Cubicin Side Effects

Generic Name: daptomycin

Please note - some side effects for Cubicin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Cubicin - for the Consumer

Cubicin

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 Cubicin:

Constipation; diarrhea; dizziness; headache; nausea; pain, swelling, or redness at the injection site; sore throat; sweating; trouble sleeping; vomiting.

Severe allergic reactions (rash; hives; itching; difficulty breathing; chest pain; tightness in the chest; swelling of the mouth, face, lips, or tongue); bloody or watery stools; change in the amount of urine produced; fever; muscle pain or weakness; numbness or tingling; severe or persistent diarrhea; stomach cramps/pain; swelling (eg, of the hands, ankles, feet); unusual tiredness or weakness.

Cubicin Side Effects - for the Professional

Cubicin

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.  The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Clinical studies sponsored by Cubist enrolled 1,667 patients treated with Cubicin and 1,319 treated with comparator.  Most adverse events reported in Cubist-sponsored Phase 1, 2, and 3 clinical studies were described as mild or moderate in intensity.  In Phase 3 cSSSI trials, Cubicin was discontinued in 15/534 (2.8%) patients due to an adverse event, while comparator was discontinued in 17/558 (3.0%) patients.  In the S. aureus bacteremia/endocarditis trial, Cubicin was discontinued in 20/120 (16.7%) patients due to an adverse event, while comparator was discontinued in 21/116 (18.1%) patients.

Gram-Negative Infections

In the S. aureus bacteremia/endocarditis trial, serious Gram-negative infections and nonserious Gram-negative bloodstream infections were reported in 10/120 (8.3%) Cubicin-treated and 0/115 comparator-treated patients.  Comparator patients received dual therapy that included initial gentamicin for 4 days.  Events were reported during treatment and during early and late follow-up.  Gram-negative infections included cholangitis, alcoholic pancreatitis, sternal osteomyelitis/mediastinitis, bowel infarction, recurrent Crohn’s disease, recurrent line sepsis, and recurrent urosepsis caused by a number of different Gram-negative organisms.  One patient with sternal osteomyelitis following mitral valve repair developed S. aureus endocarditis with a 2 cm mitral vegetation and had a course complicated with bowel infarction, polymicrobial bacteremia, and death.

Other Adverse Reactions

The rates of most common adverse events, organized by body system, observed in cSSSI patients are displayed in Table 5.

Additional adverse events that occurred in 1 to 2% of patients in either Cubicin (4 mg/kg) or comparator treatment groups in the cSSSI studies are as follows: edema, cellulitis, hypoglycemia, elevated alkaline phosphatase, cough, back pain, abdominal pain, hypokalemia, hyperglycemia, decreased appetite, anxiety, chest pain, sore throat, cardiac failure, confusion, and Candida infections.  These events occurred at rates ranging from 0.2 to 1.7% in Cubicin-treated patients and at rates of 0.4 to 1.8% in comparator-treated patients.

Additional drug-related adverse events (possibly or probably related) that occurred in <1% of patients receiving Cubicin in the cSSSI trials are as follows:

Body as a Whole: fatigue, weakness, rigors, discomfort, jitteriness, flushing, hypersensitivity
Blood/Lymphatic System: leukocytosis, thrombocytopenia, thrombocytosis, eosinophilia, increased International Normalized Ratio (INR)
Cardiovascular System: supraventricular arrhythmia
Dermatologic System: eczema
Digestive System: abdominal distension, flatulence, stomatitis, jaundice, increased serum lactate dehydrogenase
Metabolic/Nutritional System: hypomagnesemia, increased serum bicarbonate, electrolyte disturbance
Musculoskeletal System: myalgia, muscle cramps, muscle weakness, osteomyelitis
Nervous System: vertigo, mental status change, paraesthesia
Special Senses: taste disturbance, eye irritation

The rates of most common adverse events, organized by System Organ Class (SOC), observed in S. aureus bacteremia/endocarditis (6 mg/kg Cubicin) patients are displayed in Table 6.

