CAFFEINE: 3,107 Adverse Event Reports & Safety Profile

DESCRIPTION Both Caffeine Citrate Injection, USP for intravenous administration and Caffeine Citrate Oral Solution, USP are clear, colorless, sterile, non-pyrogenic, preservative-free, aqueous solutions adjusted to pH 4.7. Each mL contains 20 mg caffeine citrate (equivalent to 10 mg of caffeine base) prepared in solution by the addition of 10 mg caffeine anhydrous to 5 mg citric acid monohydrate, 8.3 mg sodium citrate dihydrate and Water for Injection, USP. Caffeine, a central nervous system stimulant, is an odorless white crystalline powder or granule, with a bitter taste. It is sparingly soluble in water and ethanol at room temperature. The chemical name of caffeine is 3,7-dihydro-1,3,7-trimethyl-1 H -purine-2,6-dione. In the presence of citric acid it forms caffeine citrate salt in solution. The structural formula and molecular weight of caffeine citrate follows. Caffeine citrate C 14 H 18 N 4 O 9 MW

386.31 Structural Formula

INDICATIONS AND USAGE Caffeine and Sodium Benzoate Injection has been used in conjunction with supportive measure to treat respiratory depression associated with overdosage with CNS depressant drugs (e.g., narcotic analgesics, alcohol). However, because of questionable benefit and transient action, most authorities believe caffeine and other analeptics should not be used in these conditions and recommend other supportive therapy.

DOSAGE AND ADMINISTRATION Prior to initiation of caffeine citrate injection USP, baseline serum levels of caffeine should be measured in infants previously treated with theophylline, since preterm infants metabolize theophylline to caffeine. Likewise, baseline serum levels of caffeine should be measured in infants born to mothers who consumed caffeine prior to delivery, since caffeine readily crosses the placenta. The recommended loading dose and maintenance doses of caffeine citrate injection, USP follow. * Using a syringe infusion pump ** Beginning 24 hours after the loading dose Dose of Caffeine Citrate Injection, USP Volume Dose of Caffeine Citrate Injection, USP mg/kg Route Frequency Loading Dose 1 mL/kg 20 mg/kg Intravenous * (over 30 minutes) One time Maintenance Dose 0.25 mL/kg 5 mg/kg Intravenous * (over 10 minutes) or Orally Every 24 hours ** NOTE THAT THE DOSE OF CAFFEINE BASE IS ONE-HALF THE DOSE WHEN EXPRESSED AS CAFFEINE CITRATE (e.g., 20 mg of caffeine citrate is equivalent to 10 mg of caffeine base). Serum concentrations of caffeine may need to be monitored periodically throughout treatment to avoid toxicity. Serious toxicity has been associated with serum levels greater than 50 mg/L. Caffeine citrate injection, USP should be inspected visually for particulate matter and discoloration prior to administration. Vials containing discolored solution or visible particulate matter should be discarded.

Drug

Compatibility To test for drug compatibility with common intravenous solutions or medications, 20 mL of caffeine citrate injection, USP were combined with 20 mL of a solution or medication, with the exception of an Intralipid ® admixture, which was combined as 80 mL/80 mL. The physical appearance of the combined solutions was evaluated for precipitation. The admixtures were mixed for 10 minutes and then assayed for caffeine. The admixtures were then continually mixed for 24 hours, with further sampling for caffeine assays at 2, 4, 8, and 24 hours. Based on this testing, caffeine citrate injection USP, 60 mg/3 mL is chemically stable for 24 hours at room temperature when combined with the following test products.

