Merrem Side Effects

Generic Name: meropenem

Please note - some side effects for Merrem may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Merrem - for the Consumer

Merrem

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Merrem:

Constipation; headache; mild diarrhea; mild pain, swelling, or redness at the injection site; nausea; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur when using Merrem:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); bloating; bloody stools; breathing problems; chest pain; dark urine; decreased urination; depression; fast, slow, or irregular heartbeat; fever, chills, or sore throat; hearing loss; joint pain or tenderness; mental or mood changes (eg, agitation, anxiety, confusion); numbness or tingling of the skin; red, swollen, blistered, or peeling skin; seizures; severe diarrhea; severe stomach cramps or pain; shortness of breath; swelling of the hands or feet; tremors or abnormal muscle movements; unusual bruising or bleeding; unusual tiredness or weakness; unusual vaginal odor or discharge; vein swelling or tenderness; white patches in the mouth; yellowing of the eyes or skin.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Merrem Side Effects - for the Professional

Merrem

The following are discussed in greater detail in other sections of labeling:

• Hypersensitivity Reactions [see Warnings and Precautions (5.1)]

• Seizure Potential [see Warnings and Precautions (5.2)]

• Interaction with Valproic Acid [see Warnings and Precautions (5.3)]

• Clostridium difficile – Associated Diarrhea [see Warnings and Precautions (5.4)]

• Development of Drug-Resistant Bacteria [see Warnings and Precautions (5.5)]

• Overgrowth of Nonsusceptible Organisms [see Warnings and Precautions (5.6)]

• Laboratory Tests [see Warnings and Precautions (5.7)]

• Patients with Renal Impairment [see Warnings and Precautions (5.8)]

• Dialysis [see Warnings and Precautions (5.9)]

Adverse Reactions from Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reactions 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.

Adult Patients:

During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with Merrem I.V. (500 mg or 1000 mg every 8 hours). Deaths in 5 patients were assessed as possibly related to meropenem; 36 (1.2%) patients had meropenem discontinued because of adverse events. Many patients in these trials were severely ill and had multiple background diseases, physiological impairments and were receiving multiple other drug therapies. In the seriously ill patient population, it was not possible to determine the relationship between observed adverse events and therapy with Merrem I.V.

The following adverse reaction frequencies were derived from the clinical trials in the 2904 patients treated with Merrem I.V.

Local Adverse Reactions

Local adverse reactions that were reported irrespective of the relationship to therapy with Merrem I.V. were as follows:

Inflammation at the injection site	2.4%
Injection site reaction	0.9%
Phlebitis/thrombophlebitis	0.8%
Pain at the injection site	0.4%
Edema at the injection site	0.2%

Systemic Adverse Reactions

Systemic adverse reactions that were reported irrespective of the relationship to Merrem I.V. occurring in greater than 1.0% of the patients were diarrhea (4.8%), nausea/vomiting (3.6%), headache (2.3%), rash (1.9%), sepsis (1.6%), constipation (1.4%), apnea (1.3%), shock (1.2%), and pruritus (1.2%).

Additional systemic adverse reactions that were reported irrespective of relationship to therapy with Merrem I.V. and occurring in less than or equal to 1.0% but greater than 0.1% of the patients are listed below within each body system in order of decreasing frequency:

Bleeding events were seen as follows: gastrointestinal hemorrhage (0.5%), melena (0.3%), epistaxis (0.2%), hemoperitoneum (0.2%), summing to 1.2%.

Body as a Whole: pain, abdominal pain, chest pain, fever, back pain, abdominal enlargement, chills, pelvic pain

Cardiovascular: heart failure, heart arrest, tachycardia, hypertension, myocardial infarction, pulmonary embolus, bradycardia, hypotension, syncope

Digestive System: oral moniliasis, anorexia, cholestatic jaundice/jaundice, flatulence, ileus, hepatic failure, dyspepsia, intestinal obstruction

Hemic/Lymphatic: anemia, hypochromic anemia, hypervolemia

Metabolic/Nutritional: peripheral edema, hypoxia

Nervous System: insomnia, agitation/delirium, confusion, dizziness, seizure, nervousness, paresthesia, hallucinations, somnolence, anxiety, depression, asthenia [see Warnings and Precautions (5.2)]

Respiratory: respiratory disorder, dyspnea, pleural effusion, asthma, cough increased, lung edema

