Yosprala (Page 3 of 9)

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of aspirin and omeprazole separately. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Aspirin

Body as a Whole: Fever, hypothermia, thirst

Cardiovascular: Dysrhythmias, hypotension, tachycardia

Central Nervous System: Agitation, cerebral edema, coma, confusion, dizziness, headache, subdural or intracranial hemorrhage, lethargy, seizures

Fluid and Electrolyte: Dehydration, hyperkalemia, metabolic acidosis, respiratory alkalosis

Gastrointestinal: Dyspepsia, GI bleeding, ulceration and perforation, nausea, vomiting, transient elevations of hepatic enzymes, hepatitis, Reye’s Syndrome [see Contraindications (4)] , pancreatitis

Hematologic: Prolongation of the prothrombin time, disseminated intravascular coagulation, coagulopathy, thrombocytopenia

Hypersensitivity: Acute anaphylaxis, angioedema, asthma, bronchospasm, laryngeal edema, urticaria

Musculoskeletal: Rhabdomyolysis

Metabolism: Hypoglycemia (in pediatrics), hyperglycemia

Reproductive: Prolonged pregnancy and labor, stillbirths, lower birth weight infants, antepartum and postpartum bleeding

Respiratory: Hyperpnea, pulmonary edema, tachypnea

Special Senses: Hearing loss, tinnitus. Patients with high frequency hearing loss may have difficulty perceiving tinnitus. In these patients, tinnitus cannot be used as a clinical indicator of salicylism.

Urogenital: Interstitial nephritis, papillary necrosis, proteinuria, renal impairment and failure

Omeprazole

Body As a Whole: Hypersensitivity reactions including anaphylaxis, anaphylactic shock, angioedema, bronchospasm [see Contraindications (4)], interstitial nephritis, urticaria (see also Skin below), systemic lupus erythematosus, fever, pain, fatigue, malaise

Cardiovascular: Chest pain or angina, tachycardia, bradycardia, palpitations, elevated blood pressure, peripheral edema

Endocrine: Gynecomastia

Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, stomatitis, abdominal swelling, dry mouth, microscopic colitis, fundic gland polyps.

Gastroduodenal carcinoids have been reported in patients with Zollinger-Ellison syndrome on long-term treatment with omeprazole. This finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors.

Hematologic: Agranulocytosis (some fatal), hemolytic anemia, pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia, leukocytosis

Hepatic: Liver disease including hepatic failure (some fatal), liver necrosis (some fatal), hepatic encephalopathy hepatocellular disease, cholestatic disease, mixed hepatitis, jaundice, and elevations of liver function tests [ALT, AST, GGT, alkaline phosphatase, and bilirubin]

Infections and Infestations: Clostridium difficile -associated diarrhea [see Warnings and Precautions (5.9)]

Metabolism and Nutritional disorders: Hypoglycemia, hypomagnesemia, with or without hypocalcemia and/or hypokalemia, hyponatremia, weight gain

Musculoskeletal: Muscle weakness, myalgia, muscle cramps, joint pain, leg pain, bone fracture

Nervous System/Psychiatric: Psychiatric and sleep disturbances including depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, apathy, somnolence, anxiety, and dream abnormalities; tremors, paresthesia; vertigo

Respiratory: Epistaxis, pharyngeal pain

Skin: Severe generalized skin reactions including toxic epidermal necrolysis (some fatal), Stevens-Johnson syndrome, cutaneous lupus erythematosus and erythema multiforme; photosensitivity; urticaria; rash; skin inflammation; pruritus; petechiae; purpura; alopecia; dry skin; hyperhidrosis

Special Senses: Tinnitus, taste perversion

Ocular: Optic atrophy, anterior ischemic optic neuropathy, optic neuritis, dry eye syndrome, ocular irritation, blurred vision, double vision

Urogenital: Interstitial nephritis, hematuria, proteinuria, elevated serum creatinine, microscopic pyuria, urinary tract infection, glycosuria, urinary frequency, testicular pain

7 DRUG INTERACTIONS

Tables 2 and 3 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with YOSPRALA and instructions for preventing or managing them.

Consult the labeling of concomitantly used drugs to obtain further information about interactions with omeprazole or aspirin.

