See

Table 3: Clinically Significant Drug Interactions with Naproxen and Esomeprazole Magnesium – Affecting Drugs Co-Administered with VIMOVO and Interactions with Diagnostics
Clinical Impact:	Naproxen Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have increased the risk of serious bleeding compared to the use of either drug alone Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
	Esomeprazole Magnesium Increased INR and prothrombin time in patients treated with PPIs, including esomeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Concomitant use of esomeprazole 40 mg resulted in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [seeClinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of esomeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Monitor patients with concomitant use of VIMOVO with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [seeWarnings and Precautions (5.14)] . Clopidogrel: Avoid concomitant use of clopidogrel with VIMOVO. Consider use of alternative anti-platelet therapy [seeWarnings and Precautions (5.22)].
Aspirin
Clinical Impact:	A pharmacodynamics (PD) study has demonstrated an interaction in which lower dose naproxen (220mg/day or 220mg twice daily) interfered with the antiplatelet effect of low-dose immediate-release aspirin, with the interaction most marked during the washout period of naproxen [seeClinical Pharmacology (12.2.)]. There is reason to expect that the interaction would be present with prescription doses of naproxen or with enteric-coated low-dose aspirin; however, the peak interference with aspirin function may be later than observed in the PD study due to the longer washout period.
	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [seeWarnings and Precautions (5.2)] .
Intervention:	Because there may be an increased risk of cardiovascular events following discontinuation of naproxen due to the interference with the antiplatelet effect of aspirin during the washout period, for patients taking low-dose aspirin for cardioprotection who require intermittent analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics where appropriate.
	Concomitant use of VIMOVO and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [seeWarnings and Precautions (5.12)] . VIMOVO is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of VIMOVO and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of VIMOVO and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted or have impaired renal function, monitor for signs of worsening renal function [seeWarnings and Precautions (5.6)] .
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of VIMOVO with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [seeWarnings and Precautions (5.6)] .
Antiretrovirals
Clinical Impact:	The effect of esomeprazole magnesium on antiretroviral drugs is variable. The clinical importance and mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with esomeprazole magnesium may reduce antiviral effect and promote the development of drug resistance [seeClinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with esomeprazole magnesium may increase toxicity [seeClinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with esomeprazole magnesium.
Intervention:	Rilpivirine-containing p roducts: Concomitant use with VIMOVO is contraindicated [seeContraindications (4)] . A tazanavir: See prescribing information for atazanavir for dosing information. N elfinavir: Avoid concomitant use with VIMOVO. S aquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretro virals: See prescribing information of specific drugs.
Cilostazol
Clinical Impact:	Increased exposure of cilostazol and one of its active metabolites (3,4-dihydro-cilostazol) when coadministered with omeprazole magnesium, the racemate of esomeprazole [seeClinical Pharmacology (12.3)].
Intervention:	Consider reducing the dose of cilostazol to 50 mg twice daily.
Digoxin
Clinical Impact:	Naproxen The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Esomeprazole Magnesium Potential for increased exposure of digoxin [seeClinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations during concomitant use of VIMOVO. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations.
Lithium
Clinical Impact:	NSAIDs have produced elevations of plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of VIMOVO and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Naproxen Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Esomeprazole Magnesium Concomitant use of esomeprazole magnesium with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities [seeWarnings and Precautions (5.27)].
Intervention:	During concomitant use of VIMOVO and methotrexate, monitor patients for methotrexate toxicity. A temporary withdrawal of VIMOVO may be considered in some patients receiving high-dose methotrexate.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:	During concomitant use of VIMOVO and cyclosporine, monitor patients for signs of worsening renal function.
Tacrolimus
Clinical Impact:	Concomitant use of esomeprazole magnesium and tacrolimus may increase exposure of tacrolimus
Intervention:	During concomitant use of VIMOVO and tacrolimus, monitor tacrolimus whole blood concentrations.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [seeWarnings and Precautions (5.2)] .
Intervention:	The concomitant use of VIMOVO with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of VIMOVO and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of VIMOVO and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, mycophenoloate mofetil, ketoconazole)
Clinical Impact:	Esomeprazole magnesium can reduce the absorption of other drugs due to its effect on reducing intragastric acidity
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole, of which esomeprazole magnesium is an enantiomer, 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 esomeprazole and MMF. Use VIMOVO with caution in transplant patients receiving MMF [seeClinical Pharmacology (12.3)] . See the prescribing information for other drugs dependent on gastric pH for absorption.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors [seeWarnings and Precautions (5.26),Clinical Pharmacology (12.2)] .
Intervention:	Temporarily stop VIMOVO 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.
Diazepam
Clinical Impact:	Increased exposure of diazepam [seeClinical Pharmacology (12.3)].
Intervention:	Monitor patients for increased sedation and adjust the dose of diazepam as needed.

and

Table 4: Clinically Significant Interactions with Esomeprazole Magnesium -- Affecting Co- Administered Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of esomeprazole when used concomitantly with strong inducers [seeClinical Pharmacology (12.3)].
Intervention:	St. John's Wort, rifampin: Avoid concomitant use with VIMOVO [seeWarnings and Precautions (5.25)].
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of esomeprazole [seeClinical Pharmacology (12.3)].
Intervention:	V oriconazole: Avoid concomitant use with VIMOVO.

for clinically significant drug interactions and interactions with diagnostics with naproxen and esomeprazole magnesium.

Clinical Impact:

Naproxen

Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have increased the risk of serious bleeding compared to the use of either drug alone
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.

Esomeprazole Magnesium

Increased INR and prothrombin time in patients treated with PPIs, including esomeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Concomitant use of esomeprazole 40 mg resulted in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition
[see
12.3 Pharmacokinetics
Absorption
Naproxen
At steady state following administration of VIMOVO twice daily, peak plasma concentrations of naproxen are reached on average 3 hours following both the morning and the evening dose.
Bioequivalence between VIMOVO and enteric-coated naproxen, based on both area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C_max) of naproxen, has been demonstrated for both the 375 mg and 500 mg doses.
Naproxen is absorbed from the gastrointestinal tract with an
in vivo
bioavailability of 95%.
Steady-state levels of naproxen are reached in 4 to 5 days.
Esomeprazole
Following administration of VIMOVO twice daily, esomeprazole is rapidly absorbed with peak plasma concentration reached within on average, 0.43 to 1.2 hours, following the morning and evening dose on both the first day of administration and at steady state. The peak plasma concentrations of esomeprazole are higher at steady state compared to on first day of dosing of VIMOVO.
Figure 1 represents the pharmacokinetics of naproxen and esomeprazole following administration of VIMOVO 500 mg/20 mg.
Figure 1: Mean plasma concentrations of naproxen and esomeprazole following single dose administration of VIMOVO (500mg/20 mg)
Figure 1
Food Effect
Administration of VIMOVO together with high-fat food in healthy volunteers does not affect the extent of absorption of naproxen but significantly prolongs tmax by 10 hours and decreases peak plasma concentration (C_max) by about 12%.
Administration of VIMOVO together with high-fat food in healthy volunteers delays tmax of esomeprazole by 1 hour and significantly reduces the extent of absorption, resulting in 52% and 75% reductions of area under the plasma concentration versus time curve (AUC) and peak plasma concentration (C_max), respectively.
Administration of VIMOVO 30 minutes before high-fat food intake in healthy volunteers does not affect the extent of absorption of naproxen but delays the absorption by about 4 hours and decreases peak plasma concentration (C_max) by about 17%, but has no significant effect on the rate or extent of esomeprazole absorption compared to administration under fasted conditions
[seeDosage and Administration (2)]
.
Administration of VIMOVO 60 minutes before high-fat food intake in healthy volunteers has no effect on the rate and extent of naproxen absorption; however, increases the esomeprazole AUC by 25% and C_maxby 50% compared to administration under fasted conditions. This increase in esomeprazole Cmax does not raise a safety issue since the approved dosing regimen of esomeprazole at 40 mg QD would result in higher C_max
[seeDosage and Administration (2)]
.
Therefore, VIMOVO should be taken at least 30 minutes before the meal.
Distribution
Naproxen
Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough C_ss36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma
[seeUse in Specific Populations (8.2)]
.
Esomeprazole
The apparent volume of distribution at steady state in healthy subjects is approximately 16L. Esomeprazole is 97% plasma protein bound.
Elimination
Metabolism
Naproxen
Naproxen is extensively metabolized in the liver by the cytochrome P450 system (CYP), CYP2C9 and CYP1A2, to 6-0-desmethyl naproxen. Neither the parent drug nor the metabolites induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites. Consistent with the half- life of naproxen, the area under the plasma concentration time curve increases with repeated dosing of VIMOVO twice daily.
Esomeprazole
Esomeprazole is extensively metabolized in the liver by the CYP enzyme system. The major part of the metabolism of esomeprazole is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxyl- and desmethyl metabolites of esomeprazole. The remaining part is dependent on another specific isoform CYP3A4, responsible for the formation of esomeprazole sulphone, the main metabolite in plasma. The major metabolites of esomeprazole have no effect on gastric acid secretion.
The area under the plasma esomeprazole concentration-time curve increases with repeated administration of VIMOVO. This increase is dose-dependent and results in a non-linear dose- AUC relationship after repeated administration. An increased absorption of esomeprazole with repeated administration of VIMOVO probably also contributes to the time-and dose-dependency.
Excretion
Naproxen
Following administration of VIMOVO twice daily, the mean elimination half-life for naproxen is approximately 15 hours following the evening dose, with no change with repeated dosing.
The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (<1%), 6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal failure, metabolites may accumulate
[seeWarnings and Precautions (5.6)]
.
Esomeprazole
Following administration of VIMOVO twice daily, the mean elimination half-life of esomeprazole is approximately 1 hour following both the morning and evening dose on day 1, with a slightly longer elimination half-life at steady state (1.2-1.5 hours).
Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the feces. Less than 1% of the parent drug is found in the urine.
Specific Populations
Geriatric Patients
There is no specific data on the pharmacokinetics of VIMOVO in patients over age 65.
Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is <1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients
[seeAdverse Reactions (6)
and
Use in Specific Populations (8.5)]
.
The AUC and C_maxvalues of esomeprazole were slightly higher (25% and 18%, respectively) in the elderly as compared to younger subjects at steady state. Dosage adjustment for the esomeprazole component based on age is not necessary.
Male and Female Patients
The AUC and C_maxvalues of esomeprazole were slightly higher (13%) in females than in males at steady state. Dosage adjustment for the esomeprazole component based on gender is not necessary.
Racial or Ethnic Groups
Pharmacokinetic differences due to race have not been studied for naproxen.
Approximately 3% of Caucasians and 15 to 20% of Asians lack a functional CYP2C19 enzyme and are called poor metabolizers. In these individuals the metabolism of esomeprazole is probably mainly catalyzed by CYP3A4. After repeated once-daily administration of 40 mg esomeprazole, the mean area under the plasma concentration-time curve was approximately 100% higher in poor metabolizers than in subjects having a functional CYP2C19 enzyme (extensive metabolizers).
Patients with Renal Impairment
The pharmacokinetics of VIMOVO or naproxen have not been determined in subjects with renal impairment.
Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal impairment. Elimination of naproxen is decreased in patients with severe renal impairment. Naproxen- containing products, including VIMOVO, is not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 ml/min)
[seeDosage and Administration (2),Warnings and Precautions (5.6)
,
Use in Specific Populations (8.7)]
.
No studies have been performed with esomeprazole in patients with decreased renal function. Since the kidney is responsible for the excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function.
Patients with Hepatic Impairment
The pharmacokinetics of VIMOVO or naproxen have not been determined in subjects with hepatic impairment.
In patients with severe hepatic impairment, VIMOVO should be avoided due to increase of risk of NSAID associated bleeding and/or renal failure associated with naproxen.
Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. The implication of this finding for the naproxen component of VIMOVO dosing is unknown but it is prudent to use the lowest effective dose.
The AUCs of esomeprazole in patients with severe hepatic impairment (Child Pugh Class C) have been shown to be 2-3 times higher than in patients with normal liver function. For this reason, it has been recommended that esomeprazole doses not exceed 20 mg daily in patients with severe hepatic impairment. However, there is no dose adjustment necessary for patients with Child Pugh Class A and B for the esomeprazole component of VIMOVO. There is no VIMOVO dosage form that contains less than 20 mg esomeprazole for twice daily dosing
[seeDosage and Administration (2),Warnings and Precautions (5.3)]
.
Drug Interaction Studies
Effect of Naproxen on Other Drugs
Aspirin
: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. SeeTable 3for clinically significant drug interactions of NSAIDs with aspirin
[seeDrug Interactions (7)]
.
Effect of Esomeprazole on Other Drugs
Cytochrome P 450 Interactions
Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4.
In vitro
and
in vivo
studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1 and 3A4. No clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with phenytoin, warfarin, quinidine, clarithromycin or amoxicillin.
Clopidogrel:
Results from a crossover study in healthy subjects have shown a pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg p.o. once daily) when co-administered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 35% to 40% over this time period. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation was related to the change in the exposure to clopidogrel active metabolite
[seeWarnings and Precautions (5.22),Drug Interactions (7)]
.
Mycophenolate Mofetil:
Administration of omeprazole 20 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of omeprazole to 12 healthy subjects in a cross-over study resulted in a 52% reduction in the C_maxand 23% reduction in the AUC of MPA
[seeDrug Interactions (7)].
Cilostazol:
Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased C_maxand AUC of cilostazol by 18% and 26% respectively. C_maxand AUC of one of its active metabolites, 3,4- dihydrocilostazol, which has 4-7 times the activity of cilostazol, were increased by 29% and 69% respectively
[seeDrug Interactions (7)].
Nelfinavir:
Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg once a day), AUC was decreased by 36% and 92%, C_maxby 37% and 89% and C_minby 39% and 75% respectively for nelfinavir and main oxidative metabolite, hydroxy-
t
-butylamide (M8)
[seeDrug Interactions (7)]
.
Atazanavir:
Following multiple doses of atazanavir (400 mg, once a day) and omeprazole (40 mg, once a day, 2 hr before atazanavir), AUC was decreased by 94%, C_maxby 96%, and C_minby 95%
[seeDrug Interactions (7)]
.
Saquinavir:
Elevated serum levels have been reported with an increase in AUC by 82% in C_maxby 75% and in C_minby 106% following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice a day for 15 days with omeprazole 40 mg once a day co-administered on days 11 to 15
[seeDrug Interactions (7)]
.
Diazepam:
Co-administration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam
[seeDrug Interactions (7)].
Digoxin:
Concomitant administration of omeprazole 20 mg once daily and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects)
[seeDrug Interactions (7)].
Effect of Other Drugs on Esomeprazole
Because esomeprazole is metabolized by CYP2C19 and CYP3A4, inducers and inhibitors of these enzymes may potentially alter exposure of esomeprazole.
St. John's Wort
: In a cross-over study in 12 healthy male subjects, St. John's Wort (300 mg three times daily for 14 days) significantly decreased the systemic exposure of omeprazole in CYP2C19 poor metabolizers (C_maxand AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolizers (C_maxand AUC decreased by 49.6% and 43.9%, respectively)
[seeWarnings and Precautions (5.25),Drug Interactions (7)].
Voriconazole:
Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. When voriconazole (400 mg every 12 hours for one day, followed by 200 mg once daily for 6 days) was given with omeprazole (40 mg once daily for 7 days) to healthy subjects, the steady-state C_maxand AUC_0-24of omeprazole significantly increased: an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4), respectively, as compared to when omeprazole was given without voriconazole
[seeDrug Interactions (7)]
.
].
There are no adequate combination studies of a lower dose of esomeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.