Skin and Appendages: urticaria, sweating, skin ulcer

Urogenital System: dysuria, kidney failure, vaginal moniliasis, urinary incontinence

Adverse Laboratory Changes

Adverse laboratory changes that were reported irrespective of relationship to Merrem I.V. and occurring in greater than 0.2% of the patients were as follows:

Hepatic: increased SGPT (ALT), SGOT (AST), alkaline phosphatase, LDH, and bilirubin

Hematologic: increased platelets, increased eosinophils, decreased platelets, decreased hemoglobin, decreased hematocrit, decreased WBC, shortened prothrombin time and shortened partial thromboplastin time, leukocytosis, hypokalemia

Renal: increased creatinine and increased BUN

NOTE: For patients with varying degrees of renal impairment, the incidence of heart failure, kidney failure, seizure and shock reported irrespective of relationship to Merrem I.V., increased in patients with moderately severe renal impairment (creatinine clearance >10 to 26 mL/min) [see Dosage and Administration (2.2), Warnings and Precautions (5.8), Use in Specific Populations (8.5) and (8.6) and Clinical Pharmacology (12.3)].

Urinalysis: presence of red blood cells

Complicated Skin and Skin Structure Infections

In a study of complicated skin and skin structure infections, the adverse reactions were similar to those listed above. The most common adverse events occurring in >5% of the patients were: headache (7.8%), nausea (7.8%), constipation (7.0%), diarrhea (7.0%), anemia (5.5%), and pain (5.1%). Adverse events with an incidence of >1%, and not listed above, include: pharyngitis, accidental injury, gastrointestinal disorder, hypoglycemia, peripheral vascular disorder, and pneumonia.

Pediatric Patients

Clinical Adverse Reactions

Merrem I.V. was studied in 515 pediatric patients (≥ 3 months to < 13 years of age) with serious bacterial infections (excluding meningitis. See next section.) at dosages of 10 to 20 mg/kg every 8 hours. The types of clinical adverse events seen in these patients are similar to the adults, with the most common adverse events reported as possibly, probably, or definitely related to Merrem I.V. and their rates of occurrence as follows:

Diarrhea		3.5%
Rash		1.6%
Nausea and Vomiting		0.8%

Merrem I.V. was studied in 321 pediatric patients (> 3 months to < 17 years of age) with meningitis at a dosage of 40 mg/kg every 8 hours. The types of clinical adverse events seen in these patients are similar to the adults, with the most common adverse events reported as possibly, probably, or definitely related to Merrem I.V. and their rates of occurrence as follows:

Diarrhea	4.7%
Rash (mostly diaper area moniliasis)	3.1%
Oral Moniliasis	1.9%
Glossitis	1.0%

In the meningitis studies, the rates of seizure activity during therapy were comparable between patients with no CNS abnormalities who received meropenem and those who received comparator agents (either cefotaxime or ceftriaxone). In the Merrem I.V. treated group, 12/15 patients with seizures had late onset seizures (defined as occurring on day 3 or later) versus 7/20 in the comparator arm.

Adverse Laboratory Changes

Laboratory changes seen in the pediatric studies, including the meningitis studies, were similar to those reported in the adult studies.

There is no experience in pediatric patients with renal impairment.

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of Merrem I.V. 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.

Worldwide post-marketing adverse reactions not otherwise listed in the Adverse Reactions section of this product label and reported as possibly, probably, or definitely drug related are listed within each body system in order of decreasing severity. Hematologic - agranulocytosis, neutropenia, and leukopenia; a positive direct or indirect Coombs test, and hemolytic anemia. Skin-toxic epidermal necrolysis, Stevens-Johnson Syndrome, angioedema, and erythema multiforme.

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Side Effects by Body System - for Healthcare Professionals

Gastrointestinal

Clostridium difficile associated diarrhea (CDAD) has been reported in patients treated with carbapenem antibiotics. If diarrhea occurs and it is unresponsive to discontinuation of the drug and/or standard therapy, CDAD should be considered.

Gastrointestinal side effects have included diarrhea (4.8%), nausea/vomiting (3.6%), and constipation (1.4%). Oral moniliasis, anorexia, flatulence, ileus, dyspepsia, and intestinal obstruction have been reported in greater than 0.1% to 1% of patients.