Table 2: Clinically Relevant Interactions Affecting Drugs Co-Administered with YOSPRALA and Interaction with Diagnostics
Antiretrovirals
Clinical Impact: The effect of PPIs, such as omeprazole, on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
  • Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)].
  • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)].
  • There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention: Rilpivirine-containing products: Concomitant use with YOSPRALA is contraindicated [see Contraindications (4)]. Atazanavir: Avoid concomitant use with YOSPRALA. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with YOSPRALA. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Heparin and Warfarin
Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Aspirin can increase the anticoagulant activity of heparin and warfarin, increasing bleeding risk.
Intervention: Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range. Monitor and adjust the dose of heparin and warfarin as needed.
Methotrexate
Clinical Impact: Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs, such as omeprazole, have been conducted [see Warnings and Precautions (5.17)].
Intervention: A temporary withdrawal of YOSPRALA may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact: Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention: Avoid concomitant use with YOSPRALA. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.4)].
Citalopram
Clinical Impact: Concomitant use of omeprazole results in increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention: Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact: Concomitant use of omeprazole results in increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol).
Intervention: Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact: Potential for increased exposure of phenytoin with concomitant omeprazole. Aspirin can displace protein-bound phenytoin leading to a decrease in the total concentration of phenytoin.
Intervention: Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact: Increased exposure of diazepam with concomitant omeprazole [see Clinical Pharmacology (12.3)].
Intervention: Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Ticagrelor
Clinical Impact: Maintenance doses of aspirin above 100 mg reduce the effectiveness of ticagrelor.
Intervention: Avoid concomitant use of ticagrelor with the 325 mg/40 mg tablet strength of YOSPRALA [see Warnings and Precautions (5.5)].
Digoxin
Clinical Impact: Potential for increased exposure of digoxin with concomitant omeprazole [see Clinical Pharmacology (12.3)].
Intervention: Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact: Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention: Mycophenolate mofetil (MMF): Co-administration of omeprazole 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 omeprazole and MMF. Use Yosprala with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Tacrolimus
Clinical Impact: Potential for increased exposure of tacrolimus with concomitant omeprazole, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention: Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
ACE-Inhibitors
Clinical Impact: Aspirin may diminish the antihypertensive effect of ACE-inhibitors.
Intervention: Monitor blood pressure as needed.
Beta Blockers
Clinical Impact: The hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin.
Intervention: Monitor blood pressure as needed in patients taking YOSPRALA concomitantly with beta blockers for hypertension.
Diuretics
Clinical Impact: The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin.
Intervention: Monitor blood pressure as needed.
NSAIDs
Clinical Impact: The concurrent use of NSAIDs and aspirin may increase the risk of serious adverse events, including increased bleeding or decreased renal function.
Intervention: Monitor for signs and symptoms of bleeding or decreased renal function.
Oral Hypoglycemics
Clinical Impact: Moderate doses of aspirin may increase the effectiveness of oral hypoglycemic drugs, leading to hypoglycemia.
Intervention: Monitor blood sugar as needed.
Acetazolamide
Clinical Impact: Concurrent use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity).
Intervention: Adjust the dose of acetazolamide if signs of toxicity occur.
Uricosuric Agents (Probenecid)
Clinical Impact: Aspirin antagonizes the uricosuric action of uricosuric agents.
Intervention: Monitor serum uric acid levels as needed.
Valproic Acid
Clinical Impact: Concomitant use of aspirin can displace protein-bound valproic acid, leading to an increase in serum concentrations of valproic acid.
Intervention: Monitor valproic acid serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for valproic acid.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact: Serum chromogranin A (CgA) levels increase secondary to omeprazole-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.16), Clinical Pharmacology (12.2)].
Intervention: Temporarily stop YOSPRALA 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.
Interaction with Secretin Stimulation Test
Clinical Impact: Omeprazole can cause a hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention: Temporarily stop YOSPRALA treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact: There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs such as omeprazole.
Intervention: An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact: There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram) with omeprazole.
Intervention: Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with YOSPRALA.
Table 3: Clinically Relevant Interactions Affecting YOSPRALA When Co- Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact: Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention: St. John’s Wort, rifampin: Avoid concomitant use with YOSPRALA [see Warnings and Precautions (5.15)]. Ritonavir-containing products: See prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact: Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention: Voriconazole: Avoid concomitant use with YOSPRALA.

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