FDA label 6d6034ac-47ef-4a5d-b99f-1548898b017e

5 WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity: Based on animal findings for omeprazole and clarithromycin, OMECLAMOX-PAK may cause fetal harm. OMECLAMOX-PAK is not recommended for use in pregnant women except in clinical circumstances when there is no appropriate alternative therapy. ( 5.1 ) Severe Cutaneous Adverse Reactions: Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. ( 5.2 ) Colchicine interaction: Concomitant use of clarithromycin and colchicine has resulted in deaths, especially in the elderly with renal insufficiency. Monitor patients for clinical symptoms of colchicine toxicity. ( 5.3 , 7.1 ) Myasthenia gravis: Exacerbation of symptoms and new onset of symptoms reported with clarithromycin. Monitor patients for symptoms. ( 5.4 ) Clostridioides difficile -associated diarrhea: Reported with use of clarithromycin and amoxicillin; evaluate if diarrhea occurs. ( 5.5 ) Risk of gastric malignancy: Symptomatic response does not preclude concomitant underlying malignancy. ( 5.6 ) Acute Tubulointerstitial Nephritis: has been observed in patients taking proton pump inhibitors (PPIs), including omeprazole. Discontinue OMECLAMOX-PAK and evaluate patients ( 5.7 ) Cutaneous and Systemic Lupus Erythematosus: Mostly cutaneous; new onset or exacerbation of existing disease; discontinue OMECLAMOX- PAK and evaluate ( 5.8 ) 5.1 Embryo-Fetal Toxicity Clarithromycin, a component of OMECLAMOX-PAK, has demonstrated adverse effects on pregnancy outcomes and/or embryo-fetal development in monkeys, rats, mice, and rabbits at doses that produced plasma concentrations 2 to 17 times the serum concentrations achieved in humans at the maximum recommended human dose. Based on findings in animal studies, OMECLAMOX-PAK is not recommended for use in pregnant women except in clinical circumstances where no alternative therapy is appropriate. If OMECLAMOX-PAK is used during pregnancy, or if pregnancy occurs while the patient is taking this drug, the patient should be apprised of the potential hazard to the fetus [ see Use in Specific Populations ( 8.1 ) ]. 5.2 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the components of OMECLAMOX-PAK: omeprazole, clarithromycin, and amoxicillin [see Adverse Reactions ( 6.3 )] . Discontinue OMECLAMOX-PAK at the first signs or symptoms of SCAR or other signs of hypersensitivity and consider further evaluation. 5.3 Colchicine Toxicity with Clarithromycin There have been postmarketing reports of colchicine toxicity, some fatal, with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Monitor patients for clinical symptoms of colchicine toxicity [ see Drug Interactions ( 7.1 ) ]. 5.4 Myasthenia Gravis Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome have been reported in patients receiving clarithromycin therapy. Monitor patients for symptoms. 5.5 Clostridioides difficile-associated diarrhea Clostridioides difficile -associated diarrhea (CDAD) has been reported with use of clarithromycin and amoxicillin, and may range in severity from mild diarrhea to fatal colitis [ see Adverse Reactions ( 6.3 ) ]. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated. 5.6 Concomitant Gastric Malignancy Symptomatic response to therapy with omeprazole does not preclude the presence of gastric malignancy. 5.7 AcuteTubulointerstitial Nephritis Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs including omeprazole, a component of OMECLAMOX-PAK. TIN may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions, to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue OMECLAMOX-PAK and evaluate patients with suspected acute TIN [ see Contraindications ( 4.1 ) ]. 5.8 Cutaneous and Systemic Lupus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including omeprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE. The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement. Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported. Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving OMECLAMOX-PAK, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g. ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations. 5.9 Development of Bacterial Superinfections The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy with OMECLAMOX-PAK due to the clarithromycin and amoxicillin components. If superinfections occur, OMECLAMOX-PAK should be discontinued and appropriate therapy instituted. 5.10 Mononucleosis and Ampicillin A high percentage of patients with mononucleosis who receive ampicillin develop an erythematosus skin rash. Thus, administration of ampicillin-class antibiotics is not recommended in patients with mononucleosis. 5.11 Development of Drug Resistant Bacteria Prescribing OMECLAMOX-PAK (clarithromycin or amoxicillin component) in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Hypersensitivity [ see Contraindications ( 4.1 ) ] Myasthenia Gravis [ see Warnings and Precautions ( 5.4 ) ] Clostridioides difficile -associated diarrhea [ see Warnings and Precautions ( 5.5 ) ] Acute Tubulointerstitial Nephritis [ see Warnings and Precautions ( 5.7 ) ] Most frequent adverse reactions (> 7%) with triple therapy were diarrhea, taste perversion, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Cumberland Pharmaceuticals Inc. at 1-877-484-2700 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials using triple therapy with omeprazole, clarithromycin, and amoxicillin, no adverse reactions unique to triple therapy were observed. Adverse reactions observed were limited to those previously reported with omeprazole, clarithromycin, or amoxicillin alone. The most frequent adverse reactions observed in clinical trials using combination therapy with omeprazole, clarithromycin, and amoxicillin (n = 274) were diarrhea (14%), taste perversion (10%), and headache (7%). None of these occurred at a higher frequency than that reported by patients taking antimicrobial agents alone. 