The following events, not included above, were reported as possibly or probably drug-related in the Cubicin-treated group:

Blood and Lymphatic System Disorders: eosinophilia (1.7%), lymphadenopathy (<1%), thrombocythaemia (<1%), thrombocytopenia (<1%)
Cardiac Disorders: atrial fibrillation (<1%), atrial flutter (<1%), cardiac arrest (<1%)
Ear and Labyrinth Disorders: tinnitus (<1%)
Eye Disorders: vision blurred (<1%)
Gastrointestinal Disorders: dry mouth (<1%), epigastric discomfort (<1%), gingival pain (<1%), hypoaesthesia oral (<1%)
Infections and Infestations: candidal infection NOS (1.7%), vaginal candidiasis (1.7%), fungaemia (<1%), oral candidiasis (<1%), urinary tract infection fungal (<1%)
Investigations: blood phosphorous increased (2.5%), blood alkaline phosphatase increased (1.7%), INR increased (1.7%), liver function test abnormal (1.7%), alanine aminotransferase increased (<1%), aspartate aminotransferase increased (<1%), prothrombin time prolonged (<1%)
Metabolism and Nutrition Disorders: appetite decreased NOS (<1%)
Musculoskeletal and Connective Tissue Disorders: myalgia (<1%)
Nervous System Disorders: dyskinesia (<1%), paraesthesia (<1%)
Psychiatric Disorders: hallucination NOS (<1%)
Renal and Urinary Disorders: proteinuria (<1%), renal impairment NOS (<1%)
Skin and Subcutaneous Tissue Disorders: heat rash (<1%), pruritus generalized (<1%), rash vesicular (<1%)

In Phase 3 studies of community-acquired pneumonia (CAP), the death rate and rates of serious cardiorespiratory adverse events were higher in Cubicin-treated patients than in comparator-treated patients.  These differences were due to lack of therapeutic effectiveness of Cubicin in the treatment of CAP in patients experiencing these adverse events.

Laboratory Changes

In Phase 3 comparator-controlled cSSSI and CAP studies, there was no clinically or statistically significant difference (p<0.05) in the incidence of CPK elevations between patients treated with Cubicin and those treated with comparator.  CPK elevations in both groups were generally related to medical conditions—for example, skin and skin structure infection, surgical procedures, or intramuscular injections—and were not associated with muscle symptoms.

In the Phase 3 cSSSI studies, 0.2% of patients treated with Cubicin had symptoms of muscle pain or weakness associated with CPK elevations to greater than 4X ULN.  The symptoms resolved within 3 days and CPK returned to normal within 7 to 10 days after discontinuing treatment.  Table 7 summarizes the CPK shifts from Baseline through End of Therapy in the cSSSI trials.

In the S. aureus bacteremia/endocarditis study, a total of 11 Cubicin-treated patients (9.2%) had treatment-emergent elevations in CPK to >500 U/L, including 4 patients with elevations >10X ULN.  Three of these 11 patients had CPK levels return to the normal range during continued Cubicin treatment, 6 had values return to the normal range during follow-up, 1 had values returning toward baseline at the last assessment, and 1 did not have follow-up values reported.  Three patients discontinued Cubicin due to CPK elevation.

There was more renal dysfunction in comparator-treated patients than in Cubicin-treated patients.  The incidence of decreased renal function, defined as the proportion of patients with a creatinine clearance level <50 mL/min if baseline clearance was ≥50 mL/min or with a decrease of ≥10 mL/min if baseline clearance was <50 mL/min, is shown in Table 8.

Post-Marketing Experience

The following adverse reactions have been reported with Cubicin in worldwide post-marketing experience.  Because these events are reported voluntarily from a population of unknown size, estimates of frequency cannot be made and causal relationship cannot be precisely established.

