Colostrum ImmuFend by Foster Regal

POSSIBLY EFFECTIVE

• Common cold. Taking echinacea orally while still healthy may help prevent the common cold, but the benefit is probably modest. Echinacea does not seem to have a significant benefit for treating colds that have already developed. Details: Three meta-analyses show a 10% to 58% reduction in the risk of developing a cold when taking various forms of echinacea (17520,17522,95652). A large clinical study shows that adults who use a specific echinacea extract (Echinaforce, A. Vogel Bioforce AG) 0.9 mL three times daily (2400 mg echinacea daily) for 4 months, with an increase to 0.9 mL five times daily (4000 mg echinacea daily) at the first sign of a cold, have 59% fewer cold episodes and 26% fewer days with cold symptoms than those taking placebo (18225). Many smaller studies have shown a non-significant trend toward a prophylactic benefit, but they were likely underpowered to detect a statistically significant difference (3282,6386,17521,95652). Research in adults who are deliberately infected with cold viruses shows that taking echinacea products either does not reduce the incidence of colds, or has a limited effect which is not statistically significant. Products used include E. angustifolia root extract 300 mg three times daily for 7 days before and 5 days after experimental infection (13419), an alcoholic extract of E. purpurea above-ground parts (EchinaGuard, Madaus AG) 2.5 mL three times daily for 7 days before and 7 days after experimental infection (12354), or echinacea 300 mg three times daily for 14 days before and 5 days after experimental infection (8228). These studies are small and have methodological problems. Some small clinical studies have suggested that taking E. purpurea extracts as a tincture or tea to treat the common cold modestly reduces symptom severity and reduces cold duration by a couple of days (6384,10320,10802,12355,14419,20062,111530). Specific products used in these studies include Echinilin by Inovobiologic Inc., and Echinacin and EchinaGuard by Madaus AG (10320,10802,12355,20062). In contrast, higher quality clinical research shows that taking E. purpurea alone or with E. angustifolia does not reduce duration or severity of cold symptoms when compared with placebo (10800,11970,17519,20059). Echinacea has also been evaluated in children. Preliminary clinical research in healthy children 4-12 years old shows that taking a specific E. purpurea product (Echinaforce Junior, A. Vogel) 400 mg three times daily for 4 months reduces the occurrence of cold symptoms, respiratory complications (such as pneumonia and otitis media), and antibiotic prescriptions by 30%, 52%, and 62%, respectively, when compared with vitamin C 50 mg three times daily. Taking echinacea also reduces the average duration of symptoms during respiratory illness by an average of 1.4 days when compared with vitamin C (105719). However, other clinical research in children has found no benefit with a specific E. purpurea product (Echinacin, Madaus AG) (4989,95653).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Anxiety. It is unclear if oral echinacea reduces anxiety. Details: Preliminary clinical research shows that taking a specific E. angustifolia extract (ExtractumPharma ZRT) 40 mg once or twice daily for 7 days reduces anxiety scores on the State-Trait Anxiety Inventory scale when compared with placebo (20064,103233). This extract seems to be more effective in patients with high baseline anxiety scores (103233). A lower dose of 20 mg daily appears to be ineffective (20064). Conversely, a small clinical study in physically healthy adults with mild to moderate anxiety shows that taking the same E. angustifolia extract at doses of 20 or 40 mg twice daily for 6 weeks does not reduce anxiety when compared with placebo (106626).
• Athletic performance. It is unclear if oral echinacea improves athletic performance in healthy, recreationally active males. Details: Preliminary clinical research in healthy, recreationally active males shows that taking echinacea (Puritan's Pride) 2 grams four times daily for 28 days increases serum erythropoietin levels and maximal oxygen consumption (VO2max) during exercise tests (20066). However, two small clinical studies in endurance trained athletes and in non-athletes with high aerobic fitness show that taking E. purpurea 8 or 16 grams once daily for 35 days in combination with other ingredients (Biomedical Research Lab), or taking E. purpurea (Puritan's Pride) 8 grams daily for 42 days, has no effect on erythropoietin levels, VO2max, or aerobic capacity (95651,101593).
