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lansoprazole, amoxicillin and clarithromycin
Overview
What is PREVPAC?
PREVPAC consists of a daily administration card containing two PREVACID 30 mg delayed release capsules, four amoxicillin 500 mg capsules, USP, and two clarithromycin 500 mg tablets, USP, for oral administration.
What does PREVPAC look like?
What are the available doses of PREVPAC?
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What should I talk to my health care provider before I take PREVPAC?
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How should I use PREVPAC?
What interacts with PREVPAC?
PREVPAC is contraindicated in patients with known severe hypersensitivity to any component of the formulation of PREVACID. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute interstitial nephritis, and urticaria (see ). Proton Pump Inhibitors (PPIs), including PREVACID, are contraindicated with rilpivirine-containing products (see ).
A history of severe hypersensitivity reactions (e.g., anaphylaxis or Stevens-Johnson Syndrome) to amoxicillin or other beta-lactam antibiotics (e.g., penicillins and cephalosporins) is a contraindication.
Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin, erythromycin, or any of the macrolide antibiotics.
Clarithromycin is contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of clarithromycin.
Clarithromycin should not be given to patients with history of QT prolongation or ventricular cardiac arrhythmia, including .
Concomitant administration of clarithromycin, a component of PREVPAC, and any of the following drugs is contraindicated: cisapride, pimozide, astemizole, terfenadine, ergotamine or dihydroergotamine (see ). There have been postmarketing reports of drug interactions when clarithromycin and/or erythromycin are coadministered with cisapride, pimozide, astemizole, or terfenadine resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and ) most likely due to inhibition of metabolism of these drugs by erythromycin and clarithromycin. Fatalities have been reported.
Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment.
Clarithromycin should not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis (see ).
What are the warnings of PREVPAC?
Acute Hypersensitivity Reactions
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy, including amoxicillin. Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral penicillins. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Before initiating therapy with PREVPAC careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and Henoch-Schonlein purpura PREVPAC should be discontinued immediately and appropriate treatment should be urgently initiated.
Use in Pregnancy
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 INFORMED 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 TWO TO 17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM RECOMMENDED HUMAN DOSES (
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Hepatotoxicity
Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin. This hepatic dysfunction may be severe and is usually reversible. In some instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications. Symptoms of hepatitis can include anorexia, jaundice, dark urine, pruritus, or tender abdomen. Discontinue clarithromycin immediately if signs and symptoms of hepatitis occur.
QT Prolongation
Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Cases of have been spontaneously reported during postmarketing surveillance in patients receiving clarithromycin. Fatalities have been reported. Clarithromycin should be avoided in patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia (see ) and in patients receiving Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents. Elderly patients may be more susceptible to drug-associated effects on the QT interval.
Presence of Gastric Malignancy
In adults, symptomatic response to therapy with lansoprazole does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI. In older patients, also consider an endoscopy.
Acute Interstitial Nephritis
Acute interstitial nephritis (AIN) has been observed in patients taking proton pump inhibitors (PPIs) including lansoprazole. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue lansoprazole if AIN develops (see ).
Cutaneous and Systemic Lupus Erythematosus
Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including lansoprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE.
The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement.
Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported.
Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving PREVPAC, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in four to 12 weeks. Serological testing (e.g., ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.
Drug Interactions
Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4 substrates. These include colchicine toxicity with colchicine; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; hypoglycemia with disopyramide, and hypotension and acute kidney injury with calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem, nifedipine). Most reports of acute kidney injury with calcium channel blockers metabolized by CYP3A4 involved elderly patients 65 years of age or older (see and ). Clarithromycin should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme (see ).
Colchicine
Life-threatening and fatal drug interactions have been reported in patients treated with clarithromycin and colchicine. Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both drugs at their recommended doses. If coadministration of clarithromycin and colchicine is necessary in patients with normal renal and hepatic function, the dose of colchicine should be reduced. Patients should be monitored for clinical symptoms of colchicine toxicity. Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment (see and ).
Benzodiazepines
Increased sedation and prolongation of sedation have been reported with concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam, and midazolam.
Oral Hypoglycemic Agents/Insulin
The concomitant use of clarithromycin and oral hypoglycemic agents and/or insulin can result in significant hypoglycemia. With certain hypoglycemic drugs such as nateglinide, pioglitazone, repaglinide and rosiglitazone, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypoglycemia when used concomitantly. Careful monitoring of glucose is recommended.