Immune System Disorders: anaphylaxis; hypersensitivity reactions, including pruritus, hives, shortness of breath, difficulty swallowing, truncal erythema, and pulmonary eosinophilia
Musculoskeletal Disorders: myoglobin increased; rhabdomyolysis (some reports involved patients treated concurrently with Cubicin and HMG-CoA reductase inhibitors)
Nervous System Disorders: peripheral neuropathy
Skin and Subcutaneous Tissue Disorders: vesiculobullous rash with or without mucous membrane involvement

Side Effects by Body System

General

Most adverse events reported in clinical trials were mild to moderate in severity. Daptomycin was discontinued in 2.8% of patients due to side effects in phase 3 trials and 16.7% to 18.1% in postmarketing and comparison trials.

Gastrointestinal

Gastrointestinal side effects have included constipation (6.2% to 10.8%); nausea (5.8% to 10%); diarrhea (5.2% to 11.7%); vomiting (3.2% to 11.7%); dyspepsia (0.9% to 4.2%); loose stools (4.2%); gastrointestinal disorders (unspecified; 1.7%); gastrointestinal hemorrhage (1.7%); abdominal distention, flatulence, and stomatitis (less than 1%); abnormal bowel sounds; and aphthous stomatitis.

Local

Local side effects have included injection site reactions (2.5% to 5.8%) and injection site phlebitis.

Nervous system

Nervous system side effects have included peripheral nervous system events (such as paresthesias, dysesthesias, and peripheral neuropathies; 9.2%), headache (5.4% to 6.7%), insomnia (4.5% to 9.2%), dizziness (2.2% to 5.8%), anxiety (0.2 to 5%), nervous system disorders (unspecified; 3.3%), confusion (0.2% to 1.7%); vertigo, mental status change, and paresthesia (less than 1%); and hypoesthesia. Peripheral neuropathy has been reported during postmarketing experience.

Dermatologic

Dermatologic side effects have included rash (4.3% to 6.7%), pruritus (2.8% to 5.8%), sweating (5%), erythema (5%), cellulitis (0.2% to 1.7 %), eczema (less than 1%), and papular rash. Vesiculobullous rash (with or without mucous membrane involvement) has been reported during postmarketing experience.

Hepatic

Hepatic side effects have included abnormal liver function tests (3%), elevated alkaline phosphatase (0.2 to 1.7%), jaundice (less than 1%), increased lactate dehydrogenase (less than 1%), and hepatobiliary disorder (unspecified; at least 1 patient).

Musculoskeletal

Musculoskeletal side effects have included elevated creatine phosphokinase (CPK; 2.8% to 6.7%), limb pain (1.5% to 9.2%), back pain (6.7%), arthralgia (0.9% to 3.3%); myalgia, myositis, muscle cramps, muscle weakness, and osteomyelitis (less than 1%); and muscle twitching. In clinical studies, 0.2% of patients developed CPK elevations greater than 4 times ULN and muscle pain or weakness. After discontinuation of daptomycin, CPK returned to normal within 7 to 10 days and symptoms resolved within 3 days. Myopathy with minor increases in creatine kinase has also been reported. Case reports of rhabdomyolysis with secondary acute renal failure and other reports of severe myopathy and possible hepatotoxicity were recorded with use of daptomycin therapy. Increased myoglobin has been reported during postmarketing experience.

A 45-year-old female with refractory acute myeloid leukemia was admitted to the blood and marrow transplant unit for a second attempt to induce remission with myeloablative chemotherapy of high-dose cytarabine. Two months prior, the patient's first course of induction therapy was complicated by neutropenic fever and vancomycin- resistant Enterococcus faecium (VRE) bacteremia that was treated with linezolid for 14 days. The patient was also receiving aztreonam, levofloxacin, acyclovir, amphotericin B lipid complex, and azithromycin. Once her clinical status stabilized, she was transferred from the intensive care unit (ICU) back to the blood and marrow transplant unit. After receiving 8 of 12 scheduled doses of cytarabine, the patient required readmission to the medical ICU due to a decrease in mental status, supraventricular tachycardia, and hypotension. Cultures of blood and urine samples at the time of her transfer showed VRE with intermediate resistance to linezolid. The patient, who was neutropenic at this time, was started on intravenous daptomycin 550 mg (6 mg/kg) every 24 hours.