Hepatic

Hepatic side effects have included increased AST, ALT, alkaline phosphatase, LDH, and bilirubin in greater than 0.2% of patients. Hepatic failure, cholestatic jaundice, and jaundice have been reported in greater than 0.1% to 1% of patients.

Nervous system

Seizures have been infrequently reported in clinical trials (0.5% of patients). They have occurred most commonly in patients with renal insufficiency, history of seizure, or CNS abnormality.

Nervous system side effects have included headache (2.3%) and hearing loss (9% greater than 60 dB; 8% 40 to 60 dB; 20% 20 to 40 dB). Insomnia, agitation/delirium, confusion, dizziness, seizure, nervousness, paresthesia, hallucinations, somnolence, anxiety, depression, and asthenia have been reported in greater than 0.1% to 1% of patients. Seizures occur more commonly in patients with moderately severe renal dysfunction.

Local

Local side effects have included inflammation at the injection site (2.4%), injection site reactions (0.9%), phlebitis/thrombophlebitis (0.8%), pain at the injection site (0.4%), and edema at the injection site (0.2%).

Hypersensitivity

A 75-year-old female developed toxic epidermal necrolysis (TEN) over 40% of her body surface area after receiving cefotaxime. After cefotaxime discontinuation and some improvement, meropenem was started. The TEN immediately recurred and spread to previously unaffected areas of the skin, and the patient died. The authors recommend avoiding chemically similar drugs to the precipitating drug when treating patients with drug-induced TEN.

Hypersensitivity side effects including rash and pruritus were reported in 1.7% and 1.6% of patients (respectively) receiving meropenem. Toxic epidermal necrolysis, Stevens-Johnson syndrome, and serum sickness-like reactions have also been reported. Cross-sensitivity may occur in penicillin-allergic and cephalosporin-allergic patients.

Hematologic

Hematologic side effects have included epistaxis (0.2%), gastrointestinal hemorrhage (0.5%), melena (0.3%), and hemoperitoneum (0.2%). Anemia, hypochromic anemia, and hypervolemia have been reported in greater than 0.1% to 1%. Increased platelets, increased eosinophils, decreased platelets, decreased hemoglobin, decreased hematocrit, decreased WBC, decreased prothrombin time, decreased partial thromboplastin time, and leukocytosis have been reported in more than 0.2% of patients. Agranulocytosis, neutropenia, leukopenia, a positive Coombs test (direct or indirect), and hemolytic anemia have been reported during postmarketing experience.

Musculoskeletal

Musculoskeletal side effects have rarely included myalgia and arthralgia.

Dermatologic

Dermatologic side effects have included rash (1.9%), pruritus (1.2%), and diaper area moniliasis (3.1% of pediatric patients). Urticaria, sweating, and skin ulcer have been reported in greater than 0.1% to 1% of patients. Toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, and erythema multiforme have been reported during postmarketing experience.

Renal

Renal side effects have included kidney failure in greater than 0.1% to 1% of patients. Increased creatinine and BUN have been reported in more than 0.2% of patients. Kidney failure occurs more commonly in patients with moderately severe renal dysfunction.

Respiratory

Respiratory side effects have included apnea (1.3%), and respiratory disorder, dyspnea, pleural effusion, asthma, increased cough, and lung edema in greater than 0.1% to 1% of patients.

Genitourinary

Genitourinary side effects have included dysuria, vaginal moniliasis, and urinary incontinence in greater than 0.1% to 1% of patients. Urine RBCs have been reported in more than 0.2%.

General

In clinical trials (n=2904), meropenem was discontinued in 1.2% due to adverse events and 5 deaths were possibly related to meropenem.

Other

Other side effects have included sepsis (1.6%) and shock (1.2%). Pain, abdominal pain, chest pain, back pain, chills, pelvic pain, and abdominal enlargement have been reported in greater than 0.1% to 1% of patients. Shock occurs more commonly in patients with moderately severe renal dysfunction.

Cardiovascular

Cardiovascular side effects have included heart failure, heart arrest, tachycardia, hypertension, myocardial infarction, pulmonary embolus, bradycardia, hypotension, and syncope in greater than 0.1% to 1% of patients. Heart failure occurs more commonly in patients with moderately severe renal dysfunction.

Metabolic

Metabolic side effects have included peripheral edema and hypoxia in greater than 0.1% to 1% of patients and hypokalemia in more than 0.2%.

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