• Dextrose Injection, USP 5%
• 50% Dextrose Injection USP
• Intralipid ® 20% IV Fat Emulsion
• Aminosyn ® 8.5% Crystalline Amino Acid Solution
• Dopamine HCI Injection, USP 40 mg/mL diluted to 0.6 mg/mL with Dextrose Injection, USP 5%
• Calcium Gluconate Injection, USP 10% (0.465 mEq/Ca +2 /mL)
• Heparin Sodium Injection, USP 1000 units/mL diluted to 1 unit/mL with Dextrose Injection, USP 5%
• Fentanyl Citrate Injection, USP 50 mcg/mL diluted to 10 mcg/mL with Dextrose Injection, USP 5%

CONTRAINDICATIONS Coadministration of ergotamine with potent CYP 3A4 inhibitors (ritonavir, nelfinavir, indinavir, erythromycin, clarithromycin, and troleandomycin) has been associated with acute ergot toxicity (ergotism) characterized by vasospasm and ischemia of the extremities (see PRECAUTIONS : Drug Interactions ), with some cases resulting in amputation. There have been rare reports of cerebral ischemia in patients on protease inhibitor therapy when ergotamine tartrate and caffeine tablets was coadministered, at least one resulting in death. Because of the increased risk of ergotism and other serious vasospastic adverse events, ergotamine use is contraindicated with these drugs and other potent inhibitors of CYP 3A4 (e.g., ketoconazole, itraconazole) (see WARNINGS : CYP 3A4 Inhibitors ). Ergotamine tartrate and caffeine tablets may cause fetal harm when administered to pregnant women. Ergotamine tartrate and caffeine tablets is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this product, the patient should be apprised of the potential hazard to the fetus. Peripheral vascular disease, coronary heart disease, hypertension, impaired hepatic or renal function and sepsis. Hypersensitivity to any of the components.

ADVERSE REACTIONS Overall, the reported number of adverse events in the double-blind period of the controlled trial was similar for the 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 caffeine citrate-treated patients than placebo. ADVERSE EVENTS THAT OCCURRED MORE FREQUENTLY IN CAFFEINE CITRATE TREATED PATIENTS THAN PLACEBO DURING DOUBLE-BLIND THERAPY Adverse Event (AE)

Caffeine

Citrate N=46 Placebo N=39 n (%) 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 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 (ie, irritability, restlessness, jitteriness), cardiovascular effects (ie, tachycardia, increased left ventricular output, and increased stroke volume), gastrointestinal effects (ie, increased gastric aspirate, gastrointestinal intolerance), alterations in serum glucose (ie, 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.

Overdosage

Following overdose, serum caffeine levels have ranged from approximately 24 mg/L (a postmarketing spontaneous case report in which an infant exhibited irritability, poor feeding, and insomnia) to 350 mg/L. Serious toxicity has been associated with serum levels greater than 50 mg/L (see PRECAUTIONS – Laboratory tests and DOSAGE AND ADMINISTRATION ). Signs and symptoms reported in the literature after caffeine overdose in preterm infants include fever, tachypnea, jitteriness, insomnia, fine tremor of the extremities, hypertonia, opisthotonos, tonic-clonic movements, nonpurposeful jaw and lip movements, vomiting, hyperglycemia, elevated blood urea nitrogen, and elevated total leukocyte concentration. Seizures have also been reported in cases of overdose. One case of caffeine overdose complicated by development of intraventricular hemorrhage and long-term neurological sequelae has been reported. Another case of caffeine citrate overdose (from New Zealand; not caffeine citrate) of an estimated 600 mg caffeine citrate (approximately 322 mg/kg) administered over 40 minutes was complicated by tachycardia, ST depression, respiratory distress, heart failure, gastric distention, acidosis, and a severe extravasation burn with tissue necrosis at the peripheral intravenous injection site. No deaths associated with caffeine overdose have been reported in preterm infants. Treatment of caffeine overdose is primarily symptomatic and supportive. Caffeine levels have been shown to decrease after exchange transfusions. Convulsions may be treated with intravenous administration of diazepam or a barbiturate such as pentobarbital sodium.