Oral Anticoagulants
There is a risk of serious hemorrhage and significant elevations in INR and prothrombin time when clarithromycin is coadministered with warfarin. INR and prothrombin times should be frequently monitored while patients are receiving clarithromycin and oral anticoagulants concurrently.
HMG-CoA Reductase Inhibitors (statins)
Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see ) as these statins are extensively metabolized by CYP3A4, and concomitant treatment with clarithromycin increases their plasma concentration, which increases the risk of myopathy, including rhabdomyolysis. Cases of rhabdomyolysis have been reported in patients taking clarithromycin concomitantly with these statins. If treatment with clarithromycin cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment.
Caution should be exercised when prescribing clarithromycin with statins. In situations where the concomitant use of clarithromycin with atorvastatin or pravastatin cannot be avoided, atorvastatin dose should not exceed 20 mg daily and pravastatin dose should not exceed 40 mg daily. Use of a statin that is not dependent on CYP3A metabolism (e.g., fluvastatin) can be considered. It is recommended to prescribe the lowest registered dose if concomitant use cannot be avoided.
Interactions with Investigations for Neuroendocrine Tumors
Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop lansoprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary (see ).
Interaction with Methotrexate
Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients (see ).
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Clostridium Difficile
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If CDAD is suspected or confirmed, ongoing antibiotic use not directed against may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of , and surgical evaluation should be instituted as clinically indicated.
In addition, published observational studies suggest that PPI therapy, may be associated with an increased risk of CDAD, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve.
What are the precautions of PREVPAC?
General
The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. If superinfections occur, PREVPAC should be discontinued and appropriate therapy instituted.
Prescribing PREVPAC either in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
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.
Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has been reported in patients receiving clarithromycin therapy.
Information for Patients
Each dose of PREVPAC contains four pills: one pink and black capsule (PREVACID), two opaque, yellow 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.
PREVPAC may interact with some drugs; therefore patients should be advised to report to their doctor the use of any other medications.
Patients should be counseled that antibacterial drugs including PREVPAC should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When PREVPAC is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by PREVPAC or other antibacterial drugs in the future.
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
Patients should be advised to immediately report and seek care for diarrhea that does not improve. This may be a sign of associated diarrhea (see ).
Patients should be advised to immediately report and seek care for any cardiovascular or neurological symptoms including palpitations, dizziness, seizures, and tetany as these may be signs of hypomagnesemia (see ).
Advise patients to report any symptoms associated with cutaneous or systemic lupus erythematosus (see ).
Advise patients to report to their healthcare provider if they are taking rilpivirine-containing products or high-dose methotrexate (see ).
Laboratory Tests
Periodic assessment of renal, hepatic, and hematopoietic function should be made during prolonged therapy.
Drug Interactions
No drug interaction studies have been conducted specifically with PREVPAC. The following drug interactions are for the individual drug components: PREVACID (lansoprazole), amoxicillin, and clarithromycin. Therefore, the decision to adjust dosage should depend on the clinician's assessment of among other things, the cumulative or net effect of the drug components of PREVPAC.
PREVACID
Tables 5 and 6 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with PREVACID and instructions for preventing or managing them.
Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs.
| Clinical Impact: | The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. |
| Intervention: | |
| Clinical Impact: | Increased INR and prothrombin time in patients receiving PPIs and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. |
| Intervention: | Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin. |
| Clinical Impact: | Concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted (see ). |
| Intervention: | A temporary withdrawal of PREVACID may be considered in some patients receiving high-dose methotrexate. |
| Clinical Impact: | Potential for increased exposure of digoxin. |
| Intervention: | Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin. |
| Clinical Impact: | Increased clearance of theophylline (see ). |
| Intervention: | Individual patients may require additional titration of their theophylline dosage when PREVACID is started or stopped to ensure clinically effective blood concentrations. |
| Clinical Impact: | Lansoprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. |
| Intervention: | Mycophenolate mofetil (MMF): Coadministration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PREVACID and MMF. Use PREVACID with caution in transplant patients receiving MMF.See the prescribing information for other drugs dependent on gastric pH for absorption. |
| Clinical Impact: | Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions. |
| Intervention: | |
| Clinical Impact: | Potentially increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. |
| Intervention: | Monitor tacrolimus whole blood trough concentrations. Dose adjustment of tacrolimus may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. |
| Clinical Impact: | CgA levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors (see ). |
| Intervention: | Temporarily stop PREVACID treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. |
| Clinical Impact: | Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma. |
| Intervention: | Temporarily stop PREVACID treatment at least 28 days before assessing to allow gastrin levels to return to baseline (see ). |
| Clinical Impact: | There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. |
| Intervention: | An alternative confirmatory method should be considered to verify positive results. |
| Clinical Impact: | Decreased exposure of lansoprazole when used concomitantly with strong inducers (see ). |
| Intervention: | |
| Clinical Impact: | Increased exposure of lansoprazole is expected when used concomitantly with strong inhibitors (see ). |
| Intervention: | Voriconazole |
| Clinical Impact: | Decreased and delayed absorption of lansoprazole (see ). |
| Intervention: | Take PREVACID at least 30 minutes prior to sucralfate (see ). |
Amoxicillin
Drug/Laboratory Test Interactions
High urine concentrations of ampicillin may result in false-positive reactions when testing for the presence of glucose in urine using CLINITEST, Benedict's Solution or Fehling's Solution. Since this effect may also occur with amoxicillin, it is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as CLINISTIX) be used.