The patient's baseline creatine phosphokinase (CPK) was 108 units/L and serum creatinine level was 0.8 mg/dL. Over the following 7 days, the patient's CPK level gradually increased, and on day 10 of daptomycin treatment, her CPK level was 996 units/L, blood urea nitrogen level (BUN) was 73 mg/dL, and serum creatinine level was 1.9 mg/dL. To evaluate for rhabdomyolysis, urine myoglobin was measured and reported at 30,890 ng/mL. Rhabdomyolysis was diagnosed based on increased CPK and urine myoglobin level in a patient with acute renal failure.

Daptomycin was discontinued and the patient was started on treatment for rhabdomyolysis. Despite aggressive hydration and diuresis, CPK and urine myoglobin levels continued to increase up to 5350 units/L and 47,166 ng/mL, respectively. Over 2 weeks, the patient's CPK and urine myoglobin levels slowly resolved. The final CPK and urine myoglobin levels measured were 3395 units/L and 451 ng/mL, respectively.

In another case, a 53-year-old African-American female with a history of hypertension, diabetes mellitus, and peripheral vascular disease was admitted to the hospital and an MRI revealed L5-S1 discitis and osteomyelitis. After an 8-week course of empirical antibiotic therapy with vancomycin and levofloxacin an open biopsy was performed. Specimens from the biopsy cultured positive for Torulopsis glabrata, VRE, and methicillin-resistant Staphylococcus aureus (MRSA) and the patient was started on daptomycin 360 mg (6 mg/kg) intravenously as a single daily dose and voriconazole 250 mg twice daily.

Ten days after the start of daptomycin therapy, the patient developed generalized muscular weakness that progressed to the point she was unable to get out of bed. The patient then developed nonoliguric acute renal failure with a serum creatinine of 27 mg/mL up from baseline of 9 mg/mL. A CPK level drawn was elevated to 21,243 units/L and was associated with elevated levels aspartate aminotransferase (AST) 375 units/L, alanine aminotransferase (ALT) 219 units/L, and lactate dehydrogenase (LDH) 666 units/L. Urinalysis was positive for hemoglobin, myoglobin, and red blood cells which conferred a diagnosis of acute renal failure secondary to daptomycin-induced rhabdomyolysis.

After daptomycin was discontinued and intravenous fluid was administered to alkalinize the urine, renal function, CPK, and liver function tests returned to baseline as well as dissipation of muscular weakness. Myoglobin, hemoglobin and the red blood cells disappeared from urine as well.

In another similar case, a 52-year-old male with a history hepatitis C, intravenous drug abuse, idiopathic thrombocytopenia, and hyperlipidemia was admitted to the hospital and an MRI revealed findings compatible with L3-L4 discitis and osteomyelitis. He was started on vancomycin but it was discontinued after a rash developed. Daptomycin was started at 500 mg (6.5 mg/kg) intravenous as a single daily dose. The patient was also on simvastatin, however, it was discontinued prior to initiation of daptomycin therapy. After nine days into the course of daptomycin therapy, the patient developed generalized muscle weakness progressing to the point where he was unable to get out of bed. The patient's CPK rose to 20,771 units/L from a baseline of 102 units/L. AST 239 units/L and ALT 40 units/L were elevated from baseline and alkaline phosphatase was elevated to 118 units/L.

Daptomycin was discontinued and the patient was admitted to the intensive care unit for close monitoring and hydration. The patient slowly improved and recovered all muscle strength and within two weeks his enzymes returned to baseline.

Genitourinary

Genitourinary side effects have included urinary tract infections (2.4% to 6.7%), vaginal discharge, and asymptomatic foamy urine.