Intervention:

Monitor patients with concomitant use of VIMOVO with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding

[see

5.14 Laboratory Monitoring

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and chemistry profile periodically

[seeWarnings and Precautions (5.2,5.3,5.6)].

Patients with initial hemoglobin values of 10 g or less who are to receive long-term therapy should have hemoglobin values determined periodically.

]

Clopidogrel:

Avoid concomitant use of clopidogrel with VIMOVO. Consider use of alternative anti-platelet therapy

[see

5.22 Interaction with Clopidogrel

Avoid concomitant use of esomeprazole with clopidogrel. Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as esomeprazole, that inhibit CYP2C19 activity. Concomitant use of clopidogrel with 40 mg esomeprazole reduces the pharmacological activity of clopidogrel. When using esomeprazole, a component of VIMOVO, consider alternative anti-platelet therapy

[seeDrug Interactions (7),Clinical Pharmacology (12.3)]

Aspirin

Clinical Impact:

A pharmacodynamics (PD) study has demonstrated an interaction in which lower dose naproxen (220mg/day or 220mg twice daily) interfered with the antiplatelet effect of low-dose

immediate-release

aspirin, with the interaction most marked during the washout period of naproxen

[see

12.2 Pharmacodynamics

Interaction with Aspirin

In a healthy volunteer study, 10 days of concomitant administration of naproxen 220 mg once-daily with low-dose immediate-release aspirin (81 mg) showed an interaction with the antiplatelet activity of aspirin as measured by % serum thromboxane B₂inhibition at 24 hours following the day 10 dose [98.7% (aspirin alone) vs 93.1% (naproxen and aspirin)]. The interaction was observed even following discontinuation of naproxen on day 11 (while aspirin dose was continued) but normalized by day 13. In the same study, the interaction was greater when naproxen was administered 30 minutes prior to aspirin [98.7% vs 87.7%] and minimal when aspirin was administered 30 minutes prior to naproxen [98.7% vs 95.4%].

Following administration of naproxen 220 mg twice-daily with low-dose immediate-release aspirin (first naproxen dose given 30 minutes prior to aspirin), the interaction was minimal at 24 h following day 10 dose [98.7% vs 95.7%]. However, the interaction was more prominent after discontinuation of naproxen (washout) on day 11 [98.7% vs 84.3%] and did not normalize completely by day 13 [98.5% vs 90.7%]

[seeDrug Interactions (7)]

Antisecretory Activity

The effect of VIMOVO on intragastric pH was determined in 25 healthy volunteers in one study. Three VIMOVO combinations (naproxen 500 mg combined with either esomeprazole 10, 20, or 30 mg) were administered twice daily over 9 days. The results are shown in the following table:

Table 5: Effect on Intragastric pH on Day 9 (N=25)
	Naproxen 500 mg combined with esomeprazole
	10 mg	20 mg	30 mg
LS Mean (SE)
% Time Gastric pH >4Gastric pH was measured over a 24-hour period	41.1 (3.0)	71.5 (3.0)	76.8 (3.0)
Coefficient of variation	55%	18%	16%

Serum Gastrin Effects

The effect of esomeprazole on serum gastrin concentrations was evaluated in approximately 2,700 patients in clinical trials up to 8 weeks and in over 1,300 patients for up to 6-12 months.

The mean fasting gastrin level increased in a dose-related manner. This increase reached a plateau within two to three months of therapy and returned to baseline levels within four weeks after discontinuation of therapy.

Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum Chromogranin A (CgA) levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop esomeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high.

Enterochromaffin-like (ECL) Cell Effects

In over 1,000 patients treated with esomeprazole (10, 20 or 40 mg/day) up to 6-12 months, the prevalence of ECL cell hyperplasia increased with time and dose. No patient developed ECL cell carcinoids, dysplasia, or neoplasia in the gastric mucosa.

Endocrine Effects

Esomeprazole had no effect on thyroid function when given in oral doses of 20 or 40 mg for 4 weeks. Other effects of esomeprazole on the endocrine system were assessed using omeprazole studies. Omeprazole given in oral doses of 30 or 40 mg for 2 to 4 weeks had no effect on carbohydrate metabolism, circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin or secretin.

Effects on Gastrointestinal Microbial Ecology

Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as

Salmonella

and

Campylobacter

and, in hospitalized patients, possibly also

Clostridium difficile

There is reason to expect that the interaction would be present with prescription doses of naproxen or with

enteric-coated

low-dose aspirin; however, the peak interference with aspirin function may be later than observed in the PD study due to the longer washout period.

Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone

[see

5.2 Gastrointestinal Bleeding, Ulceration, and Perforation

NSAIDs, including naproxen, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

Risk Factors for GI Bleeding, Ulceration, and Perforation

Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events are in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.

Strategies to Minimize the GI Risks in NSAID-treated patients:

Use the lowest effective dosage for the shortest possible duration.
Avoid administration of more than one NSAID at a time.
Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such as patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.
Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue VIMOVO until a serious GI adverse event is ruled out.
In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding
[seeDrug Interactions (7)]
.

NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn's disease) as their condition may be exacerbated.

]

Intervention:

Because there may be an increased risk of cardiovascular events following discontinuation of naproxen due to the interference with the antiplatelet effect of aspirin during the washout period, for patients taking low-dose aspirin for cardioprotection who require intermittent analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics where appropriate.

Concomitant use of VIMOVO and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding

[see

5.12 Hematologic Toxicity

Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with VIMOVO has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including VIMOVO, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin and other anticoagulants, antiplatelet agents (e.g., aspirin), and serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase the risk. Monitor these patients for signs of bleeding

[seeDrug Interactions (7)]

]

.

VIMOVO is not a substitute for low dose aspirin for cardiovascular protection.

ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers

Clinical Impact:

NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.

Intervention:

During concomitant use of VIMOVO and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
During concomitant use of VIMOVO and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted or have impaired renal function, monitor for signs of worsening renal function
[see
5.6 Renal Toxicity and Hyperkalemia
Renal Toxicity
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE-inhibitors or ARBs, and the elderly.
Discontinuation of NSAID therapy was usually followed by recovery to the pretreatment state.
No information is available from controlled clinical studies regarding the use of VIMOVO in patients with advanced renal disease. The renal effects of VIMOVO may hasten the progression of renal dysfunction in patients with pre-existing renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating VIMOVO. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of VIMOVO
[seeDrug Interactions (7)].
Avoid the use of VIMOVO in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal failure. If VIMOVO is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.
Hyperkalemia
Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.
]
.

Diuretics

Clinical Impact:

Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.

Intervention:

During concomitant use of VIMOVO with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects

[see

5.6 Renal Toxicity and Hyperkalemia

Renal Toxicity

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE-inhibitors or ARBs, and the elderly.

Discontinuation of NSAID therapy was usually followed by recovery to the pretreatment state.

No information is available from controlled clinical studies regarding the use of VIMOVO in patients with advanced renal disease. The renal effects of VIMOVO may hasten the progression of renal dysfunction in patients with pre-existing renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating VIMOVO. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of VIMOVO

[seeDrug Interactions (7)].

Avoid the use of VIMOVO in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal failure. If VIMOVO is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.

Hyperkalemia

Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.

]

Antiretrovirals

Clinical Impact:

The effect of esomeprazole magnesium on antiretroviral drugs is variable. The clinical importance and mechanisms behind these interactions are not always known.

Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with esomeprazole magnesium may reduce antiviral effect and promote the development of drug resistance
[see
12.3 Pharmacokinetics
Absorption
Naproxen
At steady state following administration of VIMOVO twice daily, peak plasma concentrations of naproxen are reached on average 3 hours following both the morning and the evening dose.
Bioequivalence between VIMOVO and enteric-coated naproxen, based on both area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C_max) of naproxen, has been demonstrated for both the 375 mg and 500 mg doses.
Naproxen is absorbed from the gastrointestinal tract with an
in vivo
bioavailability of 95%.
Steady-state levels of naproxen are reached in 4 to 5 days.
Esomeprazole
Following administration of VIMOVO twice daily, esomeprazole is rapidly absorbed with peak plasma concentration reached within on average, 0.43 to 1.2 hours, following the morning and evening dose on both the first day of administration and at steady state. The peak plasma concentrations of esomeprazole are higher at steady state compared to on first day of dosing of VIMOVO.
Figure 1 represents the pharmacokinetics of naproxen and esomeprazole following administration of VIMOVO 500 mg/20 mg.
Figure 1: Mean plasma concentrations of naproxen and esomeprazole following single dose administration of VIMOVO (500mg/20 mg)
Figure 1
Food Effect
Administration of VIMOVO together with high-fat food in healthy volunteers does not affect the extent of absorption of naproxen but significantly prolongs tmax by 10 hours and decreases peak plasma concentration (C_max) by about 12%.
Administration of VIMOVO together with high-fat food in healthy volunteers delays tmax of esomeprazole by 1 hour and significantly reduces the extent of absorption, resulting in 52% and 75% reductions of area under the plasma concentration versus time curve (AUC) and peak plasma concentration (C_max), respectively.
Administration of VIMOVO 30 minutes before high-fat food intake in healthy volunteers does not affect the extent of absorption of naproxen but delays the absorption by about 4 hours and decreases peak plasma concentration (C_max) by about 17%, but has no significant effect on the rate or extent of esomeprazole absorption compared to administration under fasted conditions
[seeDosage and Administration (2)]
.
Administration of VIMOVO 60 minutes before high-fat food intake in healthy volunteers has no effect on the rate and extent of naproxen absorption; however, increases the esomeprazole AUC by 25% and C_maxby 50% compared to administration under fasted conditions. This increase in esomeprazole Cmax does not raise a safety issue since the approved dosing regimen of esomeprazole at 40 mg QD would result in higher C_max
[seeDosage and Administration (2)]
.
Therefore, VIMOVO should be taken at least 30 minutes before the meal.
Distribution
Naproxen
Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough C_ss36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma
[seeUse in Specific Populations (8.2)]
.
Esomeprazole
The apparent volume of distribution at steady state in healthy subjects is approximately 16L. Esomeprazole is 97% plasma protein bound.
Elimination
Metabolism
Naproxen
Naproxen is extensively metabolized in the liver by the cytochrome P450 system (CYP), CYP2C9 and CYP1A2, to 6-0-desmethyl naproxen. Neither the parent drug nor the metabolites induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites. Consistent with the half- life of naproxen, the area under the plasma concentration time curve increases with repeated dosing of VIMOVO twice daily.
Esomeprazole
Esomeprazole is extensively metabolized in the liver by the CYP enzyme system. The major part of the metabolism of esomeprazole is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxyl- and desmethyl metabolites of esomeprazole. The remaining part is dependent on another specific isoform CYP3A4, responsible for the formation of esomeprazole sulphone, the main metabolite in plasma. The major metabolites of esomeprazole have no effect on gastric acid secretion.
The area under the plasma esomeprazole concentration-time curve increases with repeated administration of VIMOVO. This increase is dose-dependent and results in a non-linear dose- AUC relationship after repeated administration. An increased absorption of esomeprazole with repeated administration of VIMOVO probably also contributes to the time-and dose-dependency.
Excretion
Naproxen
Following administration of VIMOVO twice daily, the mean elimination half-life for naproxen is approximately 15 hours following the evening dose, with no change with repeated dosing.
The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (<1%), 6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal failure, metabolites may accumulate
[seeWarnings and Precautions (5.6)]
.
Esomeprazole
Following administration of VIMOVO twice daily, the mean elimination half-life of esomeprazole is approximately 1 hour following both the morning and evening dose on day 1, with a slightly longer elimination half-life at steady state (1.2-1.5 hours).
Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the feces. Less than 1% of the parent drug is found in the urine.
Specific Populations
Geriatric Patients
There is no specific data on the pharmacokinetics of VIMOVO in patients over age 65.
Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is <1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients
[seeAdverse Reactions (6)
and
Use in Specific Populations (8.5)]
.
The AUC and C_maxvalues of esomeprazole were slightly higher (25% and 18%, respectively) in the elderly as compared to younger subjects at steady state. Dosage adjustment for the esomeprazole component based on age is not necessary.
Male and Female Patients
The AUC and C_maxvalues of esomeprazole were slightly higher (13%) in females than in males at steady state. Dosage adjustment for the esomeprazole component based on gender is not necessary.
Racial or Ethnic Groups
Pharmacokinetic differences due to race have not been studied for naproxen.
Approximately 3% of Caucasians and 15 to 20% of Asians lack a functional CYP2C19 enzyme and are called poor metabolizers. In these individuals the metabolism of esomeprazole is probably mainly catalyzed by CYP3A4. After repeated once-daily administration of 40 mg esomeprazole, the mean area under the plasma concentration-time curve was approximately 100% higher in poor metabolizers than in subjects having a functional CYP2C19 enzyme (extensive metabolizers).
Patients with Renal Impairment
The pharmacokinetics of VIMOVO or naproxen have not been determined in subjects with renal impairment.
Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal impairment. Elimination of naproxen is decreased in patients with severe renal impairment. Naproxen- containing products, including VIMOVO, is not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 ml/min)
[seeDosage and Administration (2),Warnings and Precautions (5.6)
,
Use in Specific Populations (8.7)]
.
No studies have been performed with esomeprazole in patients with decreased renal function. Since the kidney is responsible for the excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function.
Patients with Hepatic Impairment
The pharmacokinetics of VIMOVO or naproxen have not been determined in subjects with hepatic impairment.
In patients with severe hepatic impairment, VIMOVO should be avoided due to increase of risk of NSAID associated bleeding and/or renal failure associated with naproxen.
Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. The implication of this finding for the naproxen component of VIMOVO dosing is unknown but it is prudent to use the lowest effective dose.
The AUCs of esomeprazole in patients with severe hepatic impairment (Child Pugh Class C) have been shown to be 2-3 times higher than in patients with normal liver function. For this reason, it has been recommended that esomeprazole doses not exceed 20 mg daily in patients with severe hepatic impairment. However, there is no dose adjustment necessary for patients with Child Pugh Class A and B for the esomeprazole component of VIMOVO. There is no VIMOVO dosage form that contains less than 20 mg esomeprazole for twice daily dosing
[seeDosage and Administration (2),Warnings and Precautions (5.3)]
.
Drug Interaction Studies
Effect of Naproxen on Other Drugs
Aspirin
: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. SeeTable 3for clinically significant drug interactions of NSAIDs with aspirin
[seeDrug Interactions (7)]
.
Effect of Esomeprazole on Other Drugs
Cytochrome P 450 Interactions
Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4.
In vitro
and
in vivo
studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1 and 3A4. No clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with phenytoin, warfarin, quinidine, clarithromycin or amoxicillin.
Clopidogrel:
Results from a crossover study in healthy subjects have shown a pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg p.o. once daily) when co-administered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 35% to 40% over this time period. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation was related to the change in the exposure to clopidogrel active metabolite
[seeWarnings and Precautions (5.22),Drug Interactions (7)]
.
Mycophenolate Mofetil:
Administration of omeprazole 20 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of omeprazole to 12 healthy subjects in a cross-over study resulted in a 52% reduction in the C_maxand 23% reduction in the AUC of MPA
[seeDrug Interactions (7)].
Cilostazol:
Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased C_maxand AUC of cilostazol by 18% and 26% respectively. C_maxand AUC of one of its active metabolites, 3,4- dihydrocilostazol, which has 4-7 times the activity of cilostazol, were increased by 29% and 69% respectively
[seeDrug Interactions (7)].
Nelfinavir:
Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg once a day), AUC was decreased by 36% and 92%, C_maxby 37% and 89% and C_minby 39% and 75% respectively for nelfinavir and main oxidative metabolite, hydroxy-
t
-butylamide (M8)
[seeDrug Interactions (7)]
.
Atazanavir:
Following multiple doses of atazanavir (400 mg, once a day) and omeprazole (40 mg, once a day, 2 hr before atazanavir), AUC was decreased by 94%, C_maxby 96%, and C_minby 95%
[seeDrug Interactions (7)]
.
Saquinavir:
Elevated serum levels have been reported with an increase in AUC by 82% in C_maxby 75% and in C_minby 106% following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice a day for 15 days with omeprazole 40 mg once a day co-administered on days 11 to 15
[seeDrug Interactions (7)]
.
Diazepam:
Co-administration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam
[seeDrug Interactions (7)].
Digoxin:
Concomitant administration of omeprazole 20 mg once daily and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects)
[seeDrug Interactions (7)].
Effect of Other Drugs on Esomeprazole
Because esomeprazole is metabolized by CYP2C19 and CYP3A4, inducers and inhibitors of these enzymes may potentially alter exposure of esomeprazole.
St. John's Wort
: In a cross-over study in 12 healthy male subjects, St. John's Wort (300 mg three times daily for 14 days) significantly decreased the systemic exposure of omeprazole in CYP2C19 poor metabolizers (C_maxand AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolizers (C_maxand AUC decreased by 49.6% and 43.9%, respectively)
[seeWarnings and Precautions (5.25),Drug Interactions (7)].
Voriconazole:
Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. When voriconazole (400 mg every 12 hours for one day, followed by 200 mg once daily for 6 days) was given with omeprazole (40 mg once daily for 7 days) to healthy subjects, the steady-state C_maxand AUC_0-24of omeprazole significantly increased: an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4), respectively, as compared to when omeprazole was given without voriconazole
[seeDrug Interactions (7)]
.
].
Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with esomeprazole magnesium may increase toxicity
[see
12.3 Pharmacokinetics
Absorption
Naproxen
At steady state following administration of VIMOVO twice daily, peak plasma concentrations of naproxen are reached on average 3 hours following both the morning and the evening dose.
Bioequivalence between VIMOVO and enteric-coated naproxen, based on both area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C_max) of naproxen, has been demonstrated for both the 375 mg and 500 mg doses.
Naproxen is absorbed from the gastrointestinal tract with an
in vivo
bioavailability of 95%.
Steady-state levels of naproxen are reached in 4 to 5 days.
Esomeprazole
Following administration of VIMOVO twice daily, esomeprazole is rapidly absorbed with peak plasma concentration reached within on average, 0.43 to 1.2 hours, following the morning and evening dose on both the first day of administration and at steady state. The peak plasma concentrations of esomeprazole are higher at steady state compared to on first day of dosing of VIMOVO.
Figure 1 represents the pharmacokinetics of naproxen and esomeprazole following administration of VIMOVO 500 mg/20 mg.
Figure 1: Mean plasma concentrations of naproxen and esomeprazole following single dose administration of VIMOVO (500mg/20 mg)
Figure 1
Food Effect
Administration of VIMOVO together with high-fat food in healthy volunteers does not affect the extent of absorption of naproxen but significantly prolongs tmax by 10 hours and decreases peak plasma concentration (C_max) by about 12%.
Administration of VIMOVO together with high-fat food in healthy volunteers delays tmax of esomeprazole by 1 hour and significantly reduces the extent of absorption, resulting in 52% and 75% reductions of area under the plasma concentration versus time curve (AUC) and peak plasma concentration (C_max), respectively.
Administration of VIMOVO 30 minutes before high-fat food intake in healthy volunteers does not affect the extent of absorption of naproxen but delays the absorption by about 4 hours and decreases peak plasma concentration (C_max) by about 17%, but has no significant effect on the rate or extent of esomeprazole absorption compared to administration under fasted conditions
[seeDosage and Administration (2)]
.
Administration of VIMOVO 60 minutes before high-fat food intake in healthy volunteers has no effect on the rate and extent of naproxen absorption; however, increases the esomeprazole AUC by 25% and C_maxby 50% compared to administration under fasted conditions. This increase in esomeprazole Cmax does not raise a safety issue since the approved dosing regimen of esomeprazole at 40 mg QD would result in higher C_max
[seeDosage and Administration (2)]
.
Therefore, VIMOVO should be taken at least 30 minutes before the meal.
Distribution
Naproxen
Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough C_ss36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma
[seeUse in Specific Populations (8.2)]
.
Esomeprazole
The apparent volume of distribution at steady state in healthy subjects is approximately 16L. Esomeprazole is 97% plasma protein bound.
Elimination
Metabolism
Naproxen
Naproxen is extensively metabolized in the liver by the cytochrome P450 system (CYP), CYP2C9 and CYP1A2, to 6-0-desmethyl naproxen. Neither the parent drug nor the metabolites induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites. Consistent with the half- life of naproxen, the area under the plasma concentration time curve increases with repeated dosing of VIMOVO twice daily.
Esomeprazole
Esomeprazole is extensively metabolized in the liver by the CYP enzyme system. The major part of the metabolism of esomeprazole is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxyl- and desmethyl metabolites of esomeprazole. The remaining part is dependent on another specific isoform CYP3A4, responsible for the formation of esomeprazole sulphone, the main metabolite in plasma. The major metabolites of esomeprazole have no effect on gastric acid secretion.
The area under the plasma esomeprazole concentration-time curve increases with repeated administration of VIMOVO. This increase is dose-dependent and results in a non-linear dose- AUC relationship after repeated administration. An increased absorption of esomeprazole with repeated administration of VIMOVO probably also contributes to the time-and dose-dependency.
Excretion
Naproxen
Following administration of VIMOVO twice daily, the mean elimination half-life for naproxen is approximately 15 hours following the evening dose, with no change with repeated dosing.
The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (<1%), 6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal failure, metabolites may accumulate
[seeWarnings and Precautions (5.6)]
.
Esomeprazole
Following administration of VIMOVO twice daily, the mean elimination half-life of esomeprazole is approximately 1 hour following both the morning and evening dose on day 1, with a slightly longer elimination half-life at steady state (1.2-1.5 hours).
Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the feces. Less than 1% of the parent drug is found in the urine.
Specific Populations
Geriatric Patients
There is no specific data on the pharmacokinetics of VIMOVO in patients over age 65.
Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is <1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients
[seeAdverse Reactions (6)
and
Use in Specific Populations (8.5)]
.
The AUC and C_maxvalues of esomeprazole were slightly higher (25% and 18%, respectively) in the elderly as compared to younger subjects at steady state. Dosage adjustment for the esomeprazole component based on age is not necessary.
Male and Female Patients
The AUC and C_maxvalues of esomeprazole were slightly higher (13%) in females than in males at steady state. Dosage adjustment for the esomeprazole component based on gender is not necessary.
Racial or Ethnic Groups
Pharmacokinetic differences due to race have not been studied for naproxen.
Approximately 3% of Caucasians and 15 to 20% of Asians lack a functional CYP2C19 enzyme and are called poor metabolizers. In these individuals the metabolism of esomeprazole is probably mainly catalyzed by CYP3A4. After repeated once-daily administration of 40 mg esomeprazole, the mean area under the plasma concentration-time curve was approximately 100% higher in poor metabolizers than in subjects having a functional CYP2C19 enzyme (extensive metabolizers).
Patients with Renal Impairment
The pharmacokinetics of VIMOVO or naproxen have not been determined in subjects with renal impairment.
Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal impairment. Elimination of naproxen is decreased in patients with severe renal impairment. Naproxen- containing products, including VIMOVO, is not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 ml/min)
[seeDosage and Administration (2),Warnings and Precautions (5.6)
,
Use in Specific Populations (8.7)]
.
No studies have been performed with esomeprazole in patients with decreased renal function. Since the kidney is responsible for the excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function.
Patients with Hepatic Impairment
The pharmacokinetics of VIMOVO or naproxen have not been determined in subjects with hepatic impairment.
In patients with severe hepatic impairment, VIMOVO should be avoided due to increase of risk of NSAID associated bleeding and/or renal failure associated with naproxen.
Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. The implication of this finding for the naproxen component of VIMOVO dosing is unknown but it is prudent to use the lowest effective dose.
The AUCs of esomeprazole in patients with severe hepatic impairment (Child Pugh Class C) have been shown to be 2-3 times higher than in patients with normal liver function. For this reason, it has been recommended that esomeprazole doses not exceed 20 mg daily in patients with severe hepatic impairment. However, there is no dose adjustment necessary for patients with Child Pugh Class A and B for the esomeprazole component of VIMOVO. There is no VIMOVO dosage form that contains less than 20 mg esomeprazole for twice daily dosing
[seeDosage and Administration (2),Warnings and Precautions (5.3)]
.
Drug Interaction Studies
Effect of Naproxen on Other Drugs
Aspirin
: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. SeeTable 3for clinically significant drug interactions of NSAIDs with aspirin
[seeDrug Interactions (7)]
.
Effect of Esomeprazole on Other Drugs
Cytochrome P 450 Interactions
Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4.
In vitro
and
in vivo
studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1 and 3A4. No clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with phenytoin, warfarin, quinidine, clarithromycin or amoxicillin.
Clopidogrel:
Results from a crossover study in healthy subjects have shown a pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg p.o. once daily) when co-administered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 35% to 40% over this time period. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation was related to the change in the exposure to clopidogrel active metabolite
[seeWarnings and Precautions (5.22),Drug Interactions (7)]
.
Mycophenolate Mofetil:
Administration of omeprazole 20 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of omeprazole to 12 healthy subjects in a cross-over study resulted in a 52% reduction in the C_maxand 23% reduction in the AUC of MPA
[seeDrug Interactions (7)].
Cilostazol:
Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased C_maxand AUC of cilostazol by 18% and 26% respectively. C_maxand AUC of one of its active metabolites, 3,4- dihydrocilostazol, which has 4-7 times the activity of cilostazol, were increased by 29% and 69% respectively
[seeDrug Interactions (7)].
Nelfinavir:
Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg once a day), AUC was decreased by 36% and 92%, C_maxby 37% and 89% and C_minby 39% and 75% respectively for nelfinavir and main oxidative metabolite, hydroxy-
t
-butylamide (M8)
[seeDrug Interactions (7)]
.
Atazanavir:
Following multiple doses of atazanavir (400 mg, once a day) and omeprazole (40 mg, once a day, 2 hr before atazanavir), AUC was decreased by 94%, C_maxby 96%, and C_minby 95%
[seeDrug Interactions (7)]
.
Saquinavir:
Elevated serum levels have been reported with an increase in AUC by 82% in C_maxby 75% and in C_minby 106% following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice a day for 15 days with omeprazole 40 mg once a day co-administered on days 11 to 15
[seeDrug Interactions (7)]
.
Diazepam:
Co-administration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam
[seeDrug Interactions (7)].
Digoxin:
Concomitant administration of omeprazole 20 mg once daily and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects)
[seeDrug Interactions (7)].
Effect of Other Drugs on Esomeprazole
Because esomeprazole is metabolized by CYP2C19 and CYP3A4, inducers and inhibitors of these enzymes may potentially alter exposure of esomeprazole.
St. John's Wort
: In a cross-over study in 12 healthy male subjects, St. John's Wort (300 mg three times daily for 14 days) significantly decreased the systemic exposure of omeprazole in CYP2C19 poor metabolizers (C_maxand AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolizers (C_maxand AUC decreased by 49.6% and 43.9%, respectively)
[seeWarnings and Precautions (5.25),Drug Interactions (7)].
Voriconazole:
Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. When voriconazole (400 mg every 12 hours for one day, followed by 200 mg once daily for 6 days) was given with omeprazole (40 mg once daily for 7 days) to healthy subjects, the steady-state C_maxand AUC_0-24of omeprazole significantly increased: an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4), respectively, as compared to when omeprazole was given without voriconazole
[seeDrug Interactions (7)]
.
].
There are other antiretroviral drugs which do not result in clinically relevant interactions with esomeprazole magnesium.