Warnings Reye's syndrome Children and teenagers who have or are recovering from chicken pox or flu-like symptoms should not use this product. When using this product, if changes in behavior with nausea and vomiting occur, consult a doctor because these symptoms could be an early sign of Reye's syndrome, a rare but serious illness. Allergy alert Salicylates (NSAIDs) may cause a severe allergic reaction which may include: hives skin reddening rash facial swelling shock asthma (wheezing) Stomach bleeding warning This product contains an NSAID, which may cause severe stomach bleeding. The chance is higher if you: are age 60 or older have had stomach ulcers or bleeding problems take blood thinning (anticoagulant) or steroid drug take other drugs containing prescription or nonprescription NSAIDs (aspirin, ibuprofen, naproxen, or others) have 3 or more alcoholic drinks every day while using this product take more or for a longer time than directed Do not use if you ever had an allergic reaction to salicylates (including aspirin) or any other pain reliever/ fever reducer. Ask a doctor before use if stomach bleeding warning applies to you you have high blood pressure, heart disease, liver cirrhosis, or kidney disease you are taking a diuretic you have a history of stomach problems such as heartburn, upset stomach, stomach pain, or ulcers you have asthma Ask a doctor or pharmacist before use if under a doctor's care for any serious condition taking a prescription drug for diabetes, gout, or arthritis. When using this product limit the use of caffeine-containing medications, foods, or beverages because too much caffeine may cause nervousness, irritability, sleeplessness, and occasionally, rapid heart beat the recommended dose of this product contains about as much caffeine as a cup of coffee take with food or milk if stomach upset occurs Stop use and ask a doctor if an allergic reaction occurs. Seek medical help right away. you experience any of the following signs of stomach bleeding: ○ feel faint ○ vomit blood ○ have bloody or black stools ○ have stomach pain that does not get better symptoms do not improve pain gets worse or lasts more than 10 days ringing in the ears or loss of hearing occurs redness or swelling is present new symptoms occur fever gets worse or lasts more than 3 days If pregnant or breast-feeding, ask a health professional before use. It is especially important not to use salicylates (NSAIDs) during the last 3 months of pregnancy unless definitely directed to do so by a doctor because it may cause problems in the unborn child or complications during delivery. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away.

PRECAUTIONS General Apnea of prematurity is a diagnosis of exclusion. Other causes of apnea (e.g., central nervous system disorders, primary lung disease, anemia, sepsis, metabolic disturbances, cardiovascular abnormalities, or obstructive apnea) should be ruled out or properly treated prior to initiation of caffeine citrate. Caffeine is a central nervous system stimulant and in cases of caffeine overdose, seizures have been reported. Caffeine citrate should be used with caution in infants with seizure disorders. The duration of treatment of apnea of prematurity in the placebo-controlled trial was limited to 10 to 12 days. The safety and efficacy of caffeine citrate for longer periods of treatment have not been established. Safety and efficacy of caffeine citrate for use in the prophylactic treatment of sudden infant death syndrome (SIDS) or prior to extubation in mechanically ventilated infants have also not been established.

Cardiovascular

Although no cases of cardiac toxicity were reported in the placebo-controlled trial, caffeine has been shown to increase heart rate, left ventricular output, and stroke volume in published studies. Therefore, caffeine citrate should be used with caution in infants with cardiovascular disease. Renal and Hepatic Systems Caffeine citrate should be administered with caution in infants with impaired renal or hepatic function. Serum concentrations of caffeine should be monitored and dose administration of caffeine citrate should be adjusted to avoid toxicity in this population (see CLINICAL PHARMACOLOGY : Pharmacokinetics, Elimination and Special Populations . Information for Patients Parents/caregivers of patients receiving caffeine citrate oral solution should receive the following instructions: 1. Caffeine citrate oral solution does not contain any preservatives and each vial is for single use only. Any unused portion of the medication should be discarded. 2. It is important that the dose of caffeine citrate oral solution be measured accurately, i.e., with a 1cc or other appropriate syringe. 3. Consult your physician if the baby continues to have apnea events; do not increase the dose of caffeine citrate oral solution without medical consultation. 4. Consult your physician if the baby begins to demonstrate signs of gastrointestinal intolerance, such as abdominal distention, vomiting, or bloody stools, or seems lethargic. 5. Caffeine citrate oral solution should be inspected visually for particulate matter and discoloration prior to its administration. Vials containing discolored solution or visible particulate matter should be discarded.

