Lansoprazole, Amoxicillin and Clarithromycin

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.

PREVACID (lansoprazole) Delayed-Release Capsules

The active ingredient in PREVACID delayed-release capsules is lansoprazole, a proton pump inhibitor. Its empirical formula is C16H14F3N3O2S with a molecular weight of 369.37. PREVACID has the following structure:

Lansoprazole is a white to brownish-white odorless crystalline powder which melts with decomposition at approximately 166°C. Lansoprazole is freely soluble in dimethylformamide; soluble in methanol; sparingly soluble in ethanol; slightly soluble in ethyl acetate, dichloromethane and acetonitrile; very slightly soluble in ether; and practically insoluble in hexane and water.

Each delayed-release capsule contains enteric-coated granules consisting of 30 mg of lansoprazole (active ingredient) and the following inactive ingredients: sugar sphere, sucrose, methacrylic acid copolymer, low substituted hydroxypropyl cellulose, starch, magnesium carbonate, talc, polyethylene glycol, titanium dioxide, polysorbate 80, hydroxypropyl cellulose, colloidal silicon dioxide D&C Red No. 28, FD&C Blue No. 1, and FD&C Red No. 40.

Amoxicillin Capsules, USP

Amoxicillin is a penicillin class antibacterial, with a broad spectrum of bactericidal activity against many gram-positive and gram-negative microorganisms. Chemically it is (2S, 5R, 6R)-6-[(R)-(-)-2-amino-2-(phydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid trihydrate. The molecular formula is C16H19N3O5S • 3H2O and the molecular weight is 419.45. Amoxicillin has the following structure:

Amoxicillin capsules are intended for oral administration.

Each capsule, with yellow opaque cap and body, contains 500 mg amoxicillin trihydrate. Inactive ingredients: Capsule shells -yellow ferric oxide, titanium dioxide, gelatin, black ferric oxide; Capsule contents – cellulose microcrystalline and magnesium stearate.

Meets USP Dissolution Test 2.

BIAXIN Filmtab (Clarithromycin Tablets, USP)

Clarithromycin is a macrolide antimicrobial. Chemically, it is 6-0-methylerythromycin. The molecular formula is C38H69NO13, and the molecular weight is 747.96. Clarithromycin has the following structure:

Clarithromycin is a white to off-white crystalline powder. It is soluble in acetone, slightly soluble in methanol, ethanol, and acetonitrile, and practically insoluble in water.

Each yellow oval film-coated immediate-release tablet contains 500 mg of clarithromycin and the following inactive ingredients: hypromellose, hydroxypropyl cellulose, colloidal silicon dioxide, croscarmellose sodium, D&C Yellow No. 10, magnesium stearate, microcrystalline cellulose, povidone, propylene glycol, sorbic acid, sorbitan monooleate, titanium dioxide, and vanillin.

PREVPAC is supplied as an individual daily administration card, each containing:

PREVACID Capsules

–Two opaque, hard gelatin, black and pink capsules with “TAP” and “PREVACID 30” imprinted on the capsules.

Amoxicillin Capsules, USP

−Four yellow, opaque, hard gelatin 500-mg capsules imprinted with AMOX 500 on one side and GG 849 on the other side.

BIAXIN Filmtab

–Two yellow, oval film-coated 500-mg tablets debossed with the “a” logo on one side and the code “KL” on the other side of the tablets.

NDC 64764-702-01 Carton containing 14 daily administration cards

NDC 64764-702-11 Daily administration card

Store between 20°C and 25°C (68°F and 77°F)[see USP Controlled Room Temperature]. Protect from light and moisture.

Distributed by: Takeda Pharmaceuticals America, Inc.Deerfield, IL 60015, U.S.A. Revised: Mar 2017

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.

Amoxicillin

In case of amoxicillin overdosage, discontinue medication, treat symptomatically and institute supportive measures as needed. If the overdosage is very recent and there is no contraindication, an attempt at emesis or other means of removal of drug from the stomach may be performed. A prospective study of 51 pediatric patients at a poison-control center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms and do not require gastric emptying.2

Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdosage with amoxicillin.

Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin crystalluria. Renal impairment appears to be reversible with cessation of drug administration. High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of amoxicillin. Amoxicillin can be removed from circulation by hemodialysis.

Clarithromycin

Overdosage of clarithromycin can cause gastrointestinal symptoms such as abdominal pain, vomiting, nausea, and diarrhea.

Adverse reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed drug and supportive measures. As with other macrolides, clarithromycin serum concentrations are not expected to be appreciably affected by hemodialysis or peritoneal dialysis.