Intervention:

Rilpivirine-containing p

roducts: Concomitant use with VIMOVO is contraindicated

[see

4 CONTRAINDICATIONS

VIMOVO is contraindicated in the following patients:

Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to naproxen, esomeprazole magnesium, substituted benzimidazoles, or to any components of the drug product, including omeprazole. Hypersensitivity reactions to esomeprazole may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria
[seeWarnings and Precautions (5.7,5.8,5.9,5.18),Adverse Reactions (6.2)]
.
History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients
[seeWarnings and Precautions (5.7,5.8)]
.
In the setting of coronary artery bypass graft (CABG) surgery
[seeWarnings and Precautions (5.1)]
.
Proton pump inhibitors (PPIs), including esomeprazole magnesium, are contraindicated in patients receiving rilpivirine-containing products
[seeDrug Interactions (7)]
.

Known hypersensitivity to naproxen, esomeprazole magnesium, substituted benzimidazoles, or to any components of the drug product including omeprazole. (4)
History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. (4)
In the setting of coronary artery bypass graft (CABG) surgery. (4)
In patients receiving rilpivirine-containing products. (4,7)

]

tazanavir: See prescribing information for atazanavir for dosing information.

elfinavir: Avoid concomitant use with VIMOVO.

aquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.

Other antiretro

virals: See prescribing information of specific drugs.

Cilostazol

Clinical Impact:

Increased exposure of cilostazol and one of its active metabolites (3,4-dihydro-cilostazol) when coadministered with omeprazole magnesium, the racemate of esomeprazole

[see

12.3 Pharmacokinetics

Absorption

Naproxen

At steady state following administration of VIMOVO twice daily, peak plasma concentrations of naproxen are reached on average 3 hours following both the morning and the evening dose.

Bioequivalence between VIMOVO and enteric-coated naproxen, based on both area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C_max) of naproxen, has been demonstrated for both the 375 mg and 500 mg doses.

Naproxen is absorbed from the gastrointestinal tract with an

in vivo

bioavailability of 95%.

Steady-state levels of naproxen are reached in 4 to 5 days.

Esomeprazole

Following administration of VIMOVO twice daily, esomeprazole is rapidly absorbed with peak plasma concentration reached within on average, 0.43 to 1.2 hours, following the morning and evening dose on both the first day of administration and at steady state. The peak plasma concentrations of esomeprazole are higher at steady state compared to on first day of dosing of VIMOVO.

Figure 1 represents the pharmacokinetics of naproxen and esomeprazole following administration of VIMOVO 500 mg/20 mg.

Figure 1: Mean plasma concentrations of naproxen and esomeprazole following single dose administration of VIMOVO (500mg/20 mg)

Referenced Image

Food Effect

Administration of VIMOVO together with high-fat food in healthy volunteers does not affect the extent of absorption of naproxen but significantly prolongs tmax by 10 hours and decreases peak plasma concentration (C_max) by about 12%.

Administration of VIMOVO together with high-fat food in healthy volunteers delays tmax of esomeprazole by 1 hour and significantly reduces the extent of absorption, resulting in 52% and 75% reductions of area under the plasma concentration versus time curve (AUC) and peak plasma concentration (C_max), respectively.

Administration of VIMOVO 30 minutes before high-fat food intake in healthy volunteers does not affect the extent of absorption of naproxen but delays the absorption by about 4 hours and decreases peak plasma concentration (C_max) by about 17%, but has no significant effect on the rate or extent of esomeprazole absorption compared to administration under fasted conditions

[seeDosage and Administration (2)]

Administration of VIMOVO 60 minutes before high-fat food intake in healthy volunteers has no effect on the rate and extent of naproxen absorption; however, increases the esomeprazole AUC by 25% and C_maxby 50% compared to administration under fasted conditions. This increase in esomeprazole Cmax does not raise a safety issue since the approved dosing regimen of esomeprazole at 40 mg QD would result in higher C_max

[seeDosage and Administration (2)]

Therefore, VIMOVO should be taken at least 30 minutes before the meal.

Distribution

Naproxen

Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough C_ss36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma

[seeUse in Specific Populations (8.2)]

Esomeprazole

The apparent volume of distribution at steady state in healthy subjects is approximately 16L. Esomeprazole is 97% plasma protein bound.

Elimination

Metabolism

Naproxen

Naproxen is extensively metabolized in the liver by the cytochrome P450 system (CYP), CYP2C9 and CYP1A2, to 6-0-desmethyl naproxen. Neither the parent drug nor the metabolites induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites. Consistent with the half- life of naproxen, the area under the plasma concentration time curve increases with repeated dosing of VIMOVO twice daily.

Esomeprazole

Esomeprazole is extensively metabolized in the liver by the CYP enzyme system. The major part of the metabolism of esomeprazole is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxyl- and desmethyl metabolites of esomeprazole. The remaining part is dependent on another specific isoform CYP3A4, responsible for the formation of esomeprazole sulphone, the main metabolite in plasma. The major metabolites of esomeprazole have no effect on gastric acid secretion.