Laboratory Tests

Prior to initiation of caffeine citrate, baseline serum levels of caffeine should be measured in infants previously treated with theophylline, since preterm infants metabolize theophylline to caffeine. Likewise, baseline serum levels of caffeine should be measured in infants born to mothers who consumed caffeine prior to delivery, since caffeine readily crosses the placenta. In the placebo-controlled clinical trial, caffeine levels ranged from 8 to 40 mg/L. A therapeutic plasma concentration range of caffeine could not be determined from the placebo-controlled clinical trial. Serious toxicity has been reported in the literature when serum caffeine levels exceed 50 mg/L. Serum concentrations of caffeine may need to be monitored periodically throughout treatment to avoid toxicity. In clinical studies reported in the literature, cases of hypoglycemia and hyperglycemia have been observed. Therefore, serum glucose may need to be periodically monitored in infants receiving caffeine citrate.

Drug Interactions

Cytochrome P450 1A2 (CYP1A2) is known to be the major enzyme involved in the metabolism of caffeine. Therefore, caffeine has the potential to interact with drugs that are substrates for CYP1A2, inhibit CYP1A2, or induce CYP1A2. Few data exist on drug interactions with caffeine in preterm neonates. Based on adult data, lower doses of caffeine may be needed following coadministration of drugs which are reported to decrease caffeine elimination (e.g., cimetidine and ketoconazole) and higher caffeine doses may be needed following coadministration of drugs that increase caffeine elimination (e.g., phenobarbital and phenytoin). Caffeine administered concurrently with ketoprofen reduced the urine volume in four healthy volunteers. The clinical significance of this interaction in preterm neonates is not known. Interconversion between caffeine and theophylline has been reported in preterm neonates. The concurrent use of these drugs is not recommended. Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year study in Sprague-Dawley rats, caffeine (as caffeine base) administered in drinking water was not carcinogenic in male rats at doses up to 102 mg/kg or in female rats at doses up to 170 mg/kg (approximately 2 and 4 times, respectively, the maximum recommended intravenous loading dose for infants on a mg/m 2 basis). In an 18-month study in C57BL/6 mice, no evidence of tumorigenicity was seen at dietary doses up to 55 mg/kg (less than the maximum recommended intravenous loading dose for infants on a mg/m 2 basis). Caffeine (as caffeine base) increased the sister chromatid exchange (SCE) SCE/cell metaphase (exposure time dependent) in an in vivo mouse metaphase analysis. Caffeine also potentiated the genotoxicity of known mutagens and enhanced the micronuclei formation (5-fold) in folate-deficient mice. However, caffeine did not increase chromosomal aberrations in in vitro Chinese hamster ovary cell (CHO) and human lymphocyte assays and was not mutagenic in an in vitro CHO/hypoxanthine guanine phosphoribosyltransferase (HGPRT) gene mutation assay, except at cytotoxic concentrations. In addition, caffeine was not clastogenic in an in vivo mouse micronucleus assay. Caffeine (as caffeine base) administered to male rats at 50 mg/kg/day subcutaneously (approximately equal to the maximum recommended intravenous loading dose for infants on a mg/m 2 basis) for 4 days prior to mating with untreated females, caused decreased male reproductive performance in addition to causing embryotoxicity. In addition, long-term exposure to high oral doses of caffeine (3 g over 7 weeks) was toxic to rat testes as manifested by spermatogenic cell degeneration. Pregnancy: Teratogenic Effects: Pregnancy Category C Concern for the teratogenicity of caffeine is not relevant when administered to infants. In studies performed in adult animals, caffeine (as caffeine base) administered to pregnant mice as sustained release pellets at 50 mg/kg (less than the maximum recommended intravenous loading dose for infants on a mg/m 2 basis), during the period of organogenesis, caused a low incidence of cleft palate and exencephaly in the fetuses. There are no adequate and well-controlled studies in pregnant women.

