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Overall, the reported number of adverse events in the double-blind period of the controlled trial was similar for the CAFCIT (caffeine citrate) (caffeine citrate) and placebo groups. The following table shows adverse events that occurred in the double-blind period of the controlled trial and that were more frequent in CAFCIT (caffeine citrate) treated patients than placebo.

ADVERSE EVENTS THAT OCCURRED MORE FREQUENTLY IN CAFCIT (caffeine citrate) TREATED PATIENTS THAN PLACEBO DURING DOUBLE-BLIND THERAPY

Adverse Event (AE) CAFCIT (caffeine citrate)
N=46
n (%)
Placebo
N=39
n (%)
BODY AS A WHOLE
  Accidental Injury 1 (2.2) 0 (0.0)
  Feeding Intolerance 4 (8.7) 2 (5.1)
  Sepsis 2 (4.3) 0 (0.0)
CARDIOVASCULAR SYSTEM
  Hemorrhage 1 (2.2) 0 (0.0)
DIGESTIVE SYSTEM
  Necrotizing Enterocolitis 2 (4.3) 1 (2.6)
  Gastritis 1 (2.2) 0 (0.0)
  Gastrointestinal Hemorrhage 1 (2.2) 0 (0.0)
HEMIC AND LYMPHATIC SYSTEM
  Disseminated Intravascular 1 (2.2) 0 (0.0)
  Coagulation    
METABOLIC AND NUTRITIVE DISORDERS
  Acidosis 1 (2.2) 0 (0.0)
  Healing Abnormal 1 (2.2) 0 (0.0)
NERVOUS SYSTEM
  Cerebral Hemorrhage 1 (2.2) 0 (0.0)
RESPIRATORY SYSTEM
  Dyspnea 1 (2.2) 0 (0.0)
  Lung Edema 1 (2.2) 0 (0.0)
SKIN AND APPENDAGES
  Dry Skin 1 (2.2) 0 (0.0)
  Rash 4 (8.7) 3 (7.7)
  Skin Breakdown 1 (2.2) 0 (0.0)
SPECIAL SENSES
  Retinopathy of Prematurity 1 (2.2) 0 (0.0)
UROGENITAL SYSTEM
  Kidney Failure 1 (2.2) 0 (0.0)

In addition to the cases above, three cases of necrotizing enterocolitis were diagnosed in patients receiving CAFCIT (caffeine citrate) during the open-label phase of the study.

Three of the infants who developed necrotizing enterocolitis during the trial died. All had been exposed to caffeine. Two were randomized to caffeine, and one placebo patient was “rescued” with open-label caffeine for uncontrolled apnea.

Adverse events described in the published literature include: central nervous system stimulation (i.e., irritability, restlessness, jitteriness), cardiovascular effects (i.e., tachycardia, increased left ventricular output, and increased stroke volume), gastrointestinal effects (i.e., increased gastric aspirate, gastrointestinal intolerance), alterations in serum glucose (hypoglycemia and hyperglycemia) and renal effects (increased urine flow rate, increased creatinine clearance, and increased sodium and calcium excretion). Published long-term follow-up studies have not shown caffeine to adversely affect neurological development or growth parameters.