Prevacid

PREVACID is not removed from the circulation by hemodialysis. In one reported overdose, a patient consumed 600 mg of PREVACID with no adverse reaction. Oral PREVACID doses up to 5000 mg/kg in rats (approximately 650 times the recommended human dose of 60 mg/day based on BSA) and in mice (about 338 times the recommended human dose of 60 mg/day based on BSA) did not produce deaths or any clinical signs.

Pharmacokinetics

Pharmacokinetics when all three of the lansoprazole/amoxicillin/clarithromycin components (lansoprazole capsules, amoxicillin capsules, clarithromycin tablets) were coadministered has not been studied. Studies have shown no clinically significant interactions of lansoprazole and amoxicillin or lansoprazole and clarithromycin when administered together. There is no information about the gastric mucosal concentrations of Lansoprazole, 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.

Absorption

Lansoprazole capsules contain an enteric-coated granule formulation of lansoprazole. Absorption of lansoprazole begins only after the granules leave the stomach. The absorption of lansoprazole is rapid, with the mean Cmax occurring approximately 1.7 hours after oral dosing, and the absolute bioavailability is over 80%. Both the Cmax and AUC are diminished by about 50% to 70% if lansoprazole is given 30 minutes after food, compared to the fasting condition. There is no significant food effect if lansoprazole is given before meals.

Distribution

Lansoprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 0.05 to 5.0 mcg/mL.

Metabolism

Lansoprazole is extensively metabolized in the liver. Two metabolites have been identified in measurable quantities in plasma (the hydroxylated sulfinyl and sulfone derivatives of lansoprazole). These metabolites have very little or no antisecretory activity. Lansoprazole is thought to be transformed into two active species which inhibit acid secretion by blocking the proton pump [(H+,K+)-ATPase enzyme system] at the secretory surface of the gastric parietal cell. The two active species are not present in the systemic circulation. Therefore, the plasma elimination half-life of lansoprazole does not reflect its duration of suppression of gastric acid secretion.

Elimination

Following single-dose oral administration of lansoprazole, virtually no unchanged lansoprazole was excreted in the urine. In one study, after a single oral dose of 14C-lansoprazole, approximately one-third of the administered radiation was excreted in the urine and two-thirds was recovered in the feces. This implies a significant biliary excretion of the lansoprazole metabolites.

Absorption

Amoxicillin is stable in the presence of gastric acid and may be given without regard to meals. It is rapidly absorbed after oral administration. Orally administered doses of 500 mg amoxicillin capsules result in average peak blood levels one to two hours after administration in the range of 5.5 mcg/mL to 7.5 mcg/mL.

Distribution

Amoxicillin diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluid, except when meninges are inflamed. In blood serum, amoxicillin is approximately 20% protein-bound.

Metabolism/Elimination

The elimination half-life of amoxicillin is 61.3 minutes. Detectable serum levels are observed up to eight hours after an orally administered dose of amoxicillin. Approximately 60% of the orally administered dose of amoxicillin is excreted unchanged in the urine within six to eight hours post-dose; its excretion can be delayed by concurrent administration of probenecid.

Absorption

Clarithromycin is rapidly absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability of 250 mg clarithromycin tablets was approximately 50%. For a single 500 mg dose of clarithromycin, food slightly delays the onset of clarithromycin absorption, increasing the peak time from approximately two to 2.5 hours. Food also increases the clarithromycin peak plasma concentration by about 24%, but does not affect the extent of clarithromycin bioavailability. Food does not affect the onset of formation of the antimicrobially active metabolite, 14-OH clarithromycin or its peak plasma concentration but does slightly decrease the extent of metabolite formation, indicated by an 11% decrease in area under the plasma concentration-time curve (AUC). Therefore, clarithromycin tablets may be given without regard to food.

In nonfasting, healthy human subjects (males and females), peak plasma concentrations were attained within two to three hours after oral dosing. Steady-state peak plasma clarithromycin concentrations were attained within three days and were approximately 3 to 4 mcg/mL with a 500 mg dose administered every eight to 12 hours.

Metabolism/Elimination

The elimination half-life of clarithromycin was five to seven hours with 500 mg administered every eight to 12 hours. The nonlinearity of clarithromycin pharmacokinetics is slight at the recommended dose of 500 mg administered every eight to 12 hours. With a 500 mg every eight to 12 hours dosing, the peak steady-state concentration of 14-OH clarithromycin is up to 1 mcg/mL, and its elimination half-life is about seven to nine hours. The steady-state concentration of this metabolite is generally attained within three to four days.

After a 500 mg tablet every 12 hours, the urinary excretion of clarithromycin is approximately 30%. The renal clearance of clarithromycin approximates the normal glomerular filtration rate. The major metabolite found in urine is 14-OH clarithromycin, which accounts for an additional 10% to 15% of the dose with a 500 mg tablet administered every 12 hours.