6.2 Adverse Reactions from Labeling for the Individual Components of OMECLAMOX-PAK The safety data below reflect exposure to omeprazole delayed-release capsules and clarithromycin worldwide in clinical trials for various indications using doses and durations of therapy that may differ from how they are used as a component of OMECLAMOX-PAK. For complete information on these reactions, see the full prescribing information for omeprazole delayed-release capsules and clarithromycin. Omeprazole : The most common adverse reactions reported (i.e., with an incidence rate ≥ 2%) in 3096 patients from omeprazole delayed-release capsules-treated patients enrolled in clinical trials included headache (6.9%), abdominal pain (5.2%), nausea (4.0%), diarrhea (3.7%), vomiting (3.2%), and flatulence (2.7%). Additional adverse reactions that were reported with an incidence rate ≥ 1% included acid regurgitation (1.9%), upper respiratory infection (1.9%), constipation (1.5%), dizziness (1.5%), rash (1.5%), asthenia (1.3%), back pain (1.1%), and cough (1.1%). The clinical trial safety profile in patients greater than 65 years of age was similar to that in patients 65 years of age or less. Clarithromycin : The most frequently reported events in adults were diarrhea (3%), nausea (3%), abnormal taste (3%), dyspepsia (2%), abdominal pain/discomfort (2%), and headache (2%). Most of these events were described as mild or moderate in severity. Of the reported adverse events, only 1% were described as severe. Fewer than 3% of adult patients without mycobacterial infections discontinued therapy because of drug-related side effects. 6.3 Post-Marketing Experience with the Individual Components of OMECLAMOX-PAK Because these reactions are voluntarily reported from a population of uncertain size, it is not always possible to reliably estimate their actual frequency or establish a causal relationship to drug exposure. Omeprazole : Body As a Whole: Hypersensitivity reactions including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, urticaria, (see also Skin below); 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. During treatment with omeprazole, gastric fundic gland polyps have been noted rarely. These polyps are benign and appear to be reversible when treatment is discontinued. 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. 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]. Metabolic/Nutritional: Hypoglycemia, hypomagnesemia with or without hypocalcemia and/or hypokalemia, hyponatremia, weight gain. Musculoskeletal: Muscle weakness, myalgia, muscle cramps, joint pain, leg pain. 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: SCAR, including TEN (some fatal), SJS, DRESS, and AGEP; 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, erectile dysfunction. Hematologic: Agranulocytosis (some fatal), hemolytic anemia, pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia, leukocytosis. Clarithromycin : Hypersensitivity Reactions: Allergic reactions ranging from urticaria and mild skin eruptions to rare cases of anaphylaxis have occurred. Gastrointestinal: Glossitis, stomatitis, oral moniliasis, anorexia, vomiting, pancreatitis, tongue discoloration. Hematologic: Thrombocytopenia, leukopenia, neutropenia. Other: There have been reports of tooth discoloration in patients treated with clarithromycin. Tooth discoloration is usually reversible with professional dental cleaning. Nervous System/Psychiatric: There have been isolated reports of hearing loss, which is usually reversible, occurring chiefly in elderly women. Reports of alterations of the sense of smell, usually in conjunction with taste perversion or taste loss have also been reported. Transient CNS events including anxiety, behavioral changes, confusional states, convulsions, depersonalization, disorientation, hallucinations, insomnia, manic behavior, nightmares, psychosis, tinnitus, tremor, dizziness and vertigo have been reported during postmarketing surveillance. Events usually resolve with discontinuation of the drug. Hepatic: Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been infrequently reported with clarithromycin. This hepatic dysfunction may be severe and is usually reversible. In very rare instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications. Metabolic: There have been rare reports of hypoglycemia, some of which have occurred in patients taking oral hypoglycemic agents or insulin. Cardiac: As with other macrolides, clarithromycin has been associated with QT prolongation and ventricular arrhythmias, including ventricular tachycardia and torsades de pointes. Renal: There have been reports of interstitial nephritis coincident with clarithromycin use. Skin: SCAR, including TEN, SJS, DRESS, and AGEP. Amoxicillin : Gastrointestinal: Nausea, vomiting, diarrhea, anorexia, gastritis, black hairy tongue, glossitis, stomatitis, and hemorrhagic/ C.difficile -associated colitis. [ see Warnings and Precautions ( 5.5 ) ]. Hypersensitivity Reactions: Serum sickness like reactions, erythematous maculopapular rashes, erythema multiforme, exfoliative dermatitis, hypersensitivity vasculitis and urticaria have been reported. Reactions are more likely to occur in individuals who have previously demonstrated hypersensitivity to penicillins and in those with a history of allergy, asthma, hay fever, or urticaria. Hepatic: A moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted, but the significance of this finding is unknown. Hepatic dysfunction including cholestatic jaundice, hepatic cholestasis and acute cytolytic hepatitis have been reported. Renal: Crystalluria has also been reported [ see Overdosage ( 10 ) ]. Hemic and Lymphatic Systems: Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia and agranulocytosis have been reported during therapy with penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. Nervous System/Psychiatric: Reversible hyperactivity, agitation, anxiety, insomnia, confusion, aseptic meningitis, behavioral changes, and/or dizziness have been reported rarely. Miscellaneous: Tooth discoloration (brown, yellow, or gray staining) has been rarely reported. Most reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or dental cleaning in most cases. Skin: SCAR, including TEN, SJS, DRESS, and AGEP. Changes in Laboratory Values: Changes in laboratory values with possible clinical significance were as follows: Hepatic – elevated SGPT (ALT) less than 1%, SGOT (AST) less than 1%, GGT less than 1%, alkaline phosphatase less than 1%, LDH less than 1%, total bilirubin less than 1%; Hematologic – decreased WBC less than 1%, elevated prothrombin time 1%; Renal – elevated BUN 4%, elevated serum creatinine less than 1%. GGT, alkaline phosphatase, and prothrombin time data are from adult studies only.