore, proton pump inhibitors should be taken at least 30 minutes prior
to sucralfate. In clinical trials, antacids were administered concomitantly
with PREVACID Delayed-Release Capsules; this did not interfere with its effect.
PREVACID causes a profound and long-lasting inhibition of gastric acid secretion;
therefore, it is theoretically possible that PREVACID may interfere with the
absorption of drugs where gastric pH is an important determinant of bioavailability
(eg, ketoconazole, ampicillin esters, iron salts, digoxin).
Clarithromycin:
Clarithromycin use in patients who are receiving theophylline may be associated
with an increase of serum theophylline concentrations. Monitoring of serum theophylline
concentrations should be considered for patients receiving high doses of theophylline
or with baseline concentrations in the upper therapeutic range. In two studies
in which theophylline was administered with clarithromycin (a theophylline sustained-release
formulation was dosed at either 6.5 mg/kg or 12 mg/kg together with 250 or 500
mg q12h clarithromycin), the steady-state levels of C max , C min
, and the area under the serum concentration time curve (AUC) of theophylline
increased about 20%.
Concomitant administration of single doses of clarithromycin and carbamazepine
has been shown to result in increased plasma concentrations of carbamazepine.
Blood level monitoring of carbamazepine may be considered.
When clarithromycin and terfenadine were coadministered, plasma concentrations
of the active acid metabolite of terfenadine were threefold higher, on average,
than the values observed when terfenadine was administered alone. The pharmacokinetics
of clarithromycin and the 14-hydroxy-clarithromycin were not significantly affected
by coadministration of terfenadine once clarithromycin reached steady-state
conditions. Concomitant administration of clarithromycin with terfenadine is
contraindicated. (See CONTRAINDICATIONS .)
Spontaneous reports in the postmarketing period suggest that concomitant administration
of clarithromycin and oral anticoagulants may potentiate the effects of the
oral anticoagulants. Prothrombin times should be carefully monitored while patients
are receiving clarithromycin and oral anticoagulants simultaneously.
Elevated digoxin serum concentrations in patients receiving clarithromycin
and digoxin concomitantly have also been reported in postmarketing surveillance.
Some patients have shown clinical signs consistent with digoxin toxicity, including
potentially fatal arrhythmias. Serum digoxin levels should be carefully monitored
while patients are receiving digoxin and clarithromycin simultaneously.
For information on interactions between clarithromycin in combination with
other drugs which may be administered to HIV-infected patients, see the BIAXIN
package insert, Drug Interactions, under the PRECAUTIONS
section.
The following drug interactions, other than increased serum concentrations
of carbamazepine and active acid metabolite of terfenadine, have not been reported
in clinical trials with clarithromycin; however, they have been observed with
erythromycin products and/or with clarithromycin in postmarketing experience.
Concurrent use of erythromycin or clarithromycin and ergotamine or dihydroergotamine
has been associated in some patients with acute ergot toxicity characterized
by severe peripheral vasospasm and dysesthesia.
Erythromycin has been reported to decrease the clearance of triazolam and,
thus, may increase the pharmacologic effect of triazolam. There have been
postmarketing reports of drug interactions and CNS effects (e.g., somnolence
and confusion) with the concomitant use of clarithromycin and triazolam.
There have been reports of an interaction between erythromycin and astemizole
resulting in QT prolongation and torsades de pointes. Concomitant administration
of erythromycin and astemizole is contraindicated. Because clarithromycin
is also metabolized by cytochrome P 450 , concomitant administration
of clarithromycin with astemizole is not recommended.
As with other macrolides, clarithromycin has been reported to increase concentrations
of HMG-CoA reductase inhibitors (e.g., lovastatin and simvastatin), through
inhibition of cytochrome P 450 metabolism of these drugs. Rare
reports of rhabdomyolysis have been reported in patients taking these drugs
concomitantly.
The use of erythromycin and clarithromycin in patients concurrently taking
drugs metabolized by the cytochrome P 450 system may be associated
with elevations in serum levels of these other drugs. There have been reports
of interactions of erythromycin and/or clarithromycin with carbamazepine,
cyclosporine, tacrolimus, hexobarbital, phenytoin, alfentanil, disopyramide,
lovastatin, bromocriptine, valproate, terfenadine, cisapride, pimozide, rifabutin,
and astemizole. Serum concentrations of drugs metabolized by the cytochrome
P 450 system should be monitored closely in patients concurrently
receiving these drugs.
Carcinogenesis, Mutagenesis, Impairment of Fertility
PREVACID:
In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated orally
with doses of 5 to 150 mg/kg/day, about 1 to 40 times the exposure on a body
surface (mg/m 2 ) basis, of a 50-kg person of average height (1.46
m 2 body surface area) given the recommended human dose of 30 mg/day
(22.2 mg/m 2 ). Lansoprazole produced dose-related gastric enterochromaffin-like
(ECL) cell hyperplasia and ECL cell carcinoids in both male and female rats.
It also increased the incidence of intestinal metaplasia of the gastric epithelium
in both sexes. In male rats, lansoprazole produced a dose-related increase of
testicular interstitial cell adenomas. The incidence of these adenomas in rats
receiving doses of 15 to 150 mg/kg/day (4 to 40 times the recommended human
dose based on body surface area) exceeded the low background incidence (range
= 1.4 to 10%) for this strain of rat. Testicular interstitial cell adenoma also
occurred in 1 of 30 rats treated with 50 mg/kg/day (13 times the recommended
human dose based on body surface area) in a 1-year toxicity study.