Steady-state concentrations of clarithromycin and 14-OH clarithromycin observed following administration of 500 mg doses of clarithromycin every 12 hours to adult patients with HIV were similar to those observed in healthy volunteers. In adult HIV-infected patients taking 500-mg doses of clarithromycin every 12 hours, steady-state clarithromycin Cmax values ranged from 2 to 4 mcg/mL.

The steady-state concentrations of clarithromycin in subjects with impaired hepatic function did not differ from those in normal subjects; however, the 14-OH clarithromycin concentrations were lower in the hepatically impaired subjects. The decreased formation of 14-OH clarithromycin was at least partially offset by an increase in renal clearance of clarithromycin in the subjects with impaired hepatic function when compared to healthy subjects.

The pharmacokinetics of clarithromycin was also altered in subjects with impaired renal function (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Clarithromycin and the 14-OH clarithromycin metabolite distribute readily into body tissues and fluids. There are no data available on cerebrospinal fluid penetration. Because of high intercellular concentrations, tissue concentrations are higher than serum concentrations.

Geriatric Use

The clearance of lansoprazole is decreased in the elderly; with elimination half-life increased approximately 50% to 100%. Because the mean half-life in the elderly remains between 1.9 to 2.9 hours, repeated once daily dosing does not result in accumulation of lansoprazole. Peak plasma levels were not increased in the elderly.

Renal Impairment

In patients with severe renal impairment, plasma protein binding decreased by 1.0% to 1.5% after administration of 60 mg of lansoprazole. Patients with renal impairment had a shortened elimination half-life and decreased total AUC (free and bound). The AUC for free lansoprazole in plasma, however, was not related to the degree of renal impairment; and the Cmax and Tmax (time to reach the maximum concentration) were not different than the Cmax and Tmax from subjects with normal renal function (see DOSAGE AND ADMINISTRATION).

Hepatic Impairment

In patients with various degrees of chronic hepatic impairment, the mean plasma half-life of lansoprazole was prolonged from 1.5 hours to 3.2 to 7.2 hours. An increase in the mean AUC of up to 500% was observed at steady state in hepatically-impaired patients compared to healthy subjects. Consider reduction of lansoprazole dosage in patients with severe hepatic impairment.

Gender

In a study comparing 12 male and six female human subjects who received lansoprazole, no gender differences were found in pharmacokinetics and intragastric pH results.

Race

The pooled pharmacokinetic parameters of lansoprazole from twelve U.S. Phase I studies (N=513) were compared to the mean pharmacokinetic parameters from two Asian studies (N=20). The mean AUCs of lansoprazole in Asian subjects were approximately twice those seen in pooled U.S. data; however, the inter-individual variability was high. The Cmax values were comparable.

Pharmacodynamics

Lansoprazole, clarithromycin and/or amoxicillin have been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Clarithromycin pretreatment resistance rates were 9.5% (91/960) by E-test and 11.3% (12/106) by agar dilution in the dual and triple therapy clinical trials (M93-125, M93-130, M93-131, M95-392, and M95-399).

Amoxicillin pretreatment susceptible isolates (≤0.25 mcg /mL) occurred in 97.8% (936/957) and 98.0% (98/100) of the patients in the dual and triple therapy clinical trials by E-test and agar dilution, respectively. Twenty-one of 957 patients (2.2%) by E-test, and two of 100 patients (2.0%) by agar dilution, had amoxicillin pretreatment MICs of greater than 0.25 mcg/mL. One patient on the 14-day triple therapy regimen had an unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of greater than 256 mcg/mL by E-test and the patient was eradicated of H. pylori.

Patients not eradicated of H. pylori following lansoprazole/amoxicillin/clarithromycin triple therapy will likely have clarithromycin resistant H. pylori isolates. Therefore, for those patients who fail therapy, clarithromycin susceptibility testing should be done if possible. Patients with clarithromycin resistant H. pylori should not be treated with lansoprazole/amoxicillin/clarithromycin triple therapy or other regimens which include clarithromycin as the sole antimicrobial agent.

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes

In the dual and triple therapy clinical trials, 82.6% (195/236) of the patients that had pretreatment amoxicillin susceptible MICs (≤0.25 mcg/mL) were eradicated of H. pylori. Of those with pretreatment amoxicillin MICs of greater than 0.25 mcg/mL, three of six had the H. pylori eradicated. A total of 30% (21/70) of the patients failed lansoprazole 30 mg three times daily per amoxicillin 1 g three times daily dual therapy and a total of 12.8% (22/172) of the patients failed the 10- and 14-day triple therapy regimens. Post-treatment susceptibility results were not obtained on 11 of the patients who failed therapy. Nine of the 11 patients with amoxicillin post-treatment MICs that failed the triple therapy regimen also had clarithromycin resistant H. pylori isolates.