The area under the plasma esomeprazole concentration-time curve increases with repeated administration of VIMOVO. This increase is dose-dependent and results in a non-linear dose- AUC relationship after repeated administration. An increased absorption of esomeprazole with repeated administration of VIMOVO probably also contributes to the time-and dose-dependency.

Excretion

Naproxen

Following administration of VIMOVO twice daily, the mean elimination half-life for naproxen is approximately 15 hours following the evening dose, with no change with repeated dosing.

The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (<1%), 6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal failure, metabolites may accumulate

[seeWarnings and Precautions (5.6)]

Esomeprazole

Following administration of VIMOVO twice daily, the mean elimination half-life of esomeprazole is approximately 1 hour following both the morning and evening dose on day 1, with a slightly longer elimination half-life at steady state (1.2-1.5 hours).

Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the feces. Less than 1% of the parent drug is found in the urine.

Specific Populations

Geriatric Patients

There is no specific data on the pharmacokinetics of VIMOVO in patients over age 65.

Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is <1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients

[seeAdverse Reactions (6)

and

Use in Specific Populations (8.5)]

The AUC and C_maxvalues of esomeprazole were slightly higher (25% and 18%, respectively) in the elderly as compared to younger subjects at steady state. Dosage adjustment for the esomeprazole component based on age is not necessary.

Male and Female Patients

The AUC and C_maxvalues of esomeprazole were slightly higher (13%) in females than in males at steady state. Dosage adjustment for the esomeprazole component based on gender is not necessary.

Racial or Ethnic Groups

Pharmacokinetic differences due to race have not been studied for naproxen.

Approximately 3% of Caucasians and 15 to 20% of Asians lack a functional CYP2C19 enzyme and are called poor metabolizers. In these individuals the metabolism of esomeprazole is probably mainly catalyzed by CYP3A4. After repeated once-daily administration of 40 mg esomeprazole, the mean area under the plasma concentration-time curve was approximately 100% higher in poor metabolizers than in subjects having a functional CYP2C19 enzyme (extensive metabolizers).

Patients with Renal Impairment

The pharmacokinetics of VIMOVO or naproxen have not been determined in subjects with renal impairment.

Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal impairment. Elimination of naproxen is decreased in patients with severe renal impairment. Naproxen- containing products, including VIMOVO, is not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 ml/min)

[seeDosage and Administration (2),Warnings and Precautions (5.6)

Use in Specific Populations (8.7)]

No studies have been performed with esomeprazole in patients with decreased renal function. Since the kidney is responsible for the excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function.

Patients with Hepatic Impairment

The pharmacokinetics of VIMOVO or naproxen have not been determined in subjects with hepatic impairment.

In patients with severe hepatic impairment, VIMOVO should be avoided due to increase of risk of NSAID associated bleeding and/or renal failure associated with naproxen.

Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. The implication of this finding for the naproxen component of VIMOVO dosing is unknown but it is prudent to use the lowest effective dose.

The AUCs of esomeprazole in patients with severe hepatic impairment (Child Pugh Class C) have been shown to be 2-3 times higher than in patients with normal liver function. For this reason, it has been recommended that esomeprazole doses not exceed 20 mg daily in patients with severe hepatic impairment. However, there is no dose adjustment necessary for patients with Child Pugh Class A and B for the esomeprazole component of VIMOVO. There is no VIMOVO dosage form that contains less than 20 mg esomeprazole for twice daily dosing

[seeDosage and Administration (2),Warnings and Precautions (5.3)]

Drug Interaction Studies

Effect of Naproxen on Other Drugs

Aspirin

: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. SeeTable 3for clinically significant drug interactions of NSAIDs with aspirin

[seeDrug Interactions (7)]

Effect of Esomeprazole on Other Drugs

Cytochrome P 450 Interactions

Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4.

In vitro

and

in vivo

studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1 and 3A4. No clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with phenytoin, warfarin, quinidine, clarithromycin or amoxicillin.

Clopidogrel:

Results from a crossover study in healthy subjects have shown a pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg p.o. once daily) when co-administered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 35% to 40% over this time period. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation was related to the change in the exposure to clopidogrel active metabolite

[seeWarnings and Precautions (5.22),Drug Interactions (7)]

Mycophenolate Mofetil:

Administration of omeprazole 20 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of omeprazole to 12 healthy subjects in a cross-over study resulted in a 52% reduction in the C_maxand 23% reduction in the AUC of MPA

[seeDrug Interactions (7)].

Cilostazol:

Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased C_maxand AUC of cilostazol by 18% and 26% respectively. C_maxand AUC of one of its active metabolites, 3,4- dihydrocilostazol, which has 4-7 times the activity of cilostazol, were increased by 29% and 69% respectively

[seeDrug Interactions (7)].

Nelfinavir:

Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg once a day), AUC was decreased by 36% and 92%, C_maxby 37% and 89% and C_minby 39% and 75% respectively for nelfinavir and main oxidative metabolite, hydroxy-

-butylamide (M8)

[seeDrug Interactions (7)]

Atazanavir:

Following multiple doses of atazanavir (400 mg, once a day) and omeprazole (40 mg, once a day, 2 hr before atazanavir), AUC was decreased by 94%, C_maxby 96%, and C_minby 95%

[seeDrug Interactions (7)]

Saquinavir:

Elevated serum levels have been reported with an increase in AUC by 82% in C_maxby 75% and in C_minby 106% following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice a day for 15 days with omeprazole 40 mg once a day co-administered on days 11 to 15

[seeDrug Interactions (7)]

Diazepam:

Co-administration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam

[seeDrug Interactions (7)].

Digoxin:

Concomitant administration of omeprazole 20 mg once daily and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects)

[seeDrug Interactions (7)].

Effect of Other Drugs on Esomeprazole

Because esomeprazole is metabolized by CYP2C19 and CYP3A4, inducers and inhibitors of these enzymes may potentially alter exposure of esomeprazole.

St. John's Wort

: In a cross-over study in 12 healthy male subjects, St. John's Wort (300 mg three times daily for 14 days) significantly decreased the systemic exposure of omeprazole in CYP2C19 poor metabolizers (C_maxand AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolizers (C_maxand AUC decreased by 49.6% and 43.9%, respectively)

[seeWarnings and Precautions (5.25),Drug Interactions (7)].

Voriconazole:

Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. When voriconazole (400 mg every 12 hours for one day, followed by 200 mg once daily for 6 days) was given with omeprazole (40 mg once daily for 7 days) to healthy subjects, the steady-state C_maxand AUC_0-24of omeprazole significantly increased: an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4), respectively, as compared to when omeprazole was given without voriconazole

[seeDrug Interactions (7)]

Intervention:

Consider reducing the dose of cilostazol to 50 mg twice daily.

Digoxin

Clinical Impact:

Naproxen

The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.

Esomeprazole Magnesium

Potential for increased exposure of digoxin
[see
12.3 Pharmacokinetics
Absorption
Naproxen
At steady state following administration of VIMOVO twice daily, peak plasma concentrations of naproxen are reached on average 3 hours following both the morning and the evening dose.
Bioequivalence between VIMOVO and enteric-coated naproxen, based on both area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C_max) of naproxen, has been demonstrated for both the 375 mg and 500 mg doses.
Naproxen is absorbed from the gastrointestinal tract with an
in vivo
bioavailability of 95%.
Steady-state levels of naproxen are reached in 4 to 5 days.
Esomeprazole
Following administration of VIMOVO twice daily, esomeprazole is rapidly absorbed with peak plasma concentration reached within on average, 0.43 to 1.2 hours, following the morning and evening dose on both the first day of administration and at steady state. The peak plasma concentrations of esomeprazole are higher at steady state compared to on first day of dosing of VIMOVO.
Figure 1 represents the pharmacokinetics of naproxen and esomeprazole following administration of VIMOVO 500 mg/20 mg.
Figure 1: Mean plasma concentrations of naproxen and esomeprazole following single dose administration of VIMOVO (500mg/20 mg)
Figure 1
Food Effect
Administration of VIMOVO together with high-fat food in healthy volunteers does not affect the extent of absorption of naproxen but significantly prolongs tmax by 10 hours and decreases peak plasma concentration (C_max) by about 12%.
Administration of VIMOVO together with high-fat food in healthy volunteers delays tmax of esomeprazole by 1 hour and significantly reduces the extent of absorption, resulting in 52% and 75% reductions of area under the plasma concentration versus time curve (AUC) and peak plasma concentration (C_max), respectively.
Administration of VIMOVO 30 minutes before high-fat food intake in healthy volunteers does not affect the extent of absorption of naproxen but delays the absorption by about 4 hours and decreases peak plasma concentration (C_max) by about 17%, but has no significant effect on the rate or extent of esomeprazole absorption compared to administration under fasted conditions
[seeDosage and Administration (2)]
.
Administration of VIMOVO 60 minutes before high-fat food intake in healthy volunteers has no effect on the rate and extent of naproxen absorption; however, increases the esomeprazole AUC by 25% and C_maxby 50% compared to administration under fasted conditions. This increase in esomeprazole Cmax does not raise a safety issue since the approved dosing regimen of esomeprazole at 40 mg QD would result in higher C_max
[seeDosage and Administration (2)]
.
Therefore, VIMOVO should be taken at least 30 minutes before the meal.
Distribution
Naproxen
Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough C_ss36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma
[seeUse in Specific Populations (8.2)]
.
Esomeprazole
The apparent volume of distribution at steady state in healthy subjects is approximately 16L. Esomeprazole is 97% plasma protein bound.
Elimination
Metabolism
Naproxen
Naproxen is extensively metabolized in the liver by the cytochrome P450 system (CYP), CYP2C9 and CYP1A2, to 6-0-desmethyl naproxen. Neither the parent drug nor the metabolites induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites. Consistent with the half- life of naproxen, the area under the plasma concentration time curve increases with repeated dosing of VIMOVO twice daily.
Esomeprazole
Esomeprazole is extensively metabolized in the liver by the CYP enzyme system. The major part of the metabolism of esomeprazole is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxyl- and desmethyl metabolites of esomeprazole. The remaining part is dependent on another specific isoform CYP3A4, responsible for the formation of esomeprazole sulphone, the main metabolite in plasma. The major metabolites of esomeprazole have no effect on gastric acid secretion.
The area under the plasma esomeprazole concentration-time curve increases with repeated administration of VIMOVO. This increase is dose-dependent and results in a non-linear dose- AUC relationship after repeated administration. An increased absorption of esomeprazole with repeated administration of VIMOVO probably also contributes to the time-and dose-dependency.
Excretion
Naproxen
Following administration of VIMOVO twice daily, the mean elimination half-life for naproxen is approximately 15 hours following the evening dose, with no change with repeated dosing.
The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (<1%), 6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal failure, metabolites may accumulate
[seeWarnings and Precautions (5.6)]
.
Esomeprazole
Following administration of VIMOVO twice daily, the mean elimination half-life of esomeprazole is approximately 1 hour following both the morning and evening dose on day 1, with a slightly longer elimination half-life at steady state (1.2-1.5 hours).
Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the feces. Less than 1% of the parent drug is found in the urine.
Specific Populations
Geriatric Patients
There is no specific data on the pharmacokinetics of VIMOVO in patients over age 65.
Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is <1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients
[seeAdverse Reactions (6)
and
Use in Specific Populations (8.5)]
.
The AUC and C_maxvalues of esomeprazole were slightly higher (25% and 18%, respectively) in the elderly as compared to younger subjects at steady state. Dosage adjustment for the esomeprazole component based on age is not necessary.
Male and Female Patients
The AUC and C_maxvalues of esomeprazole were slightly higher (13%) in females than in males at steady state. Dosage adjustment for the esomeprazole component based on gender is not necessary.
Racial or Ethnic Groups
Pharmacokinetic differences due to race have not been studied for naproxen.
Approximately 3% of Caucasians and 15 to 20% of Asians lack a functional CYP2C19 enzyme and are called poor metabolizers. In these individuals the metabolism of esomeprazole is probably mainly catalyzed by CYP3A4. After repeated once-daily administration of 40 mg esomeprazole, the mean area under the plasma concentration-time curve was approximately 100% higher in poor metabolizers than in subjects having a functional CYP2C19 enzyme (extensive metabolizers).
Patients with Renal Impairment
The pharmacokinetics of VIMOVO or naproxen have not been determined in subjects with renal impairment.
Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal impairment. Elimination of naproxen is decreased in patients with severe renal impairment. Naproxen- containing products, including VIMOVO, is not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 ml/min)
[seeDosage and Administration (2),Warnings and Precautions (5.6)
,
Use in Specific Populations (8.7)]
.
No studies have been performed with esomeprazole in patients with decreased renal function. Since the kidney is responsible for the excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function.
Patients with Hepatic Impairment
The pharmacokinetics of VIMOVO or naproxen have not been determined in subjects with hepatic impairment.
In patients with severe hepatic impairment, VIMOVO should be avoided due to increase of risk of NSAID associated bleeding and/or renal failure associated with naproxen.
Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. The implication of this finding for the naproxen component of VIMOVO dosing is unknown but it is prudent to use the lowest effective dose.
The AUCs of esomeprazole in patients with severe hepatic impairment (Child Pugh Class C) have been shown to be 2-3 times higher than in patients with normal liver function. For this reason, it has been recommended that esomeprazole doses not exceed 20 mg daily in patients with severe hepatic impairment. However, there is no dose adjustment necessary for patients with Child Pugh Class A and B for the esomeprazole component of VIMOVO. There is no VIMOVO dosage form that contains less than 20 mg esomeprazole for twice daily dosing
[seeDosage and Administration (2),Warnings and Precautions (5.3)]
.
Drug Interaction Studies
Effect of Naproxen on Other Drugs
Aspirin
: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. SeeTable 3for clinically significant drug interactions of NSAIDs with aspirin
[seeDrug Interactions (7)]
.
Effect of Esomeprazole on Other Drugs
Cytochrome P 450 Interactions
Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4.
In vitro
and
in vivo
studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1 and 3A4. No clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with phenytoin, warfarin, quinidine, clarithromycin or amoxicillin.
Clopidogrel:
Results from a crossover study in healthy subjects have shown a pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg p.o. once daily) when co-administered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 35% to 40% over this time period. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation was related to the change in the exposure to clopidogrel active metabolite
[seeWarnings and Precautions (5.22),Drug Interactions (7)]
.
Mycophenolate Mofetil:
Administration of omeprazole 20 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of omeprazole to 12 healthy subjects in a cross-over study resulted in a 52% reduction in the C_maxand 23% reduction in the AUC of MPA
[seeDrug Interactions (7)].
Cilostazol:
Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased C_maxand AUC of cilostazol by 18% and 26% respectively. C_maxand AUC of one of its active metabolites, 3,4- dihydrocilostazol, which has 4-7 times the activity of cilostazol, were increased by 29% and 69% respectively
[seeDrug Interactions (7)].
Nelfinavir:
Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg once a day), AUC was decreased by 36% and 92%, C_maxby 37% and 89% and C_minby 39% and 75% respectively for nelfinavir and main oxidative metabolite, hydroxy-
t
-butylamide (M8)
[seeDrug Interactions (7)]
.
Atazanavir:
Following multiple doses of atazanavir (400 mg, once a day) and omeprazole (40 mg, once a day, 2 hr before atazanavir), AUC was decreased by 94%, C_maxby 96%, and C_minby 95%
[seeDrug Interactions (7)]
.
Saquinavir:
Elevated serum levels have been reported with an increase in AUC by 82% in C_maxby 75% and in C_minby 106% following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice a day for 15 days with omeprazole 40 mg once a day co-administered on days 11 to 15
[seeDrug Interactions (7)]
.
Diazepam:
Co-administration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam
[seeDrug Interactions (7)].
Digoxin:
Concomitant administration of omeprazole 20 mg once daily and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects)
[seeDrug Interactions (7)].
Effect of Other Drugs on Esomeprazole
Because esomeprazole is metabolized by CYP2C19 and CYP3A4, inducers and inhibitors of these enzymes may potentially alter exposure of esomeprazole.
St. John's Wort
: In a cross-over study in 12 healthy male subjects, St. John's Wort (300 mg three times daily for 14 days) significantly decreased the systemic exposure of omeprazole in CYP2C19 poor metabolizers (C_maxand AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolizers (C_maxand AUC decreased by 49.6% and 43.9%, respectively)
[seeWarnings and Precautions (5.25),Drug Interactions (7)].
Voriconazole:
Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. When voriconazole (400 mg every 12 hours for one day, followed by 200 mg once daily for 6 days) was given with omeprazole (40 mg once daily for 7 days) to healthy subjects, the steady-state C_maxand AUC_0-24of omeprazole significantly increased: an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4), respectively, as compared to when omeprazole was given without voriconazole
[seeDrug Interactions (7)]
.
].