• Atopic dermatitis (eczema). Some evidence shows that an echinacea cream may be effective in mild disease, but it has not been compared to conventional treatments such as corticosteroids. Details: Preliminary clinical research in patients with mild atopic dermatitis shows that applying a cream containing echinacea (Linola Plus Cream, Dr. August Wolff GmbH & Co) 2-3 times daily for 12 weeks reduces symptoms such as erythema, edema, pruritus, and dryness when compared with a cream containing birch bark extract (Imlan Crème Pur, Birken AG). However, the echinacea product was no different to the comparator cream at the 4- and 8-week assessments, indicating that it might take up to 12 weeks to show benefit (97499).
• Attention deficit-hyperactivity disorder (ADHD). Although there has been interest in using oral echinacea for ADHD, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
• Burns. Although there has been interest in using topical echinacea for burns, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral echinacea for CFS, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
• Coronavirus disease 2019 (COVID-19). It is unclear if oral echinacea is beneficial for preventing or treating COVID-19. Details: A moderate-size open-label clinical study tested the effects of echinacea to prevent or treat respiratory viruses. This study of otherwise healthy adults in Bulgaria shows that taking echinacea extract (Echinaforce, A. Vogel AG) 2400 mg daily for cycles of 2, 2, and 1 months, with a 1-week break between each cycle, does not reduce symptomatic respiratory tract infections, including SARS-CoV-2, or respiratory virus detection overall when compared with usual care. However, echinacea extract does reduce the risk of a positive test for coronaviruses or SARS-CoV-2 by 48% and 63%, respectively. In patients who develop a symptomatic respiraA moderate-size open-label clinical study tested the effects of echinacea to prevent or treat respiratory viruses. This study of otherwise healthy adults in Bulgaria shows that taking echinacea extract (Echinaforce, A. Vogel AG) 2400 mg daily for cycles of 2, 2, and 1 months, with a 1-week break between each cycle, does not reduce symptomatic respiratory tract infections, including SARS-CoV-2, or respiratory virus detection overall when compared with usual care. However, echinacea extract does reduce the risk of a positive test for coronaviruses or SARS-CoV-2 by 48% and 63%, respectively. In patients who develop a symptomatic respiratory tract infection, this study also shows that taking the same echinacea extract 4000 mg daily for up to 10 days speeds viral clearance compared with usual care when all virus types were analyzed; however, clearance of SARS-CoV-2 was not improved. Echinacea may also reduce the number of days with a fever, but not other symptoms (111174). The validity of this study is limited by lack of blinding. Further, most patients were unvaccinated against COVID-19; it is unclear whether these results can be extrapolated to vaccinated patients.
• Genital herpes. It is unclear if oral echinacea is beneficial for genital herpes in patients with herpes simplex virus (HSV) type 1 or 2. Details: Some clinical research shows that a specific E. purpurea extract (Echinaforce, A. Vogel Bioforce AG) 800 mg orally twice daily for 6 months does not seem to prevent or reduce the frequency or duration of recurrent genital herpes in patients with herpes simplex virus (HSV) type 1 or 2 (7087).
• Gingivitis. Echinacea, in a mouth rinse or periodontal patch, has only been studied in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that using a mouth rinse containing echinacea, gotu kola, and elderberry (HM-302, Izun Pharmaceuticals) 15 mL three times daily for 14 days might prevent worsening of gingivitis when compared with a placebo rinse, but it produces only minimal improvement in symptoms (20069). Applying a periodontal patch containing echinacea, gotu kola, and elderberry (PerioPatch, Izun Pharmaceuticals) either as a single dose, or three times daily for 1 day then once daily for 2 days seems to reduce some measures of inflammation and gingivitis at some time points, but effects lack consistency (20068,20070).