Susceptibility Test for Helicobacter pylori

The reference methodology for susceptibility testing of H. pylori is agar dilution MICs. 1 One to three microliters of an inoculum equivalent to a No. 2 McFarland standard (1 × 107-1 × 108 CFU/mL for H. pylori) are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5% aged defibrinated sheep blood (greater than 2 weeks old). The agar dilution plates are incubated at 35°C in a microaerobic environment produced by a gas generating system suitable for Campylobacter species. After three days of incubation, the MICs are recorded as the lowest concentration of antimicrobial agent required to inhibit growth of the organism. The clarithromycin and amoxicillin MIC values should be interpreted according to the following criteria:

Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and ensure the accuracy and precision of supplies and reagents in the assay, and the techniques of the individual performing the test. Standard clarithromycin or amoxicillin powder should provide the following MIC ranges.

After oral administration, lansoprazole was shown to significantly decrease the basal acid output and significantly increase the mean gastric pH and percent of time the gastric pH was greater than three and greater than four. Lansoprazole also significantly reduced meal-stimulated gastric acid output and secretion volume, as well as pentagastrin-stimulated acid output. In patients with hypersecretion of acid, lansoprazole significantly reduced basal and pentagastrin-stimulated gastric acid secretion. Lansoprazole inhibited the normal increases in secretion volume, acidity and acid output induced by insulin.

The intragastric pH results of a five-day, pharmacodynamic, crossover study of 15 mg and 30 mg of once daily lansoprazole are presented in Table 2.

After the initial dose in this study, increased gastric pH was seen within one to two hours with 30 mg of lansoprazole and two to three hours with 15 mg of lansoprazole. After multiple daily dosing, increased gastric pH was seen within the first hour post-dosing with 30 mg of lansoprazole and within one to two hours post-dosing with 15 mg of lansoprazole.

Acid suppression may enhance the effect of antimicrobials in eradicating Helicobacter pylori (H. pylori). The percentage of time gastric pH was elevated above five and six was evaluated in a crossover study of lansoprazole given daily, twice daily and three times daily.

The inhibition of gastric acid secretion as measured by intragastric pH gradually returned to normal over two to four days after multiple doses. There was no indication of rebound gastric acidity.

H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence

Randomized, double-blind clinical studies performed in the U.S. in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within one year) evaluated the efficacy of lansoprazole/amoxicillin/clarithromycin as triple 14-day therapy for the eradication of H. pylori. The triple therapy regimen (lansoprazole 30 mg twice daily/amoxicillin 1 g twice daily/clarithromycin 500 mg twice daily) produced statistically significantly higher eradication rates than lansoprazole plus amoxicillin, lansoprazole plus clarithromycin, and amoxicillin plus clarithromycin dual therapies.

H. pylori eradication was defined as two negative tests (culture and histology) at four to six weeks following the end of treatment.

Triple therapy was shown to be more effective than all possible dual therapy combinations. The combination of lansoprazole plus amoxicillin and clarithromycin as triple therapy was effective in eradicating H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.

A randomized, double-blind clinical study performed in the U.S. in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of lansoprazole triple therapy for ten and 14 days. This study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating H. pylori.

Lansoprazole/amoxicillin/clarithromycin is supplied as an individual daily administration card, each containing:

Lansoprazole Delayed-Release Capsules

Amoxicillin Capsules, USP

Clarithromycin Tablets, USP

Store between 20°C and 25°C (68°F and 77°F)[see USP Controlled Room Temperature]. Protect from light and moisture.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For lansoprazole, amoxicillin, and clarithromycin, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to lansoprazole, amoxicillin, and clarithromycin or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of Prevpac® in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of Prevpac® in the elderly. However, elderly patients are more likely to have kidney or liver problems, which may require caution and an adjustment in the dose for patients receiving lansoprazole, amoxicillin, and clarithromycin.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking lansoprazole, amoxicillin, and clarithromycin, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using lansoprazole, amoxicillin, and clarithromycin with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Alfuzosin
• Amifampridine
• Amisulpride
• Astemizole
• Bepridil
• Cisapride
• Colchicine
• Conivaptan
• Dihydroergotamine
• Dronedarone
• Eletriptan
• Eliglustat
• Eplerenone
• Ergoloid Mesylates
• Ergonovine
• Ergotamine
• Flibanserin
• Fluconazole
• Isavuconazonium Sulfate
• Ivabradine
• Ketoconazole
• Lomitapide
• Lovastatin
• Lurasidone
• Maraviroc
• Mesoridazine
• Methylergonovine
• Methysergide
• Naloxegol
• Nelfinavir
• Nimodipine
• Pimozide
• Piperaquine
• Posaconazole
• Ranolazine
• Rilpivirine
• Saquinavir
• Silodosin
• Simvastatin
• Sparfloxacin
• Terfenadine
• Thioridazine
• Tolvaptan
• Venetoclax
• Ziprasidone