Intervention:

Monitor digoxin concentrations during concomitant use of VIMOVO. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations.

Lithium

Clinical Impact:

NSAIDs have produced elevations of plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.

Intervention:

During concomitant use of VIMOVO and lithium, monitor patients for signs of lithium toxicity.

Methotrexate

Clinical Impact:

Naproxen

Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).

Esomeprazole Magnesium

Concomitant use of esomeprazole magnesium with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities
[see
5.27 Concomitant Use of VIMOVO with Methotrexate
Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) 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
[seeDrug Interactions (7)]
.
].

Intervention:

During concomitant use of VIMOVO and methotrexate, monitor patients for methotrexate toxicity. A temporary withdrawal of VIMOVO may be considered in some patients receiving high-dose methotrexate.

Cyclosporine

Clinical Impact:

Concomitant use of naproxen and cyclosporine may increase cyclosporine's nephrotoxicity.

Intervention:

During concomitant use of VIMOVO and cyclosporine, monitor patients for signs of worsening renal function.

Tacrolimus

Clinical Impact:

Concomitant use of esomeprazole magnesium and tacrolimus may increase exposure of tacrolimus

Intervention:

During concomitant use of VIMOVO and tacrolimus, monitor tacrolimus whole blood concentrations.

NSAIDs and Salicylates

Clinical Impact:

Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy

[see

5.2 Gastrointestinal Bleeding, Ulceration, and Perforation

Risk Factors for GI Bleeding, Ulceration, and Perforation

Strategies to Minimize the GI Risks in NSAID-treated patients:

Use the lowest effective dosage for the shortest possible duration.
Avoid administration of more than one NSAID at a time.
Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such as patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.
Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue VIMOVO until a serious GI adverse event is ruled out.
In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding
[seeDrug Interactions (7)]
.

NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn's disease) as their condition may be exacerbated.

]

Intervention:

The concomitant use of VIMOVO with other NSAIDs or salicylates is not recommended.

Pemetrexed

Clinical Impact:

Concomitant use of VIMOVO and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).

Intervention:

During concomitant use of VIMOVO and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.

Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, mycophenoloate mofetil, ketoconazole)

Clinical Impact:

Esomeprazole magnesium can reduce the absorption of other drugs due to its effect on reducing intragastric acidity

Intervention:

Mycophenolate mofetil (MMF): Co-administration of omeprazole, of which esomeprazole magnesium is an enantiomer, 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 esomeprazole and MMF. Use VIMOVO with caution in transplant patients receiving MMF

[see

12.3 Pharmacokinetics

Absorption

Naproxen

At steady state following administration of VIMOVO twice daily, peak plasma concentrations of naproxen are reached on average 3 hours following both the morning and the evening dose.

Naproxen is absorbed from the gastrointestinal tract with an

in vivo

bioavailability of 95%.

Steady-state levels of naproxen are reached in 4 to 5 days.

Esomeprazole

Figure 1 represents the pharmacokinetics of naproxen and esomeprazole following administration of VIMOVO 500 mg/20 mg.

Figure 1: Mean plasma concentrations of naproxen and esomeprazole following single dose administration of VIMOVO (500mg/20 mg)

Referenced Image

Food Effect

[seeDosage and Administration (2)]

Therefore, VIMOVO should be taken at least 30 minutes before the meal.

Distribution

Naproxen

[seeUse in Specific Populations (8.2)]

Esomeprazole

The apparent volume of distribution at steady state in healthy subjects is approximately 16L. Esomeprazole is 97% plasma protein bound.

Elimination

Metabolism

Naproxen

Esomeprazole

Excretion

Naproxen

Following administration of VIMOVO twice daily, the mean elimination half-life for naproxen is approximately 15 hours following the evening dose, with no change with repeated dosing.

[seeWarnings and Precautions (5.6)]

Esomeprazole

Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the feces. Less than 1% of the parent drug is found in the urine.

Specific Populations

Geriatric Patients

There is no specific data on the pharmacokinetics of VIMOVO in patients over age 65.

[seeAdverse Reactions (6)

and

Use in Specific Populations (8.5)]

Male and Female Patients

The AUC and C_maxvalues of esomeprazole were slightly higher (13%) in females than in males at steady state. Dosage adjustment for the esomeprazole component based on gender is not necessary.

Racial or Ethnic Groups

Pharmacokinetic differences due to race have not been studied for naproxen.

Patients with Renal Impairment

The pharmacokinetics of VIMOVO or naproxen have not been determined in subjects with renal impairment.

[seeDosage and Administration (2),Warnings and Precautions (5.6)

Use in Specific Populations (8.7)]

Patients with Hepatic Impairment

The pharmacokinetics of VIMOVO or naproxen have not been determined in subjects with hepatic impairment.

In patients with severe hepatic impairment, VIMOVO should be avoided due to increase of risk of NSAID associated bleeding and/or renal failure associated with naproxen.

[seeDosage and Administration (2),Warnings and Precautions (5.3)]

Drug Interaction Studies

Effect of Naproxen on Other Drugs

Aspirin

[seeDrug Interactions (7)]

Effect of Esomeprazole on Other Drugs

Cytochrome P 450 Interactions

Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4.

In vitro

and

in vivo

Clopidogrel:

[seeWarnings and Precautions (5.22),Drug Interactions (7)]

Mycophenolate Mofetil:

[seeDrug Interactions (7)].

Cilostazol:

[seeDrug Interactions (7)].

Nelfinavir:

-butylamide (M8)

[seeDrug Interactions (7)]

Atazanavir:

Following multiple doses of atazanavir (400 mg, once a day) and omeprazole (40 mg, once a day, 2 hr before atazanavir), AUC was decreased by 94%, C_maxby 96%, and C_minby 95%

[seeDrug Interactions (7)]

Saquinavir:

[seeDrug Interactions (7)]

Diazepam:

Co-administration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam

[seeDrug Interactions (7)].

Digoxin:

Concomitant administration of omeprazole 20 mg once daily and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects)

[seeDrug Interactions (7)].

Effect of Other Drugs on Esomeprazole

Because esomeprazole is metabolized by CYP2C19 and CYP3A4, inducers and inhibitors of these enzymes may potentially alter exposure of esomeprazole.

St. John's Wort

[seeWarnings and Precautions (5.25),Drug Interactions (7)].

Voriconazole:

[seeDrug Interactions (7)]

]

.

See the prescribing information for other drugs dependent on gastric pH for absorption.

Interactions with Investigations of Neuroendocrine Tumors

Clinical Impact:

Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors

[see

5.26 Interactions with Diagnostic 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. Providers should temporarily stop esomeprazole 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

[seeDrug Interactions (7),Clinical Pharmacology (12.2)]

12.2 Pharmacodynamics

Interaction with Aspirin

[seeDrug Interactions (7)]

Antisecretory Activity

Table 5: Effect on Intragastric pH on Day 9 (N=25)
	Naproxen 500 mg combined with esomeprazole
	10 mg	20 mg	30 mg
LS Mean (SE)
% Time Gastric pH >4Gastric pH was measured over a 24-hour period	41.1 (3.0)	71.5 (3.0)	76.8 (3.0)
Coefficient of variation	55%	18%	16%

Serum Gastrin Effects

The effect of esomeprazole on serum gastrin concentrations was evaluated in approximately 2,700 patients in clinical trials up to 8 weeks and in over 1,300 patients for up to 6-12 months.

Enterochromaffin-like (ECL) Cell Effects

Endocrine Effects

Effects on Gastrointestinal Microbial Ecology

Salmonella

and

Campylobacter

and, in hospitalized patients, possibly also

Clostridium difficile

]

Intervention:

Temporarily stop VIMOVO 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.

