Daptomycin

Daptomycin is eliminated primarily by the kidney.

Due to limited clinical experience (see table and footnotes below) daptomycin should only be used in patients with any degree of renal impairment (CrCl <80 ml/min) when it is considered that the expected clinical benefit outweighs the potential risk. The response to treatment, renal function and creatine phosphokinase (CPK) levels should be closely monitored in all patients with any degree of renal impairment. The dosage regimen for daptomycin in paediatric patients with renal impairment has not been established.

Dose adjustments in patients with renal impairment by indication and creatinine clearance:

cSSTI = complicated skin and soft-tissue infections; SAB = S. aureus bacteraemia
¹ The safety and efficacy of the dose interval adjustment have not been evaluated in controlled clinical trials and the recommendation is based on pharmacokinetic studies and modelling results
² The same dose adjustments, which are based on pharmacokinetic data in volunteers including PK modelling results, are recommended for patients on haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). Whenever possible, daptomycin should be administered following the completion of dialysis on dialysis days.

No data are available in patients with severe hepatic impairment (Child-Pugh Class C). Therefore caution should be exercised if Cubicin is given to such patients.

There is limited experience regarding concomitant administration of daptomycin with other medicinal products that may trigger myopathy (e.g. HMG-CoA reductase inhibitors). However, some cases of marked rises in CPK levels and cases of rhabdomyolysis occurred in patients taking one of these medicinal products at the same time as daptomycin. It is recommended that other medicinal products associated with myopathy should if possible be temporarily discontinued during treatment with daptomycin unless the benefits of concomitant administration outweigh the risk. If co-administration cannot be avoided, CPK levels should be measured more frequently than once weekly and patients should be closely monitored for any signs or symptoms that might represent myopathy.

Although small changes in the pharmacokinetics of daptomycin and tobramycin were observed during coadministration by intravenous infusion over a 30-minute period using a daptomycin dose of 2 mg/kg, the changes were not statistically significant. The interaction between daptomycin and tobramycin with an approved dose of daptomycin is unknown. Caution is warranted when daptomycin is co-administered with tobramycin.

Experience with the concomitant administration of daptomycin and warfarin is limited. Studies of daptomycin with anticoagulants other than warfarin have not been conducted. Anticoagulant activity in patients receiving daptomycin and warfarin should be monitored for the first several days after therapy with daptomycin is initiated.

Clostridium difficile-associated diarrhoea (CDAD) has been reported with daptomycin. If CDAD is suspected or confirmed, daptomycin may need to be discontinued and appropriate treatment instituted as clinically indicated.

Eosinophilic pneumonia has been reported in patients receiving daptomycin. In most reported cases associated with daptomycin, patients developed fever, dyspnoea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates. The majority of cases occurred after more than 2 weeks of treatment with daptomycin and improved when daptomycin was discontinued and steroid therapy was initiated. Recurrence of eosinophilic pneumonia upon re-exposure has been reported. Patients who develop these signs and symptoms while receiving daptomycin should undergo prompt medical evaluation, including, if appropriate, bronchoalveolar lavage, to exclude other causes (e.g. bacterial infection, fungal infection, parasites, other medicinal products). Daptomycin should be discontinued immediately and treatment with systemic steroids should be initiated when appropriate.

Anaphylaxis/hypersensitivity reactions have been reported with daptomycin. If an allergic reaction to daptomycin occurs, discontinue use and institute appropriate therapy.

Patients who develop signs or symptoms that might represent a peripheral neuropathy during therapy with daptomycin should be investigated and consideration should be given to discontinuation of daptomycin.

No clinical data on pregnancies are available for daptomycin. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.

Daptomycin should not be used during pregnancy unless clearly necessary i.e., only if the expected benefit outweighs the possible risk.

In a single human case study, daptomycin was intravenously administered daily for 28 days to a nursing mother at a dose of 500 mg/day, and samples of the patient’s breast milk were collected over a 24-hour period on day 27. The highest measured concentration of daptomycin in the breast milk was 0.045 mcg/ml, which is a low concentration. Therefore, until more experience is gained, breast-feeding should be discontinued when daptomycin is administered to nursing women.

Fertility

No clinical data on fertility are available for daptomycin. Animal studies do not indicate direct or indirect harmful effects with respect to fertility.

No studies on the effects on the ability to drive and use machines have been performed.

On the basis of reported adverse drug reactions, daptomycin is presumed to be unlikely to produce an effect on the ability to drive or use machinery.

Summary of the safety profile

In clinical studies, 2,011 subjects received daptomycin. Within these trials, 1,221 subjects received a daily dose of 4 mg/kg, of whom 1,108 were patients and 113 were healthy volunteers; 460 subjects received a daily dose of 6 mg/kg, of whom 304 were patients and 156 were healthy volunteers. Adverse reactions (i.e. considered by the investigator to be possibly, probably, or definitely related to the medicinal product) were reported at similar frequencies for daptomycin and comparator regimens.