Using lansoprazole, amoxicillin, and clarithromycin with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Ado-Trastuzumab Emtansine
• Afatinib
• Ajmaline
• Alprazolam
• Amiodarone
• Amitriptyline
• Amlodipine
• Amobarbital
• Amprenavir
• Anagrelide
• Apixaban
• Apomorphine
• Aprepitant
• Aprindine
• Aprobarbital
• Aripiprazole
• Aripiprazole Lauroxil
• Arsenic Trioxide
• Artemether
• Asenapine
• Atazanavir
• Atorvastatin
• Avanafil
• Axitinib
• Azithromycin
• Bedaquiline
• Betrixaban
• Bosutinib
• Bretylium
• Brexpiprazole
• Brigatinib
• Bromocriptine
• Buserelin
• Butabarbital
• Butalbital
• Cabazitaxel
• Cabozantinib
• Calcifediol
• Carbamazepine
• Cariprazine
• Ceritinib
• Chloroquine
• Chlorpromazine
• Chlortetracycline
• Cholera Vaccine, Live
• Cilostazol
• Ciprofloxacin
• Citalopram
• Clomipramine
• Clonazepam
• Clopidogrel
• Clozapine
• Cobicistat
• Cobimetinib
• Crizotinib
• Cyclobenzaprine
• Dabigatran Etexilate
• Dabrafenib
• Daclatasvir
• Dasatinib
• Deflazacort
• Degarelix
• Delamanid
• Delavirdine
• Demeclocycline
• Desipramine
• Deslorelin
• Deutetrabenazine
• Dexamethasone
• Digoxin
• Diltiazem
• Disopyramide
• Docetaxel
• Dofetilide
• Dolasetron
• Domperidone
• Donepezil
• Doxepin
• Doxorubicin
• Doxorubicin Hydrochloride Liposome
• Doxycycline
• Droperidol
• Dutasteride
• Ebastine
• Efavirenz
• Enzalutamide
• Eribulin
• Erlotinib
• Erythromycin
• Escitalopram
• Eslicarbazepine Acetate
• Estazolam
• Eszopiclone
• Etravirine
• Everolimus
• Famotidine
• Felbamate
• Felodipine
• Fentanyl
• Fingolimod
• Flecainide
• Fluoxetine
• Fluticasone
• Fosaprepitant
• Foscarnet
• Fosphenytoin
• Galantamine
• Gatifloxacin
• Gefitinib
• Gemifloxacin
• Gonadorelin
• Goserelin
• Granisetron
• Halofantrine
• Haloperidol
• Halothane
• Histrelin
• Hydrocodone
• Hydroquinidine
• Hydroxychloroquine
• Hydroxyzine
• Ibrutinib
• Ibutilide
• Idelalisib
• Ifosfamide
• Iloperidone
• Imipramine
• Irinotecan
• Irinotecan Liposome
• Isoflurane
• Isradipine
• Itraconazole
• Ivacaftor
• Ixabepilone
• Ketoconazole
• Lapatinib
• Ledipasvir
• Letrozole
• Leuprolide
• Levofloxacin
• Levomilnacipran
• Lopinavir
• Lorcainide
• Losartan
• Lumacaftor
• Lumefantrine
• Lymecycline
• Macitentan
• Manidipine
• Meclocycline
• Mefloquine
• Mephobarbital
• Methacycline
• Methadone
• Methohexital
• Methotrexate
• Metronidazole
• Midazolam
• Midostaurin
• Mifepristone
• Minocycline
• Mizolastine
• Modafinil
• Morphine
• Morphine Sulfate Liposome
• Moxifloxacin
• Mycophenolate Mofetil
• Nafarelin
• Nafcillin
• Nelfinavir
• Netupitant
• Nicardipine
• Nifedipine
• Nilotinib
• Nisoldipine
• Norfloxacin
• Nortriptyline
• Octreotide
• Ofloxacin
• Olanzapine
• Olaparib
• Ondansetron
• Ospemifene
• Oxcarbazepine
• Oxycodone
• Oxytetracycline
• Palbociclib
• Paliperidone
• Panobinostat
• Paroxetine
• Pasireotide
• Pazopanib
• Pentamidine
• Pentobarbital
• Perampanel
• Perphenazine
• Phenobarbital
• Phenytoin
• Pimavanserin
• Pipamperone
• Pirmenol
• Pitolisant
• Pixantrone
• Ponatinib
• Probucol
• Procainamide
• Prochlorperazine
• Promethazine
• Propafenone
• Protriptyline
• Quetiapine
• Quinidine
• Quinine
• Reboxetine
• Regorafenib
• Retapamulin
• Ribociclib
• Rifabutin
• Rifapentine
• Riociguat
• Risperidone
• Ritonavir
• Rivaroxaban
• Roflumilast
• Rolitetracycline
• Romidepsin
• Ruxolitinib
• Salmeterol
• Saquinavir
• Secobarbital
• Sertindole
• Sevoflurane
• Sildenafil
• Simeprevir
• Sirolimus
• Sodium Phosphate
• Sodium Phosphate, Dibasic
• Sodium Phosphate, Monobasic
• Solifenacin
• Sonidegib
• Sorafenib
• Sotalol
• Spiramycin
• St John's Wort
• Sulfamethoxazole
• Sulpiride
• Sunitinib
• Suvorexant
• Tacrolimus
• Tadalafil
• Tamoxifen
• Tamsulosin
• Telaprevir
• Telavancin
• Telithromycin
• Temsirolimus
• Tetrabenazine
• Tetracycline
• Thiopental
• Thiotepa
• Ticagrelor
• Tizanidine
• Tolterodine
• Topotecan
• Toremifene
• Trabectedin
• Tramadol
• Trazodone
• Triazolam
• Trimethoprim
• Trimipramine
• Triptorelin
• Valbenazine
• Vandetanib
• Vardenafil
• Velpatasvir
• Vemurafenib
• Venlafaxine
• Verapamil
• Vilanterol
• Vilazodone
• Vinblastine
• Vincristine
• Vincristine Sulfate Liposome
• Vinflunine
• Vinorelbine
• Vismodegib
• Vorapaxar
• Voriconazole
• Vorinostat
• Warfarin
• Zaleplon
• Zidovudine
• Zileuton
• Zolpidem
• Zuclopenthixol