Diazepam

Clinical Impact:

Increased exposure of diazepam

[see

12.3 Pharmacokinetics

Absorption

Naproxen

At steady state following administration of VIMOVO twice daily, peak plasma concentrations of naproxen are reached on average 3 hours following both the morning and the evening dose.

Naproxen is absorbed from the gastrointestinal tract with an

in vivo

bioavailability of 95%.

Steady-state levels of naproxen are reached in 4 to 5 days.

Esomeprazole

Figure 1 represents the pharmacokinetics of naproxen and esomeprazole following administration of VIMOVO 500 mg/20 mg.

Figure 1: Mean plasma concentrations of naproxen and esomeprazole following single dose administration of VIMOVO (500mg/20 mg)

Referenced Image

Food Effect

[seeDosage and Administration (2)]

Therefore, VIMOVO should be taken at least 30 minutes before the meal.

Distribution

Naproxen

[seeUse in Specific Populations (8.2)]

Esomeprazole

The apparent volume of distribution at steady state in healthy subjects is approximately 16L. Esomeprazole is 97% plasma protein bound.

Elimination

Metabolism

Naproxen

Esomeprazole

Excretion

Naproxen

Following administration of VIMOVO twice daily, the mean elimination half-life for naproxen is approximately 15 hours following the evening dose, with no change with repeated dosing.

[seeWarnings and Precautions (5.6)]

Esomeprazole

Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the feces. Less than 1% of the parent drug is found in the urine.

Specific Populations

Geriatric Patients

There is no specific data on the pharmacokinetics of VIMOVO in patients over age 65.

[seeAdverse Reactions (6)

and

Use in Specific Populations (8.5)]

Male and Female Patients

The AUC and C_maxvalues of esomeprazole were slightly higher (13%) in females than in males at steady state. Dosage adjustment for the esomeprazole component based on gender is not necessary.

Racial or Ethnic Groups

Pharmacokinetic differences due to race have not been studied for naproxen.

Patients with Renal Impairment

The pharmacokinetics of VIMOVO or naproxen have not been determined in subjects with renal impairment.

[seeDosage and Administration (2),Warnings and Precautions (5.6)

Use in Specific Populations (8.7)]

Patients with Hepatic Impairment

The pharmacokinetics of VIMOVO or naproxen have not been determined in subjects with hepatic impairment.

In patients with severe hepatic impairment, VIMOVO should be avoided due to increase of risk of NSAID associated bleeding and/or renal failure associated with naproxen.

[seeDosage and Administration (2),Warnings and Precautions (5.3)]

Drug Interaction Studies

Effect of Naproxen on Other Drugs

Aspirin

[seeDrug Interactions (7)]

Effect of Esomeprazole on Other Drugs

Cytochrome P 450 Interactions

Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4.

In vitro

and

in vivo

Clopidogrel:

[seeWarnings and Precautions (5.22),Drug Interactions (7)]

Mycophenolate Mofetil:

[seeDrug Interactions (7)].

Cilostazol:

[seeDrug Interactions (7)].

Nelfinavir:

-butylamide (M8)

[seeDrug Interactions (7)]

Atazanavir:

Following multiple doses of atazanavir (400 mg, once a day) and omeprazole (40 mg, once a day, 2 hr before atazanavir), AUC was decreased by 94%, C_maxby 96%, and C_minby 95%

[seeDrug Interactions (7)]

Saquinavir:

[seeDrug Interactions (7)]

Diazepam:

Co-administration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam

[seeDrug Interactions (7)].

Digoxin:

Concomitant administration of omeprazole 20 mg once daily and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects)

[seeDrug Interactions (7)].

Effect of Other Drugs on Esomeprazole

Because esomeprazole is metabolized by CYP2C19 and CYP3A4, inducers and inhibitors of these enzymes may potentially alter exposure of esomeprazole.

St. John's Wort

[seeWarnings and Precautions (5.25),Drug Interactions (7)].

Voriconazole:

[seeDrug Interactions (7)]

Intervention:

Monitor patients for increased sedation and adjust the dose of diazepam as needed.