Following administration of ampicillin or amoxicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted.
Carcinogenesis, Mutagenesis, Impairment of Fertility
PREVACID
In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated with oral lansoprazole at doses of 5 to 150 mg/kg/day, about 0.5 to 20 times the recommended human dose of 60 mg/day, based on body surface area (BSA). Lansoprazole produced dose-related gastric enterochromaffin-like (ECL) cell hyperplasia and ECL cell carcinoids in both male and female rats. The incidences of intestinal metaplasia of the gastric epithelium were also increased in both sexes. In male rats, lansoprazole produced a dose-related increase in the incidence of testicular interstitial cell adenomas at doses two to 20 times the recommended human dose of 60 mg/day based on BSA.
In a 24-month carcinogenicity study, CD-1 mice were treated with oral lansoprazole at doses of 15 to 600 mg/kg/day (one to 40 times the recommended human dose of 60 mg/day based on BSA comparisons). Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. The incidence of liver tumors (hepatocellular adenoma plus carcinoma) was increased in male mice (at doses 20 to 40 times the recommended human dose of 60 mg/day based on BSA) and in female mice (treated at doses ten to 40 times the recommended human dose based on BSA). Lansoprazole treatment produced adenoma of rete testis in male mice receiving doses five to 40 times the recommended human dose of 60 mg/day based on BSA.
A 26 week p53 (+/-) transgenic mouse carcinogenicity study was not positive.
Lansoprazole was positive in the Ames test and the human lymphocyte chromosomal aberration assay. Lansoprazole was not genotoxic in the rat hepatocyte unscheduled DNA synthesis (UDS) test, the mouse micronucleus test, or the rat bone marrow cell chromosomal aberration test.
Lansoprazole at oral doses up to 150 mg/kg/day (20 times the recommended human dose of 60 mg/day based on BSA) 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 to evaluate the mutagenic or carcinogenic potential of amoxicillin alone. A 4:1 mixture of amoxicillin and potassium clavulanate was non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. The amoxicillin/potassium clavulanate mixture was also negative in the mouse micronucleus test, and in the dominant lethal assay in mice, but was weakly positive in the mouse lymphoma assay. In a multi-generation reproduction study in rats, no impairment of fertility or other adverse reproductive effects were seen at doses up to 500 mg/kg, approximately three times the human dose based on BSA comparisons.
Clarithromycin
Salmonella
In Vitro
The following mutagenicity tests have been conducted with clarithromycin:
All tests had negative results except the 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) 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 two times the human serum levels.
In the 150 mg/kg/day monkey studies, plasma levels were three 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), 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, fetal loss occurred at an intravenous dose of 33 mg/m, which is 17 times less than the maximum proposed human oral daily dose of 618 mg/m.
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of clarithromycin.
Pregnancy
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
Lansoprazole and its metabolites are excreted in the milk of rats. It is not known whether lansoprazole is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from PREVPAC, and the potential for tumorigenicity shown for lansoprazole in rat carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue PREVPAC, taking into account the importance of the therapy to the mother.
Penicillins have been shown to be excreted in human milk. Amoxicillin use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxicillin is administered to a nursing woman.
Clarithromycin and its active metabolite 14-hydroxy clarithromycin are excreted in human milk. Serum and milk samples were obtained after three days of treatment, at steady state, from one published study of 12 lactating women who were taking clarithromycin 250 mg orally twice daily. Based on the limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively human milk-fed infant would receive an estimated average of 136 mcg/kg/day of clarithromycin and its active metabolite, with this maternal dosage regimen. This is less than 2% of the maternal weight-adjusted dose (7.8 mg/kg/day, based on the average maternal weight of 64 kg), and less than 1% of the pediatric dose (15 mg/kg/day) for children greater than six months of age.