Using lansoprazole, amoxicillin, and clarithromycin with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acenocoumarol
• Alfentanil
• Conjugated Estrogens
• Cyclosporine
• Darunavir
• Delavirdine
• Diazepam
• Dicumarol
• Esterified Estrogens
• Estradiol
• Estriol
• Estrone
• Estropipate
• Ethinyl Estradiol
• Glipizide
• Glyburide
• Hexobarbital
• Indinavir
• Khat
• Levothyroxine
• Linezolid
• Methylprednisolone
• Nevirapine
• Phenprocoumon
• Pravastatin
• Prednisone
• Probenecid
• Repaglinide
• Rifampin
• Tacrolimus
• Tipranavir
• Warfarin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using lansoprazole, amoxicillin, and clarithromycin with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use lansoprazole, amoxicillin, and clarithromycin, or give you special instructions about the use of food, alcohol, or tobacco.

• Cranberry
• food

Other Medical Problems

The presence of other medical problems may affect the use of lansoprazole, amoxicillin, and clarithromycin. Make sure you tell your doctor if you have any other medical problems, especially:

• Allergy to amoxicillin or penicillins or cephalosporins, history of or
• Allergy to clarithromycin, erythromycin, or macrolide antibiotics or
• Allergy to lansoprazole—Should not be used in patients with these conditions.

• Cholestatic jaundice, history of or
• Heart rhythm problems (eg, QT prolongation, torsades de pointes, ventricular arrhythmia), history of or
• Liver disease, history of—Should not be used in patients with a history of these conditions caused by clarithromycin.

• Diarrhea or
• Kidney disease or
• Liver disease or
• Myasthenia gravis (severe muscle weakness) or
• Systemic lupus erythematosus (SLE)—Use with caution. May make these conditions worse.

• Hypokalemia (low potassium in the blood), uncorrected or
• Hypomagnesemia (low magnesium in the blood), uncorrected—Should be corrected first before using lansoprazole, amoxicillin, and clarithromycin.

• Kidney disease, severe—Use is not recommended in patients with this condition.

It is important that your doctor check your progress at regular visits. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it. Blood, urine, and other laboratory tests may be needed to check for unwanted effects. If your condition does not improve, or if it becomes worse, discuss this with your doctor.