• Herpes labialis (cold sores). Although there has been interest in using topical echinacea for herpes labialis, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
• HIV/AIDS. Although there has been interest in using oral echinacea for HIV/AIDS, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
• Human papillomavirus (HPV). Oral echinacea has only been studied in combination with other ingredients; its benefit when used alone is unclear. Details: Preliminary clinical research shows that taking a specific combination product containing echinacea, andrographis, grapefruit, papaya, pau d'arco, and cat's claw (Immune Act, Erba Vita SpA) three tablets daily for one month reduces the recurrence of anal condylomata in patients following surgical removal. After one month, the recurrence rate was about 4% in the echinacea group compared with 18% in the control group; after 6 months the recurrence rates were about 7% and 27%, respectively (20073). However, poor study methodology limits the validity of these findings.
• Influenza. Limited data suggest that oral echinacea may improve the response to influenza vaccine, and that a combination product containing echinacea may improve rates of recovery from influenza. Details: Preliminary clinical research shows that a taking a specific echinacea product (Monoselect Echinacea, PharmExtracta) 200 mg orally daily for 15 days, then 100 mg daily for 15 days, followed by 100 mg every other day for 60 days, might improve the response to influenza vaccine in people with chronic bronchitis or asthma (18226). Higher quality research is needed to confirm these results. Taking a specific combination product (Echinaforce Hot Drink, A. Vogel Bioforce AG), containing elderberry juice and extracts of E. purpurea above-ground parts and roots, 5 mL five times daily for 3 days, then three times daily for 7 days, improves rates of recovery and influenza-related respiratory complications similarly to oseltamivir 75 mg twice daily for 5 days (95650). However, due to the lack of a placebo group, it is unclear if both treatments were beneficial or if the outcomes represent the natural progression of influenza.
• Insect bite. It is unclear if topical homeopathy with a gel containing echinacea is beneficial for insect bite treatment. Oral echinacea has not been evaluated for this use. Details: Preliminary clinical research shows that using a homeopathic after-bite gel, containing echinacea, marsh Labrador tea, and stinging nettle, on affected areas does not reduce erythema or itching after a mosquito bite when compared with placebo (89235).
• Lichen planus. It is unclear if oral echinacea is beneficial for patients with this condition. Details: A small clinical study in adults with erosive oral lichen planus in Iran shows that taking a specific echinacea extract tablet (Immustim, Goldaru Corp.) 114 mg three times daily for 35 days decreases pain scores, number of lesions, and symptom severity when compared with placebo. However, all patients also used a mouthwash containing betamethasone, diphenhydramine, nystatin, and aluminum-magnesium suspension three times daily (111173).
• Malaria. Although there has been interest in using oral echinacea for malaria, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
• Migraine headache. Although there has been interest in using oral echinacea for migraine headache, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
• Otitis media. Oral echinacea does not seem to reduce the rate of recurrence of otitis media in young children, and may actually increase it. Details: Preliminary clinical research shows that taking a specific liquid extract of echinacea fresh roots and dried mature seeds, 0.5 mL three times daily for 3 days at the first sign of a common cold, followed by 0.25 mL three times daily for 7 days, does not prevent otitis media in children 1-5 years of age with a history of recurrent otitis media. In fact, the risk of an episode of otitis media during the 6 month follow-up seemed to increase by 59% in those taking echinacea when compared with placebo (20063).
• Psoriasis. Although there has been interest in using topical echinacea for psoriasis, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
• Respiratory tract infections. It is unclear if oral echinacea is beneficial for patients with respiratory tract infections. Details: A large clinical study in adults with respiratory tract infections shows that using echinacea spray or taking echinacea lozenges 16,800 mg daily during days 1-3 and 2240-3360 mg daily afterward for up to 10 days does not improve time to recovery, symptom relief, or number of sick days when compared with echinacea tablets or drops at a prophylactic dose of 2400 mg daily for 10 days. However, the higher dose from days 1-3 is associated with faster viral clearance than the prophylactic dose (111540). The validity of these effects is limited by insufficient blinding and a lack of a placebo group.