A prospective observational study of 55 breastfed infants of mothers taking a macrolide antibiotic (six were exposed to clarithromycin) were compared to 36 breastfed infants of mothers taking amoxicillin. Adverse reactions were comparable in both groups. Adverse reactions occurred in 12.7% of infants exposed to macrolides and included rash, diarrhea, loss of appetite, and somnolence.
Caution should be exercised when clarithromycin is administered to nursing women. The development and health benefits of human milk feeding should be considered along with the mother's clinical need for clarithromycin and any potential adverse effects on the human milk-fed child from the drug or from the underlying maternal condition.
Pediatric Use
The safety and effectiveness of PREVPAC in pediatric patients infected with have not been established (see and ).
Geriatric Use
Elderly patients may suffer from asymptomatic renal and hepatic dysfunction. Care should be taken when administering PREVPAC to this patient population.
An analysis of clinical studies of amoxicillin was conducted to determine whether subjects aged 65 and over respond differently from younger subjects. These analyses have not identified differences in responses between the elderly and younger patients, but a greater sensitivity of some older individuals cannot be ruled out.
Amoxicillin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
In a steady-state study in which healthy elderly subjects (age 65 to 81 years old) were given 500 mg of clarithromycin every 12 hours, the maximum serum concentrations and area under the curves of clarithromycin and 14-OH clarithromycin were increased compared to those achieved in healthy young adults. These changes in pharmacokinetics parallel known age-related decreases in renal function. In clinical trials of clarithromycin, elderly patients did not have an increased incidence of adverse events when compared to younger patients. Dosage adjustment should be considered in elderly patients with severe renal impairment. Elderly patients may be more susceptible to development of arrhythmias than younger patients (see and ).
Most reports of acute kidney injury with calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem, nifedipine) involved elderly patients 65 years of age or older (see ).
What are the side effects of PREVPAC?
PREVPAC
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The most common adverse reactions (≥3%) reported in clinical trials when all three components of this therapy were given concomitantly for 14 days are listed in Table 8.
The additional adverse reactions which were reported as possibly or probably related to treatment (less than 3%) in clinical trials when all three components of this therapy were given concomitantly are listed below and divided by body system:
Body as a Whole
Digestive System
Musculoskeletal System
Nervous System
Respiratory System
Skin and Appendages
Urogenital System
There were no statistically significant differences in the frequency of reported adverse events between the 10 and 14 day triple therapy regimens.
| Triple Therapy | ||
|---|---|---|
| Adverse Reaction | n=138(%) | |
| Diarrhea | 7.0 | |
| Headache | 6.0 | |
| Taste Perversion | 5.0 |
PREVACID
The following adverse reactions from the labeling for PREVACID are provided for information:
Worldwide, over 10,000 patients have been treated with PREVACID in Phase 2 or Phase 3 clinical trials involving various dosages and durations of treatment. In general, PREVACID treatment has been well-tolerated in both short-term and long-term trials.
Incidence in Clinical Trials
The following adverse events were reported by the treating physician to have a possible or probable relationship to drug in 1% or more of PREVACID-treated patients and occurred at a greater rate in PREVACID-treated patients than placebo-treated patients:
Headache was also seen at greater than 1% incidence but was more common on placebo. The incidence of diarrhea was similar between patients who received placebo and patients who received 30 mg of PREVACID, but higher in the patients who received 60 mg of PREVACID (2.9%, 4.2%, and 7.4%, respectively).
The most commonly reported possibly or probably treatment-related adverse event during maintenance therapy was diarrhea.
Additional adverse experiences occurring in less than 1% of patients or subjects who received PREVACID in domestic trials are shown below:
Body as a Whole
Cardiovascular System
Digestive System –
Endocrine System
Hemic and Lymphatic System
Metabolism and Nutritional Disorders –
Musculoskeletal System
Nervous System –
Respiratory System
Skin and Appendages
Special Senses –
Urogenital System
| Body System/Adverse Event | PREVACID(N= 2768)% | Placebo(N= 1023)% |
|---|---|---|
| Body as a Whole | ||
| Abdominal Pain | 2.1 | 1.2 |
| Digestive System | ||
| Constipation | 1.0 | 0.4 |
| Diarrhea | 3.8 | 2.3 |
| Nausea | 1.3 | 1.2 |
Postmarketing
Additional adverse experiences have been reported since PREVACID has been marketed. The majority of these cases are foreign-sourced and a relationship to PREVACID has not been established. Because these events were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events are listed below by COSTART body system:
Body as a Whole –
Digestive System –
Hemic and Lymphatic System
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Metabolism and Nutritional Disorders
Musculoskeletal System
Skin and Appendages
Special Senses –
Urogenital System –
Amoxicillin
The following adverse reactions from the labeling for amoxicillin are provided for information:
The most common adverse reactions (>1%) observed in clinical trials of amoxicillin capsules were diarrhea, rash, vomiting and nausea.