Do not use lansoprazole, amoxicillin, and clarithromycin if you are also using astemizole (Hismanal®), atazanavir (Reyataz®), cisapride (Propulsid®), lovastatin (Mevacor®), pimozide (Orap®), simvastatin (Zocor®), terfenadine (Seldane®), or certain ergot medicines (such as dihydroergotamine, ergotamine, D.H.E. 45®, Ergomar®, Ergostat®, or Migranal®). If you have kidney or liver disease, do not take both lansoprazole, amoxicillin, and clarithromycin and colchicine (Colcrys®). Using these medicines together may increase risk for more serious side effects.

lansoprazole, amoxicillin, and clarithromycin may cause serious allergic reactions, including anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Call your doctor right away if you have a rash, itching, fever or chills, hoarseness, sores or ulcers on the skin, trouble breathing, trouble swallowing, or any swelling of your hands, face, mouth, or throat while you are using lansoprazole, amoxicillin, and clarithromycin.

Make sure your doctor knows if you are pregnant or planning to become pregnant. If you become pregnant while using lansoprazole, amoxicillin, and clarithromycin, tell your doctor right away.

Check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, unusual tiredness or weakness, or yellow eyes or skin. These could be symptoms of a serious liver problem.

Contact your doctor right away if you have any changes to your heart rhythm. You might feel dizzy or faint, or you might have a fast, pounding, or uneven heartbeat. Make sure your doctor knows if you or anyone in your family has ever had a heart rhythm problem such as QT prolongation.

Check with your doctor right away if you have a fever, joint pain, skin rash, swelling of the body, feet, or ankles, or unusual weight gain after receiving lansoprazole, amoxicillin, and clarithromycin. These could be symptoms of acute interstitial nephritis.

lansoprazole, amoxicillin, and clarithromycin may cause diarrhea, and in some cases it can be severe. It may occur 2 months or more after you stop taking lansoprazole, amoxicillin, and clarithromycin. Do not take any medicine to treat diarrhea without first checking with your doctor. If you have any questions or if mild diarrhea continues or gets worse, check with your doctor.

Cutaneous or systemic lupus erythematosus may occur or get worse in patients receiving a PPI. Call your doctor right away if you have joint pain or a skin rash on your cheeks or arms that gets worse when exposed to the sun.

Make sure any doctor or dentist who treats you knows that you are using lansoprazole, amoxicillin, and clarithromycin. lansoprazole, amoxicillin, and clarithromycin may affect the results of certain medical tests.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Administer each dose twice per day before eating. Swallow each dosage whole.

Also see individual agents.

3% to 10%:

Central nervous system: Headache (6%), confusion (<3%), dizziness (<3%)

Dermatologic: Dermatological reaction (<3%)

Endocrine & metabolic: Increased thirst (<3%)

Gastrointestinal: Diarrhea (7%), dysgeusia (5%), abdominal pain (<3%), anorectal pruritus (<3%), darkening of stools (<3%), glossitis (<3%), nausea (<3%), oral candidiasis (<3%), stomatitis (<3%), tongue discoloration (<3%), tongue disease (<3%), vomiting (<3%), xerostomia (<3%)

Genitourinary: Vaginitis (<3%), vulvovaginal candidiasis (<3%)

Neuromuscular & skeletal: Myalgia (<3%)

<3% (Limited to important or life-threatening): Hepatotoxicity (idiosyncratic) (Chalasani 2014)

Concerns related to adverse effects:

• Altered cardiac conduction: Macrolides have been associated with rare QTc prolongation and ventricular arrhythmias, including torsade de pointes; use with caution in patients at risk of prolonged cardiac repolarization; avoid use in patients with uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, and patients receiving Class IA (eg, quinidine, procainamide) or Class III (eg, amiodarone, dofetilide, sotalol) antiarrhythmic agents.

• Anaphylactoid/hypersensitivity reactions: Serious and occasionally severe or fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy, especially with a history of beta-lactam hypersensitivity, history of sensitivity to multiple allergens, or previous IgE-mediated reactions (eg, anaphylaxis, angioedema, urticaria). Use with caution in asthmatic patients. Severe acute reactions have (rarely) been reported with clarithromycin, including anaphylaxis, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), and Henoch-Schönlein purpura (IgA vasculitis); discontinue therapy immediately and urgently initiate treatment.

• Clostridium difficile-associated diarrhea (CDAD): Use of proton pump inhibitors (PPIs) may increase risk of CDAD, especially in hospitalized patients; consider CDAD diagnosis in patients with persistent diarrhea that does not improve. Use the lowest dose and shortest duration of PPI therapy appropriate for the condition being treated. Prolonged use of amoxicillin or clarithromycin may result in fungal or bacterial superinfection, including CDAD and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

• Cutaneous and systemic lupus erythematosus: Has been reported as new onset or exacerbation of existing autoimmune disease; most cases were cutaneous lupus erythematosus (CLE), most commonly, subacute CLE (occurring within weeks to years after continuous therapy). Systemic lupus erythematosus (SLE) is less common (typically occurs within days to years after initiating treatment) and occurred primarily in young adults up to the elderly. Discontinue therapy if signs or symptoms of CLE or SLE occur and refer to specialist for evaluation; most patients improve 4 to 12 weeks after discontinuation of esomeprazole.