The most frequently reported adverse reactions (frequency common (≥1/100 to <1/10)) are: Fungal infections, urinary tract infection, candida infection, anaemia, anxiety, insomnia, dizziness, headache, hypertension, hypotension, gastrointestinal and abdominal pain, nausea, vomiting, constipation, diarrhoea, flatulence, bloating and distension, liver function tests abnormal (increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP)), rash, pruritus, limb pain, serum creatine phosphokinase (CPK) increased, infusion site reactions, pyrexia, asthenia.

Less frequently reported, but more serious, adverse reactions include hypersensitivity reactions, eosinophilic pneumonia, drug rash with eosinophilia and systemic symptoms (DRESS), angioedema and rhabdomyolysis.

Tabulated list of adverse reactions

The following adverse reactions were reported during therapy and during follow-up with frequencies corresponding to very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data):

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1. Adverse reactions from clinical studies and post-marketing reports:

Infections and infestations

Common: Fungal infections, urinary tract infection, candida infection

Uncommon: Fungaemia

Not known*: Clostridium difficile-associated diarrhoea

Blood and lymphatic system disorders

Common: Anaemia

Uncommon: Thrombocythaemia, eosinophilia, international normalised ratio (INR) increased, leukocytosis

Rare: Prothrombin time (PT) prolonged

Not known*: Thrombocytopaenia

Immune system disorders

Not known*: Hypersensitivity, manifested by isolated spontaneous reports including, but not limited to angioedema, drug rash with eosinophilia and systemic symptoms (DRESS), pulmonary eosinophilia, vesicobullous rash with mucous membrane involvement and sensation of oropharyngeal swelling, anaphylaxis, infusion reactions including the following symptoms: tachycardia, wheezing, pyrexia, rigors, systemic flushing, vertigo, syncope and metallic taste

Metabolism and nutrition disorders

Uncommon: Decreased appetite, hyperglycaemia, electrolyte imbalance

Psychiatric disorders

Common: Anxiety, insomnia

Nervous system disorders

Common: Dizziness, headache

Uncommon: Paraesthesia, taste disorder, tremor, eye irritation

Not known*: Peripheral neuropathy

Ear and labyrinth disorders

Uncommon: Vertigo

Cardiac disorders

Uncommon: Supraventricular tachycardia, extrasystole

Vascular disorders

Common: Hypertension, hypotension

Uncommon: Flushes

Respiratory, thoracic and mediastinal disorders

Not known*: Eosinophilic pneumonia¹, cough

Gastrointestinal disorders

Common: Gastrointestinal and abdominal pain, nausea, vomiting, constipation, diarrhoea, flatulence, bloating and distension

Uncommon: Dyspepsia, glossitis

Hepatobiliary disorders

Common: Liver function tests abnormal² (increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP))

Rare: Jaundice

Skin and subcutaneous tissue disorders

Common: Rash, pruritus

Uncommon: Urticaria

Not known*: Acute generalised exanthematous pustulosis

Musculoskeletal and connective tissue disorders

Common: Limb pain, serum creatine phosphokinase (CPK)² increased

Uncommon: Myositis, increased myoglobin, muscular weakness, muscle pain, arthralgia, serum lactate dehydrogenase (LDH) increased, muscle cramps

Not known*: Rhabdomyolysis³

Renal and urinary disorders

Uncommon: Renal impairment, including renal failure and renal insufficiency, serum creatinine increased

Reproductive system and breast disorders

Uncommon: Vaginitis

General disorders and administration site conditions

Common: Infusion site reactions, pyrexia, asthenia

Uncommon: Fatigue, pain

* Based on post-marketing reports. Since these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known.
¹ While the exact incidence of eosinophilic pneumonia associated with daptomycin is unknown, to date the reporting rate of spontaneous reports is very low (<1/10,000).
² In some cases of myopathy involving raised CPK and muscle symptoms, the patients also presented with elevated transaminases. These transaminase increases were likely to be related to the skeletal muscle effects. The majority of transaminase elevations were of Grade 1-3 toxicity and resolved upon discontinuation of treatment.
³ When clinical information on the patients was available to make a judgement, approximately 50% of the cases occurred in patients with pre-existing renal impairment, or in those receiving concomitant medicinal products known to cause rhabdomyolysis.

The safety data for the administration of daptomycin via 2-minute intravenous injection are derived from two pharmacokinetic studies in healthy volunteers. Based on these study results, both methods of daptomycin administration, the 2-minute intravenous injection and the 30-minute intravenous infusion, had a similar safety and tolerability profile. There was no relevant difference in local tolerability or in the nature and frequency of adverse reactions.