The most frequently reported adverse events for patients who received triple therapy (amoxicillin/clarithromycin/lansoprazole) were diarrhea (7%), headache (6%), and taste perversion (5%).
Infections and Infestations – Mucocutaneous candidiasis
Gastrointestinal –
Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment (see ).
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Liver
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Hemic and Lymphatic Systems
Central Nervous System
Miscellaneous
Clarithromycin
The following adverse reactions from the labeling for clarithromycin are provided for information:
The most frequent and common adverse reactions related to clarithromycin therapy for both adult and pediatric populations are abdominal pain, diarrhea, nausea, vomiting, and dysgeusia. These adverse reactions are consistent with the known safety profile of macrolide antibiotics.
There was no significant difference in the incidence of these gastrointestinal adverse reactions during clinical trials between the patient population with or without preexisting mycobacterial infections.
Adverse Reactions Observed During Clinical Trials of Clarithromycin
The following adverse reactions were observed in clinical trials with clarithromycin at a rate greater than or equal to 1%:
Gastrointestinal Disorders
Hepatobiliary Disorders
Immune System Disorders
Infections and Infestations – Candidiasis
Nervous System Disorders –
Psychiatric Disorders
Skin and Subcutaneous Tissue Disorders
Other Adverse Reactions Observed During Clinical Trials of Clarithromycin
The following adverse reactions were observed in clinical trials with clarithromycin at a rate less than 1%:
Blood and Lymphatic System Disorders
Cardiac Disorders
Ear and Labyrinth Disorders –
Gastrointestinal Disorders
General Disorders and Administration Site Conditions –
Hepatobiliary Disorders –
Immune System Disorders
Infections and Infestations
Investigations
Metabolism and Nutrition Disorders
Musculoskeletal and Connective Tissue Disorders
Nervous System Disorders
Psychiatric Disorders
Renal and Urinary Disorders
Respiratory, Thoracic and Mediastinal Disorders
Skin and Subcutaneous Tissue Disorders
The following adverse reactions have been identified during post approval use of clarithromycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and Lymphatic System Disorders
Array
Ear and Labyrinth Disorders
Gastrointestinal Disorders
Array
Immune System Disorders
Infections and Infestations
Investigations
Metabolism and Nutrition Disorders
Array
Nervous System Disorders
Psychiatric Disorders
There are no data on the effect of clarithromycin on the ability to drive or use machines. The potential for dizziness, vertigo, confusion and disorientation, which may occur with the medication, should be taken into account before patients drive or use machines.
Renal and Urinary Disorders
Skin and Subcutaneous Tissue Disorders
Vascular Disorders
There have been reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients (see and ).
Laboratory Values
The following changes in laboratory parameters in patients who received PREVACID were reported as adverse reactions:
Abnormal liver function tests, increased SGOT (AST), increased SGPT (ALT), increased creatinine, increased alkaline phosphatase, increased globulins, increased GGTP, increased/decreased/abnormal WBC, abnormal AG ratio, abnormal RBC, bilirubinemia, blood potassium increased, blood urea increased, crystal urine present, eosinophilia, hemoglobin decreased, hyperlipemia, increased/decreased electrolytes, increased/decreased cholesterol, increased glucocorticoids, increased LDH, increased/decreased/abnormal platelets, increased gastrin levels and positive fecal occult blood. Urine abnormalities such as albuminuria, glycosuria, and hematuria were also reported.
In the placebo-controlled studies, when SGOT (AST) and SGPT (ALT) were evaluated, 0.4% (4/978) and 0.4% (11/2677) patients, who received placebo and PREVACID, respectively, had enzyme elevations greater than three times the upper limit of normal range at the final treatment visit. None of these patients who received PREVACID reported jaundice at any time during the study.
What should I look out for while using PREVPAC?
PREVPAC is contraindicated in patients with known severe hypersensitivity to any component of the formulation of PREVACID. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute interstitial nephritis, and urticaria (see ). Proton Pump Inhibitors (PPIs), including PREVACID, are contraindicated with rilpivirine-containing products (see ).