In a 24-month carcinogenicity study, CD-1 mice were treated orally with doses
of 15 to 600 mg/kg/day, 2 to 80 times the recommended human dose based on body
surface area. Lansoprazole produced a dose-related increased incidence of gastric
ECL cell hyperplasia. It also produced an increased incidence of liver tumors
(hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treated
with 300 and 600 mg/kg/day (40 to 80 times the recommended human dose based
on body surface area) and female mice treated with 150 to 600 mg/kg/day (20
to 80 times the recommended human dose based on body surface area) exceeded
the ranges of background incidences in historical controls for this strain of
mice. Lansoprazole treatment produced adenoma of rete testis in male mice receiving
75 to 600 mg/kg/day (10 to 80 times the recommended human dose based on body
surface area).
Lansoprazole was not genotoxic in the Ames test, the ex vivo rat hepatocyte
unscheduled DNA synthesis (UDS) test, the in vivo mouse micronucleus
test or the rat bone marrow cell chromosomal aberration test. It was positive
in in vitro human lymphocyte chromosomal aberration assays.
Lansoprazole at oral doses up to 150 mg/kg/day (40 times the recommended human
dose based on body surface area) was found to have no effect on fertility and
reproductive performance of male and female rats.
Amoxicillin:
Long-term studies in animals have not been performed with amoxicillin.
Clarithromycin:
The following in vitro mutagenicity tests have been conducted with clarithromycin:
Salmonella /Mammalian Microsomes Test
Bacterial Induced Mutation Frequency Test
In vitro Chromosome Aberration Test
Rat Hepatocyte DNA Synthesis Assay
Mouse Lymphoma Assay
Mouse Dominant Lethal Study
Mouse Micronucleus Test
All tests had negative results except the in vitro Chromosome Aberration
Test which was weakly positive in one test and negative in another.
In addition, a Bacterial Reverse-Mutation Test (Ames Test) has been performed
on clarithromycin metabolites with negative results.
Fertility and reproduction studies have shown that daily doses of up to 160
mg/kg/day (1.3 times the recommended maximum human dose based on mg/m 2
) to male and female rats caused no adverse effects on the estrous cycle,
fertility, parturition, or number and viability of offspring. Plasma levels
in rats after 150 mg/kg/day were 2 times the human serum levels.
In the 150 mg/kg/day monkey studies, plasma levels were 3 times the human serum
levels. When given orally at 150 mg/kg/day (2.4 times the recommended maximum
human dose based on mg/m 2 ), clarithromycin was shown to produce
embryonic loss in monkeys. This effect has been attributed to marked maternal
toxicity of the drug at this high dose.
In rabbits, in utero fetal loss occurred at an intravenous dose of 33
mg/m 2 , which is 17 times less than the maximum proposed human oral
daily dose of 618 mg/m 2 .
Long-term studies in animals have not been performed to evaluate the carcinogenic
potential of clarithromycin.
Pregnancy
Teratogenic Effects. Pregnancy Category C
Category C is based on the pregnancy category for clarithromycin.
Four teratogenicity studies in rats (three with oral doses and one with intravenous
doses up to 160 mg/kg/day administered during the period of major organogenesis)
and two in rabbits at oral doses up to 125 mg/kg/day (approximately 2 times
the recommended maximum human dose based on mg/m 2 ) or intravenous
doses of 30 mg/kg/day administered during gestation days 6 to 18 failed to demonstrate
any teratogenicity from clarithromycin. Two additional oral studies in a different
rat strain at similar doses and similar conditions demonstrated a low incidence
of cardiovascular anomalies at doses of 150 mg/kg/day administered during gestation
days 6 to 15. Plasma levels after 150 mg/kg/day were 2 times the human serum
levels. Four studies in mice revealed a variable incidence of cleft palate following
oral doses of 1000 mg/kg/day (2 and 4 times the recommended maximum human dose
based on mg/m 2 , respectively) during gestation days 6 to 15. Cleft
palate was also seen at 500 mg/kg/day. The 1000 mg/kg/day exposure resulted
in plasma levels 17 times the human serum levels. In monkeys, an oral dose of
70 mg/kg/day (an approximate equidose of the recommended maximum human dose
based on mg/m 2 ) produced fetal growth retardation at plasma levels
that were 2 times the human serum levels.
There were no adequate and well-controlled studies of PREVPAC in pregnant women.
PREVPAC should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus. (See WARNINGS
.)
Labor and Delivery
Oral ampicillin-class antibiotics are poorly absorbed during labor. Studies
in guinea pigs showed that intravenous administration of ampicillin slightly
decreased the uterine tone and frequency of contractions, but moderately increased
the height and duration of contractions. However, it is not known whether use
of these drugs in humans during labor or delivery has immediate or delayed adverse
effects on the fetus, prolongs the duration of labor, or increases the likelihood
that forceps delivery or other obstetrical intervention or resuscitation of
the newborn will be necessary.
Nursing Mothers
Amoxicillin is excreted in human milk in very small amounts. Because of the
potential for serious adverse reactions in nursing infants from PREVPAC, a decision
should be made whether to discontinue nursing or to discontinue the drug therapy,
taking into account the importance of the therapy to the mother.
Pediatric Use
Safety and effectiveness of PREVPAC in pediatric patients infected with H.
pylori have not been established. (See CONTRAINDICATIONS and WARNINGS
.)
Geriatric Use
Elderly patients may suffer from asymptomatic renal and hepatic dysfunction.
Care should be taken when administering PREVPAC to this patient population.
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