• Fractures: Increased incidence of osteoporosis-related bone fractures of the hip, spine, or wrist may occur with proton pump inhibitor therapy. Patients on high-dose or long-term therapy (≥1 year) should be monitored. Use the lowest effective dose for the shortest duration of time, use vitamin D and calcium supplementation, and follow appropriate guidelines to reduce risk of fractures in patients at risk.

• Hepatic effects: Elevated liver function tests and hepatitis (hepatocellular, cholestatic) have been reported; usually reversible after discontinuation of clarithromycin. May lead to hepatic failure or death (rarely), especially in the presence of preexisting hepatic disease or concomitant use of hepatotoxic medications. Discontinue use if signs and symptoms of hepatitis occur.

• Hypomagnesemia: Reported rarely, usually with prolonged PPI use of ≥3 months (most cases >1 year of therapy). May be symptomatic or asymptomatic; severe cases may cause tetany, seizures, and cardiac arrhythmias. Consider obtaining serum magnesium concentrations prior to beginning long-term therapy, especially if taking concomitant digoxin, diuretics, or other drugs known to cause hypomagnesemia; and periodically thereafter. Hypomagnesemia may be corrected by magnesium supplementation, although discontinuation of lansoprazole may be necessary; magnesium levels typically return to normal within 1 week of stopping.

• Interstitial nephritis: Acute interstitial nephritis has been observed in patients taking PPIs; may occur at any time during therapy and is generally due to an idiopathic hypersensitivity reaction. Discontinue if acute interstitial nephritis develops.

• Vitamin B12 deficiency: Prolonged treatment (≥2 years) may lead to vitamin B12 malabsorption and subsequent vitamin B12 deficiency. The magnitude of the deficiency is dose-related and the association is stronger in women and those younger in age (< 30 years); prevalence is decreased after discontinuation of therapy (Lam, 2013).

Disease-related concerns:

• Coronary artery disease (CAD): Use clarithromycin with caution in patients with CAD; postmarketing safety trial suggests increased risk of cardiovascular mortality with short-term clarithromycin use (vs placebo) in patients with stable CAD. However, more smokers were randomized to the clarithromycin arm (Jespersen, 2006).

• Gastric malignancy: Relief of symptoms does not preclude the presence of a gastric malignancy.

• Gastrointestinal infection (eg, Salmonella, Campylobacter): Use of PPIs may increase risk of these infections.

• Hepatic impairment: Use lansoprazole with caution in patients with severe hepatic impairment; consider dosage reduction.

• Infectious mononucleosis: A high percentage of patients with infectious mononucleosis have developed rash during amoxicillin therapy; ampicillin-class antibiotics not recommended in these patients.

• Myasthenia gravis: Use clarithromycin with caution in patients with myasthenia gravis; exacerbation of symptoms and new onset of symptoms has occurred.

• Renal impairment: Use with caution in patients with renal impairment.

Concurrent drug therapy issues:

• Clopidogrel: Proton pump inhibitors (PPIs) may diminish the therapeutic effect of clopidogrel, thought to be due to reduced formation of the active metabolite of clopidogrel. The manufacturer of clopidogrel recommends either avoidance of both omeprazole (even when scheduled 12 hours apart) and esomeprazole or use of a PPI with comparatively less effect on the active metabolite of clopidogrel. Of the PPIs, pantoprazole has the lowest degree of CYP2C19 inhibition in vitro (Li 2004) and has been shown to have less effect on conversion of clopidogrel to its active metabolite compared to omeprazole (Angiolillo 2011). In contrast to these warnings, others have recommended the continued use of PPIs, regardless of the degree of inhibition, in patients with a history of GI bleeding or multiple risk factors for GI bleeding who are also receiving clopidogrel since no evidence has established clinically meaningful differences in outcome; however, a clinically-significant interaction cannot be excluded in those who are poor metabolizers of clopidogrel (Abraham 2010; Levine 2011).

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use of clarithromycin may increase risk of torsades de pointes, particularly with concurrent renal/hepatic impairment.

Other warnings/precautions:

• Appropriate use: Helicobacter pylori eradication: Short-term combination therapy (≤7 days) has been associated with a higher incidence of treatment failure. The American College of Gastroenterology recommends 10 to 14 days of therapy (triple or quadruple) for eradication of H. pylori (Chey 2007).