A history of severe hypersensitivity reactions (e.g., anaphylaxis or Stevens-Johnson Syndrome) to amoxicillin or other beta-lactam antibiotics (e.g., penicillins and cephalosporins) is a contraindication.
Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin, erythromycin, or any of the macrolide antibiotics.
Clarithromycin is contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of clarithromycin.
Clarithromycin should not be given to patients with history of QT prolongation or ventricular cardiac arrhythmia, including .
Concomitant administration of clarithromycin, a component of PREVPAC, and any of the following drugs is contraindicated: cisapride, pimozide, astemizole, terfenadine, ergotamine or dihydroergotamine (see ). There have been postmarketing reports of drug interactions when clarithromycin and/or erythromycin are coadministered with cisapride, pimozide, astemizole, or terfenadine resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and ) most likely due to inhibition of metabolism of these drugs by erythromycin and clarithromycin. Fatalities have been reported.
Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment.
Clarithromycin should not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis (see ).
What might happen if I take too much PREVPAC?
In case of an overdose, patients should contact a physician, poison control center, or emergency room. There is neither a pharmacologic basis nor data suggesting an increased toxicity of the combination compared to individual components.
In the event of over-exposure, treatment should be symptomatic and supportive.
If over-exposure occurs, call your poison control center at 1-800-222-1222 for current information on the management of poisoning or over-exposure.
How should I store and handle PREVPAC?
Store bottles at controlled room temperature, 59° to 86°F (15° to 30°C) and dispense in tight, light-resistant containers (USP).PREVPAC is supplied as an individual daily administration card, each containing:PREVACID Capsules:Amoxicillin Capsules, USP:BIAXIN Filmtab:PREVPAC is supplied as an individual daily administration card, each containing:PREVACID Capsules:Amoxicillin Capsules, USP:BIAXIN Filmtab:PREVPAC is supplied as an individual daily administration card, each containing:PREVACID Capsules:Amoxicillin Capsules, USP:BIAXIN Filmtab:PREVPAC is supplied as an individual daily administration card, each containing:PREVACID Capsules:Amoxicillin Capsules, USP:BIAXIN Filmtab:
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Pharmacokinetics when all three of the PREVPAC components (PREVACID capsules, amoxicillin capsules, clarithromycin tablets) were coadministered has not been studied. Studies have shown no clinically significant interactions of PREVACID and amoxicillin or PREVACID and clarithromycin when administered together. There is no information about the gastric mucosal concentrations of PREVACID, amoxicillin and clarithromycin after administration of these agents concomitantly. The systemic pharmacokinetic information presented below is based on studies in which each product was administered alone.
Non-Clinical Toxicology
PREVPAC is contraindicated in patients with known severe hypersensitivity to any component of the formulation of PREVACID. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute interstitial nephritis, and urticaria (see ). Proton Pump Inhibitors (PPIs), including PREVACID, are contraindicated with rilpivirine-containing products (see ).A history of severe hypersensitivity reactions (e.g., anaphylaxis or Stevens-Johnson Syndrome) to amoxicillin or other beta-lactam antibiotics (e.g., penicillins and cephalosporins) is a contraindication.
Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin, erythromycin, or any of the macrolide antibiotics.
Clarithromycin is contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of clarithromycin.
Clarithromycin should not be given to patients with history of QT prolongation or ventricular cardiac arrhythmia, including .
Concomitant administration of clarithromycin, a component of PREVPAC, and any of the following drugs is contraindicated: cisapride, pimozide, astemizole, terfenadine, ergotamine or dihydroergotamine (see ). There have been postmarketing reports of drug interactions when clarithromycin and/or erythromycin are coadministered with cisapride, pimozide, astemizole, or terfenadine resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and ) most likely due to inhibition of metabolism of these drugs by erythromycin and clarithromycin. Fatalities have been reported.
Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment.
Clarithromycin should not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis (see ).
No drug interaction studies have been conducted specifically with PREVPAC. The following drug interactions are for the individual drug components: PREVACID (lansoprazole), amoxicillin, and clarithromycin. Therefore, the decision to adjust dosage should depend on the clinician's assessment of among other things, the cumulative or net effect of the drug components of PREVPAC.
The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. If superinfections occur, PREVPAC should be discontinued and appropriate therapy instituted.
Prescribing PREVPAC either in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
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.
Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has been reported in patients receiving clarithromycin therapy.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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