Cardiovascular

Cardiovascular side effects have included cardiac disorders (unspecified; 7.5%), hypotension (2.4% to 5.0%), hypertension (1.1% to 5.8%), vascular disorders (unspecified; 1.7%), edema (0.2% to 1.7%), cardiac failure (0.2% to 1.7%), and supraventricular arrhythmia (less than 1%).

Renal

Renal side effects have included worsening creatinine clearance (19.8%), renal dysfunction (11%), renal impairment (interstitial nephritis, toxic nephropathy, acute prerenal failure, acute or chronic renal failure, renal impairment, and renal tubular necrosis; 6.7%), renal failure (2.2% to 3.3%), and renal and urinary disorders (unspecified; 0.8%).

Hematologic

Hematologic side effects have included anemia (2.1% to 12.5%), blood and lymphatic system disorders (unspecified; 0.8%), and leukocytosis, thrombocytopenia, thrombocytosis, eosinophilia, and increased INR in less than 1% of patients.

Respiratory

Respiratory side effects have included sore throat (0.2% to 8.3%); respiratory, thoracic, and mediastinal disorders (unspecified; 6.7%); pleural effusions (5.8%); dyspnea (2.1% to 3.3%); and cough (0.2% to 3.3%).

Metabolic

Metabolic side effects have included hypokalemia (9.2%), hyperkalemia (0.2% to 5%), metabolism and nutrition disorders (unspecified; 1.7%), hypoglycemia (0.2% to 1.7%); hypomagnesemia, increased serum bicarbonate, and electrolyte disturbance (less than 1%).

Hypersensitivity

Hypersensitivity reactions (unspecified) have been reported in less than 1% of study patients.

Immunologic

Immunologic side effects have included anaphylaxis and hypersensitivity reactions (including pruritus, hives, shortness of breath, difficulty swallowing, truncal erythema, and pulmonary eosinophilia) in postmarketing reports.

Other

Other side effects have included infections and infestations (unspecified; 31.7%); peripheral edema (6.7%); chest pain (0.2% to 6.7%); sepsis (5%); bacteremia (5%); pneumonia infection (3.3%); laboratory abnormalities (unspecified; 2.5%); general disorders and conditions at the injection site (unspecified; 2.5%); fungal infections (2.6%); injury, poisoning, and procedural complications (unspecified; 1.7%); Candida infections (0.2% to 1.7%); fungemia (less than 1%); fever (1.9%); decreased appetite (0.2% to 1.7%); abdominal pain (0.2% to 1.7%); fatigue, weakness, rigors, discomfort, jitteriness, flushing, and taste disturbance (less than 1%); and chapped lips, adenoviral upper respiratory infection, and upper respiratory tract infection (not otherwise specified). Gram negative infections and nonserious gram-negative bloodstream infections have also been reported.

Serious and nonserious gram-negative infections were reported in 8.3% (10/120) of daptomycin treated patients in the Staphylococcus aureus bacteremia/endocarditis trial compared to 0/120 in comparator-treated patients. Gram-negative infections included cholangitis, alcoholic pancreatitis, sternal osteomyelitis/mediastinitis, bowel infarction, recurrent Crohn's disease, recurrent line sepsis, and recurrent urosepsis.

One patient developed S. aureus endocarditis with a 2 cm mitral vegetation, bowel infarction, and polymicrobial bacteremia that ultimately lead to death following mitral valve repair complicated by sternal osteomyelitis.

Other

In phase 3 trials of community-acquired pneumonia, daptomycin was associated with a higher death rate and rate of serious cardiorespiratory adverse events than comparator drugs, due to lack of clinical efficacy.

Psychiatric

Psychiatric side effects have included psychiatric disorders (unspecified; 3.3%).

Ocular

Ocular side effects have included eye irritation (less than 1%).

Oncologic

Oncologic side effects have included benign and malignant neoplasms (unspecified; 0.8%).

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