Table 4: Clinically Significant Interactions with Esomeprazole Magnesium -- Affecting Co- Administered Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of esomeprazole when used concomitantly with strong inducers [see 12.3 Pharmacokinetics Absorption Naproxen At steady state following administration of VIMOVO twice daily, peak plasma concentrations of naproxen are reached on average 3 hours following both the morning and the evening dose. Bioequivalence between VIMOVO and enteric-coated naproxen, based on both area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C_max) of naproxen, has been demonstrated for both the 375 mg and 500 mg doses. Naproxen is absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. Steady-state levels of naproxen are reached in 4 to 5 days. Esomeprazole Following administration of VIMOVO twice daily, esomeprazole is rapidly absorbed with peak plasma concentration reached within on average, 0.43 to 1.2 hours, following the morning and evening dose on both the first day of administration and at steady state. The peak plasma concentrations of esomeprazole are higher at steady state compared to on first day of dosing of VIMOVO. Figure 1 represents the pharmacokinetics of naproxen and esomeprazole following administration of VIMOVO 500 mg/20 mg. Figure 1: Mean plasma concentrations of naproxen and esomeprazole following single dose administration of VIMOVO (500mg/20 mg) Figure 1 Food Effect Administration of VIMOVO together with high-fat food in healthy volunteers does not affect the extent of absorption of naproxen but significantly prolongs tmax by 10 hours and decreases peak plasma concentration (C_max) by about 12%. Administration of VIMOVO together with high-fat food in healthy volunteers delays tmax of esomeprazole by 1 hour and significantly reduces the extent of absorption, resulting in 52% and 75% reductions of area under the plasma concentration versus time curve (AUC) and peak plasma concentration (C_max), respectively. Administration of VIMOVO 30 minutes before high-fat food intake in healthy volunteers does not affect the extent of absorption of naproxen but delays the absorption by about 4 hours and decreases peak plasma concentration (C_max) by about 17%, but has no significant effect on the rate or extent of esomeprazole absorption compared to administration under fasted conditions [seeDosage and Administration (2)] . Administration of VIMOVO 60 minutes before high-fat food intake in healthy volunteers has no effect on the rate and extent of naproxen absorption; however, increases the esomeprazole AUC by 25% and C_maxby 50% compared to administration under fasted conditions. This increase in esomeprazole Cmax does not raise a safety issue since the approved dosing regimen of esomeprazole at 40 mg QD would result in higher C_max [seeDosage and Administration (2)] . Therefore, VIMOVO should be taken at least 30 minutes before the meal. Distribution Naproxen Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough C_ss36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma [seeUse in Specific Populations (8.2)] . Esomeprazole The apparent volume of distribution at steady state in healthy subjects is approximately 16L. Esomeprazole is 97% plasma protein bound. Elimination Metabolism Naproxen Naproxen is extensively metabolized in the liver by the cytochrome P450 system (CYP), CYP2C9 and CYP1A2, to 6-0-desmethyl naproxen. Neither the parent drug nor the metabolites induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites. Consistent with the half- life of naproxen, the area under the plasma concentration time curve increases with repeated dosing of VIMOVO twice daily. Esomeprazole Esomeprazole is extensively metabolized in the liver by the CYP enzyme system. The major part of the metabolism of esomeprazole is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxyl- and desmethyl metabolites of esomeprazole. The remaining part is dependent on another specific isoform CYP3A4, responsible for the formation of esomeprazole sulphone, the main metabolite in plasma. The major metabolites of esomeprazole have no effect on gastric acid secretion. The area under the plasma esomeprazole concentration-time curve increases with repeated administration of VIMOVO. This increase is dose-dependent and results in a non-linear dose- AUC relationship after repeated administration. An increased absorption of esomeprazole with repeated administration of VIMOVO probably also contributes to the time-and dose-dependency. Excretion Naproxen Following administration of VIMOVO twice daily, the mean elimination half-life for naproxen is approximately 15 hours following the evening dose, with no change with repeated dosing. The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (<1%), 6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal failure, metabolites may accumulate [seeWarnings and Precautions (5.6)] . Esomeprazole Following administration of VIMOVO twice daily, the mean elimination half-life of esomeprazole is approximately 1 hour following both the morning and evening dose on day 1, with a slightly longer elimination half-life at steady state (1.2-1.5 hours). Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the feces. Less than 1% of the parent drug is found in the urine. Specific Populations Geriatric Patients There is no specific data on the pharmacokinetics of VIMOVO in patients over age 65. Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is <1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients [seeAdverse Reactions (6) and Use in Specific Populations (8.5)] . The AUC and C_maxvalues of esomeprazole were slightly higher (25% and 18%, respectively) in the elderly as compared to younger subjects at steady state. Dosage adjustment for the esomeprazole component based on age is not necessary. Male and Female Patients The AUC and C_maxvalues of esomeprazole were slightly higher (13%) in females than in males at steady state. Dosage adjustment for the esomeprazole component based on gender is not necessary. Racial or Ethnic Groups Pharmacokinetic differences due to race have not been studied for naproxen. Approximately 3% of Caucasians and 15 to 20% of Asians lack a functional CYP2C19 enzyme and are called poor metabolizers. In these individuals the metabolism of esomeprazole is probably mainly catalyzed by CYP3A4. After repeated once-daily administration of 40 mg esomeprazole, the mean area under the plasma concentration-time curve was approximately 100% higher in poor metabolizers than in subjects having a functional CYP2C19 enzyme (extensive metabolizers). Patients with Renal Impairment The pharmacokinetics of VIMOVO or naproxen have not been determined in subjects with renal impairment. Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal impairment. Elimination of naproxen is decreased in patients with severe renal impairment. Naproxen- containing products, including VIMOVO, is not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 ml/min) [seeDosage and Administration (2),Warnings and Precautions (5.6) , Use in Specific Populations (8.7)] . No studies have been performed with esomeprazole in patients with decreased renal function. Since the kidney is responsible for the excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function. Patients with Hepatic Impairment The pharmacokinetics of VIMOVO or naproxen have not been determined in subjects with hepatic impairment. In patients with severe hepatic impairment, VIMOVO should be avoided due to increase of risk of NSAID associated bleeding and/or renal failure associated with naproxen. Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. The implication of this finding for the naproxen component of VIMOVO dosing is unknown but it is prudent to use the lowest effective dose. The AUCs of esomeprazole in patients with severe hepatic impairment (Child Pugh Class C) have been shown to be 2-3 times higher than in patients with normal liver function. For this reason, it has been recommended that esomeprazole doses not exceed 20 mg daily in patients with severe hepatic impairment. However, there is no dose adjustment necessary for patients with Child Pugh Class A and B for the esomeprazole component of VIMOVO. There is no VIMOVO dosage form that contains less than 20 mg esomeprazole for twice daily dosing [seeDosage and Administration (2),Warnings and Precautions (5.3)] . Drug Interaction Studies Effect of Naproxen on Other Drugs Aspirin : When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. SeeTable 3for clinically significant drug interactions of NSAIDs with aspirin [seeDrug Interactions (7)] . Effect of Esomeprazole on Other Drugs Cytochrome P 450 Interactions Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. In vitro and in vivo studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1 and 3A4. No clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with phenytoin, warfarin, quinidine, clarithromycin or amoxicillin. Clopidogrel: Results from a crossover study in healthy subjects have shown a pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg p.o. once daily) when co-administered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 35% to 40% over this time period. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation was related to the change in the exposure to clopidogrel active metabolite [seeWarnings and Precautions (5.22),Drug Interactions (7)] . Mycophenolate Mofetil: Administration of omeprazole 20 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of omeprazole to 12 healthy subjects in a cross-over study resulted in a 52% reduction in the C_maxand 23% reduction in the AUC of MPA [seeDrug Interactions (7)]. Cilostazol: Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased C_maxand AUC of cilostazol by 18% and 26% respectively. C_maxand AUC of one of its active metabolites, 3,4- dihydrocilostazol, which has 4-7 times the activity of cilostazol, were increased by 29% and 69% respectively [seeDrug Interactions (7)]. Nelfinavir: Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg once a day), AUC was decreased by 36% and 92%, C_maxby 37% and 89% and C_minby 39% and 75% respectively for nelfinavir and main oxidative metabolite, hydroxy- t -butylamide (M8) [seeDrug Interactions (7)] . Atazanavir: Following multiple doses of atazanavir (400 mg, once a day) and omeprazole (40 mg, once a day, 2 hr before atazanavir), AUC was decreased by 94%, C_maxby 96%, and C_minby 95% [seeDrug Interactions (7)] . Saquinavir: Elevated serum levels have been reported with an increase in AUC by 82% in C_maxby 75% and in C_minby 106% following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice a day for 15 days with omeprazole 40 mg once a day co-administered on days 11 to 15 [seeDrug Interactions (7)] . Diazepam: Co-administration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam [seeDrug Interactions (7)]. Digoxin: Concomitant administration of omeprazole 20 mg once daily and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects) [seeDrug Interactions (7)]. Effect of Other Drugs on Esomeprazole Because esomeprazole is metabolized by CYP2C19 and CYP3A4, inducers and inhibitors of these enzymes may potentially alter exposure of esomeprazole. St. John's Wort : In a cross-over study in 12 healthy male subjects, St. John's Wort (300 mg three times daily for 14 days) significantly decreased the systemic exposure of omeprazole in CYP2C19 poor metabolizers (C_maxand AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolizers (C_maxand AUC decreased by 49.6% and 43.9%, respectively) [seeWarnings and Precautions (5.25),Drug Interactions (7)]. Voriconazole: Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. When voriconazole (400 mg every 12 hours for one day, followed by 200 mg once daily for 6 days) was given with omeprazole (40 mg once daily for 7 days) to healthy subjects, the steady-state C_maxand AUC_0-24of omeprazole significantly increased: an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4), respectively, as compared to when omeprazole was given without voriconazole [seeDrug Interactions (7)] . ].
Intervention:	St. John's Wort, rifampin: Avoid concomitant use with VIMOVO [see 5.25 Concomitant Use of St. John's Wort or Rifampin with VIMOVO Drugs that induce CYP2C19 or CYP3A4 (such as St. John's Wort or rifampin) can substantially decrease esomeprazole concentrations. Avoid concomitant use of VIMOVO with St. John's Wort or rifampin [seeDrug Interactions (7)] . ].
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of esomeprazole [see 12.3 Pharmacokinetics Absorption Naproxen At steady state following administration of VIMOVO twice daily, peak plasma concentrations of naproxen are reached on average 3 hours following both the morning and the evening dose. Bioequivalence between VIMOVO and enteric-coated naproxen, based on both area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C_max) of naproxen, has been demonstrated for both the 375 mg and 500 mg doses. Naproxen is absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. Steady-state levels of naproxen are reached in 4 to 5 days. Esomeprazole Following administration of VIMOVO twice daily, esomeprazole is rapidly absorbed with peak plasma concentration reached within on average, 0.43 to 1.2 hours, following the morning and evening dose on both the first day of administration and at steady state. The peak plasma concentrations of esomeprazole are higher at steady state compared to on first day of dosing of VIMOVO. Figure 1 represents the pharmacokinetics of naproxen and esomeprazole following administration of VIMOVO 500 mg/20 mg. Figure 1: Mean plasma concentrations of naproxen and esomeprazole following single dose administration of VIMOVO (500mg/20 mg) Figure 1 Food Effect Administration of VIMOVO together with high-fat food in healthy volunteers does not affect the extent of absorption of naproxen but significantly prolongs tmax by 10 hours and decreases peak plasma concentration (C_max) by about 12%. Administration of VIMOVO together with high-fat food in healthy volunteers delays tmax of esomeprazole by 1 hour and significantly reduces the extent of absorption, resulting in 52% and 75% reductions of area under the plasma concentration versus time curve (AUC) and peak plasma concentration (C_max), respectively. Administration of VIMOVO 30 minutes before high-fat food intake in healthy volunteers does not affect the extent of absorption of naproxen but delays the absorption by about 4 hours and decreases peak plasma concentration (C_max) by about 17%, but has no significant effect on the rate or extent of esomeprazole absorption compared to administration under fasted conditions [seeDosage and Administration (2)] . Administration of VIMOVO 60 minutes before high-fat food intake in healthy volunteers has no effect on the rate and extent of naproxen absorption; however, increases the esomeprazole AUC by 25% and C_maxby 50% compared to administration under fasted conditions. This increase in esomeprazole Cmax does not raise a safety issue since the approved dosing regimen of esomeprazole at 40 mg QD would result in higher C_max [seeDosage and Administration (2)] . Therefore, VIMOVO should be taken at least 30 minutes before the meal. Distribution Naproxen Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough C_ss36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma [seeUse in Specific Populations (8.2)] . Esomeprazole The apparent volume of distribution at steady state in healthy subjects is approximately 16L. Esomeprazole is 97% plasma protein bound. Elimination Metabolism Naproxen Naproxen is extensively metabolized in the liver by the cytochrome P450 system (CYP), CYP2C9 and CYP1A2, to 6-0-desmethyl naproxen. Neither the parent drug nor the metabolites induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites. Consistent with the half- life of naproxen, the area under the plasma concentration time curve increases with repeated dosing of VIMOVO twice daily. Esomeprazole Esomeprazole is extensively metabolized in the liver by the CYP enzyme system. The major part of the metabolism of esomeprazole is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxyl- and desmethyl metabolites of esomeprazole. The remaining part is dependent on another specific isoform CYP3A4, responsible for the formation of esomeprazole sulphone, the main metabolite in plasma. The major metabolites of esomeprazole have no effect on gastric acid secretion. The area under the plasma esomeprazole concentration-time curve increases with repeated administration of VIMOVO. This increase is dose-dependent and results in a non-linear dose- AUC relationship after repeated administration. An increased absorption of esomeprazole with repeated administration of VIMOVO probably also contributes to the time-and dose-dependency. Excretion Naproxen Following administration of VIMOVO twice daily, the mean elimination half-life for naproxen is approximately 15 hours following the evening dose, with no change with repeated dosing. The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (<1%), 6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal failure, metabolites may accumulate [seeWarnings and Precautions (5.6)] . Esomeprazole Following administration of VIMOVO twice daily, the mean elimination half-life of esomeprazole is approximately 1 hour following both the morning and evening dose on day 1, with a slightly longer elimination half-life at steady state (1.2-1.5 hours). Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the feces. Less than 1% of the parent drug is found in the urine. Specific Populations Geriatric Patients There is no specific data on the pharmacokinetics of VIMOVO in patients over age 65. Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is <1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients [seeAdverse Reactions (6) and Use in Specific Populations (8.5)] . The AUC and C_maxvalues of esomeprazole were slightly higher (25% and 18%, respectively) in the elderly as compared to younger subjects at steady state. Dosage adjustment for the esomeprazole component based on age is not necessary. Male and Female Patients The AUC and C_maxvalues of esomeprazole were slightly higher (13%) in females than in males at steady state. Dosage adjustment for the esomeprazole component based on gender is not necessary. Racial or Ethnic Groups Pharmacokinetic differences due to race have not been studied for naproxen. Approximately 3% of Caucasians and 15 to 20% of Asians lack a functional CYP2C19 enzyme and are called poor metabolizers. In these individuals the metabolism of esomeprazole is probably mainly catalyzed by CYP3A4. After repeated once-daily administration of 40 mg esomeprazole, the mean area under the plasma concentration-time curve was approximately 100% higher in poor metabolizers than in subjects having a functional CYP2C19 enzyme (extensive metabolizers). Patients with Renal Impairment The pharmacokinetics of VIMOVO or naproxen have not been determined in subjects with renal impairment. Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal impairment. Elimination of naproxen is decreased in patients with severe renal impairment. Naproxen- containing products, including VIMOVO, is not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 ml/min) [seeDosage and Administration (2),Warnings and Precautions (5.6) , Use in Specific Populations (8.7)] . No studies have been performed with esomeprazole in patients with decreased renal function. Since the kidney is responsible for the excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function. Patients with Hepatic Impairment The pharmacokinetics of VIMOVO or naproxen have not been determined in subjects with hepatic impairment. In patients with severe hepatic impairment, VIMOVO should be avoided due to increase of risk of NSAID associated bleeding and/or renal failure associated with naproxen. Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. The implication of this finding for the naproxen component of VIMOVO dosing is unknown but it is prudent to use the lowest effective dose. The AUCs of esomeprazole in patients with severe hepatic impairment (Child Pugh Class C) have been shown to be 2-3 times higher than in patients with normal liver function. For this reason, it has been recommended that esomeprazole doses not exceed 20 mg daily in patients with severe hepatic impairment. However, there is no dose adjustment necessary for patients with Child Pugh Class A and B for the esomeprazole component of VIMOVO. There is no VIMOVO dosage form that contains less than 20 mg esomeprazole for twice daily dosing [seeDosage and Administration (2),Warnings and Precautions (5.3)] . Drug Interaction Studies Effect of Naproxen on Other Drugs Aspirin : When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. SeeTable 3for clinically significant drug interactions of NSAIDs with aspirin [seeDrug Interactions (7)] . Effect of Esomeprazole on Other Drugs Cytochrome P 450 Interactions Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. In vitro and in vivo studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1 and 3A4. No clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with phenytoin, warfarin, quinidine, clarithromycin or amoxicillin. Clopidogrel: Results from a crossover study in healthy subjects have shown a pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg p.o. once daily) when co-administered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 35% to 40% over this time period. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation was related to the change in the exposure to clopidogrel active metabolite [seeWarnings and Precautions (5.22),Drug Interactions (7)] . Mycophenolate Mofetil: Administration of omeprazole 20 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of omeprazole to 12 healthy subjects in a cross-over study resulted in a 52% reduction in the C_maxand 23% reduction in the AUC of MPA [seeDrug Interactions (7)]. Cilostazol: Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased C_maxand AUC of cilostazol by 18% and 26% respectively. C_maxand AUC of one of its active metabolites, 3,4- dihydrocilostazol, which has 4-7 times the activity of cilostazol, were increased by 29% and 69% respectively [seeDrug Interactions (7)]. Nelfinavir: Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg once a day), AUC was decreased by 36% and 92%, C_maxby 37% and 89% and C_minby 39% and 75% respectively for nelfinavir and main oxidative metabolite, hydroxy- t -butylamide (M8) [seeDrug Interactions (7)] . Atazanavir: Following multiple doses of atazanavir (400 mg, once a day) and omeprazole (40 mg, once a day, 2 hr before atazanavir), AUC was decreased by 94%, C_maxby 96%, and C_minby 95% [seeDrug Interactions (7)] . Saquinavir: Elevated serum levels have been reported with an increase in AUC by 82% in C_maxby 75% and in C_minby 106% following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice a day for 15 days with omeprazole 40 mg once a day co-administered on days 11 to 15 [seeDrug Interactions (7)] . Diazepam: Co-administration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam [seeDrug Interactions (7)]. Digoxin: Concomitant administration of omeprazole 20 mg once daily and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects) [seeDrug Interactions (7)]. Effect of Other Drugs on Esomeprazole Because esomeprazole is metabolized by CYP2C19 and CYP3A4, inducers and inhibitors of these enzymes may potentially alter exposure of esomeprazole. St. John's Wort : In a cross-over study in 12 healthy male subjects, St. John's Wort (300 mg three times daily for 14 days) significantly decreased the systemic exposure of omeprazole in CYP2C19 poor metabolizers (C_maxand AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolizers (C_maxand AUC decreased by 49.6% and 43.9%, respectively) [seeWarnings and Precautions (5.25),Drug Interactions (7)]. Voriconazole: Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. When voriconazole (400 mg every 12 hours for one day, followed by 200 mg once daily for 6 days) was given with omeprazole (40 mg once daily for 7 days) to healthy subjects, the steady-state C_maxand AUC_0-24of omeprazole significantly increased: an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4), respectively, as compared to when omeprazole was given without voriconazole [seeDrug Interactions (7)] . ].
Intervention:	V oriconazole: Avoid concomitant use with VIMOVO.

Drugs interactions for Vimovo®