General

Apnea of prematurity is a diagnosis of exclusion. Other causes of apnea (e.g., central nervous system disorders, primary lung disease, anemia, sepsis, metabolic disturbances, cardiovascular abnormalities, or obstructive apnea) should be ruled out or properly treated prior to initiation of caffeine citrate. Caffeine is a central nervous system stimulant and in cases of caffeine overdose, seizures have been reported. Caffeine citrate should be used with caution in infants with seizure disorders. The duration of treatment of apnea of prematurity in the placebo-controlled trial was limited to 10 to 12 days. The safety and efficacy of caffeine citrate for longer periods of treatment have not been established. Safety and efficacy of caffeine citrate for use in the prophylactic treatment of sudden infant death syndrome (SIDS) or prior to extubation in mechanically ventilated infants have also not been established.

Cardiovascular

Although no cases of cardiac toxicity were reported in the placebo-controlled trial, caffeine has been shown to increase heart rate, left ventricular output, and stroke volume in published studies. Therefore, caffeine citrate should be used with caution in infants with cardiovascular disease.

Renal and Hepatic Systems Caffeine citrate should be administered with caution in infants with impaired renal or hepatic function. Serum concentrations of caffeine should be monitored and dose administration of caffeine citrate should be adjusted to avoid toxicity in this population (see CLINICAL PHARMACOLOGY : Pharmacokinetics, Elimination and Special Populations .

Information for Patients Parents/caregivers of patients receiving caffeine citrate oral solution should receive the following instructions: 1. Caffeine citrate oral solution does not contain any preservatives and each vial is for single use only. Any unused portion of the medication should be discarded. 2. It is important that the dose of caffeine citrate oral solution be measured accurately, i.e., with a 1cc or other appropriate syringe. 3. Consult your physician if the baby continues to have apnea events; do not increase the dose of caffeine citrate oral solution without medical consultation. 4. Consult your physician if the baby begins to demonstrate signs of gastrointestinal intolerance, such as abdominal distention, vomiting, or bloody stools, or seems lethargic. 5. Caffeine citrate oral solution should be inspected visually for particulate matter and discoloration prior to its administration. Vials containing discolored solution or visible particulate matter should be discarded.

Laboratory Tests

Prior to initiation of caffeine citrate, baseline serum levels of caffeine should be measured in infants previously treated with theophylline, since preterm infants metabolize theophylline to caffeine. Likewise, baseline serum levels of caffeine should be measured in infants born to mothers who consumed caffeine prior to delivery, since caffeine readily crosses the placenta. In the placebo-controlled clinical trial, caffeine levels ranged from 8 to 40 mg/L. A therapeutic plasma concentration range of caffeine could not be determined from the placebo-controlled clinical trial. Serious toxicity has been reported in the literature when serum caffeine levels exceed 50 mg/L. Serum concentrations of caffeine may need to be monitored periodically throughout treatment to avoid toxicity. In clinical studies reported in the literature, cases of hypoglycemia and hyperglycemia have been observed. Therefore, serum glucose may need to be periodically monitored in infants receiving caffeine citrate.

Drug Interactions

Cytochrome P450 1A2 (CYP1A2) is known to be the major enzyme involved in the metabolism of caffeine. Therefore, caffeine has the potential to interact with drugs that are substrates for CYP1A2, inhibit CYP1A2, or induce CYP1A2. Few data exist on drug interactions with caffeine in preterm neonates. Based on adult data, lower doses of caffeine may be needed following coadministration of drugs which are reported to decrease caffeine elimination (e.g., cimetidine and ketoconazole) and higher caffeine doses may be needed following coadministration of drugs that increase caffeine elimination (e.g., phenobarbital and phenytoin). Caffeine administered concurrently with ketoprofen reduced the urine volume in four healthy volunteers. The clinical significance of this interaction in preterm neonates is not known. Interconversion between caffeine and theophylline has been reported in preterm neonates. The concurrent use of these drugs is not recommended.

Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year study in Sprague-Dawley rats, caffeine (as caffeine base) administered in drinking water was not carcinogenic in male rats at doses up to 102 mg/kg or in female rats at doses up to 170 mg/kg (approximately 2 and 4 times, respectively, the maximum recommended intravenous loading dose for infants on a mg/m 2 basis). In an 18-month study in C57BL/6 mice, no evidence of tumorigenicity was seen at dietary doses up to 55 mg/kg (less than the maximum recommended intravenous loading dose for infants on a mg/m 2 basis). Caffeine (as caffeine base) increased the sister chromatid exchange (SCE) SCE/cell metaphase (exposure time dependent) in an in vivo mouse metaphase analysis. Caffeine also potentiated the genotoxicity of known mutagens and enhanced the micronuclei formation (5-fold) in folate-deficient mice. However, caffeine did not increase chromosomal aberrations in in vitro Chinese hamster ovary cell (CHO) and human lymphocyte assays and was not mutagenic in an in vitro CHO/hypoxanthine guanine phosphoribosyltransferase (HGPRT) gene mutation assay, except at cytotoxic concentrations. In addition, caffeine was not clastogenic in an in vivo mouse micronucleus assay. Caffeine (as caffeine base) administered to male rats at 50 mg/kg/day subcutaneously (approximately equal to the maximum recommended intravenous loading dose for infants on a mg/m 2 basis) for 4 days prior to mating with untreated females, caused decreased male reproductive performance in addition to causing embryotoxicity. In addition, long-term exposure to high oral doses of caffeine (3 g over 7 weeks) was toxic to rat testes as manifested by spermatogenic cell degeneration.

Pregnancy: Teratogenic Effects: Pregnancy Category C Concern for the teratogenicity of caffeine is not relevant when administered to infants. In studies performed in adult animals, caffeine (as caffeine base) administered to pregnant mice as sustained release pellets at 50 mg/kg (less than the maximum recommended intravenous loading dose for infants on a mg/m 2 basis), during the period of organogenesis, caused a low incidence of cleft palate and exencephaly in the fetuses. There are no adequate and well-controlled studies in pregnant women.

Drug Interactions Cytochrome P450 1A2 (CYP1A2) is known to be the major enzyme involved in the metabolism of caffeine. Therefore, caffeine has the potential to interact with drugs that are substrates for CYP1A2, inhibit CYP1A2, or induce CYP1A2. Few data exist on drug interactions with caffeine in preterm neonates. Based on adult data, lower doses of caffeine may be needed following coadministra­tion of drugs which are reported to decrease caffeine elimination (e.g., cimeti­dine and ketoconazole) and higher caffeine doses may be needed following coadministration of drugs that increase caffeine elimination (e.g., phenobarbi­tal and phenytoin). Caffeine administered concurrently with ketoprofen reduced the urine volume in four healthy volunteers. The clinical significance of this interaction in preterm neonates is not known. Interconversion between caffeine and theophylline has been reported in preterm neonates. The concurrent use of these drugs is not recommended.

Active Ingredients: Acid Salicylic D8 (Beta Hydroxy Acid), Caffeinum D5 (Caffeinum Citrate), Colocynthis D3 (Citrullus Colocynthis), Gelsemium D3 (Carolina Jasmine), Ginkgo Biloba D4 (Maidenhair Tree), Mag Phos D7 (Magnesium Phosphoricum), Spigelia D3 (Spigelia Anthelmia)

WATER NIACINAMIDE SQUALANE COCOS NUCIFERA (COCONUT) FRUIT EXTRACT BUTYROSPERMUM PARKII (SHEA BUTTER) OIL HESPERIDIN ARGININE/LYSINE POLYPEPTIDE TOCOPHEROL ADENOSINE SODIUM HYALURONATE HYDROLYZED COLLAGEN FUCUS VESICULOSUS EXTRACT CENTELLA ASIATICA EXTRACT HYDROLYZED HIBISCUS ESCULENTUS EXTRACT MAGNOLIA OBOVATA BARK EXTRACT MAGNOLIA BIONDII FLOWER EXTRACT