• Rheumatoid arthritis (RA). Although there has been interest in using oral echinacea for RA, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
• Tonsillitis. Oral echinacea has been used with azithromycin to reduce relapses of recurrent tonsillitis in children. A throat spray containing echinacea has also been evaluated for tonsillitis-associated sore throat. It is unclear if echinacea is beneficial for either purpose. Details: Preliminary clinical research in children with recurrent tonsillitis shows that adding echinacea suspension, 250 mg root powder per 5 mL, orally 3 times daily for 10 consecutive days per month for 6 months, to azithromycin 10 mg/kg/day for 6 consecutive days per month for 6 months reduces the number of tonsillitis attacks when compared with azithromycin alone (104127). However, the study was not blinded and the number of tonsillitis episodes in both groups was very low. Other preliminary clinical research shows that applying a throat spray containing sage and echinacea whole plant extract every 2 hours up to 10 times daily for up to 5 consecutive days is as effective as a chlorhexidine-lidocaine spray in patients with sore throat due to acute pharyngitis or tonsillitis (20077).
• Tonsillopharyngitis. Oral echinacea has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized study in patients aged 12-75 years with acute tonsillopharyngitis shows that taking lozenges containing echinacea extract 800 mg and sage extract 5 times daily for 4 days reduces throat pain and tonsillopharyngitis symptoms when compared to baseline, both acutely within 90 minutes and after 4 days of treatment (111530). The validity of these effects is limited by a lack of a comparator group. It is unclear if these effects are due to echinacea, sage, or the combination.
• Upper respiratory tract infection (URTI). It is unclear if oral echinacea is beneficial for preventing or treating URTIs. Details: A moderate-size open-label clinical study tested the effects of echinacea to prevent or treat respiratory viruses. This study of otherwise healthy adults in Bulgaria shows that taking echinacea extract (Echinaforce, A. Vogel AG) 2400 mg daily for cycles of 2, 2, and 1 months, with a 1-week break between each cycle, does not reduce symptomatic respiratory tract infections, including SARS-CoV-2, or respiratory virus detection overall when compared with usual care. However, echinacea extract does reduce the risk of a positive test for coronaviruses or SARS-CoV-2 by 48% and 63%, respectively. In patients who develop a symptomatic respiratory tract infection, this study also shows that taking the same echinacea extract 4000 mg daily for up to 10 days speeds viral clearance compared with usual care when all virus types were analyzed; however, clearance of SARS-CoV-2 was not improved. Echinacea may also reduce the number of days with a fever, but not other symptoms (111174). The validity of this study is limited by lack of blinding. Further, most patients were unvaccinated against COVID-19; it is unclear whether these results can be extrapolated to vaccinated patients. Another large study in adults with URTIs shows that taking a combination product containing echinacea 1100-2200 mg, zinc, and vitamin C (EZC Pak) daily for 5 days reduces time to recovery by 1.4 days but does not reduce symptom severity when compared with placebo (111512). The validity of these effects is severely limited by multiple instances of selection bias. Additionally, it is unclear if these effects are due to echinacea, other ingredients, or the combination.
• Urinary tract infections (UTIs). Although there has been interest in using oral echinacea for UTIs, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
• Vaginal candidiasis. Although there has been interest in using oral echinacea for vaginal candidiasis, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
• Warts. It is unclear if oral echinacea is beneficial for warts when used alone or in combination with other ingredients. Details: Preliminary clinical research shows that taking echinacea 600 mg orally once daily for up to 3 months does not clear common, plantar, or plain cutaneous warts any more effectively than placebo (20080). Other preliminary clinical research shows that taking an oral supplement containing echinacea with methionine, zinc, probiotics, antioxidants and immunostimulants for 6 months, in addition to using conventional topical therapy to treat cutaneous warts, seems to increase the rate of complete remission from 54% to 86% when compared with conventional therapy alone (20071). It is unclear if these effects are due to echinacea, other ingredients, or the combination.
• Water warts. It is unclear if oral echinacea is beneficial for water warts (molluscum contagiosum). Details: In children who have been successfully treated with curettage for molluscum contagiosum, taking a combination of E. angustifolia and E. purpurea orally daily for 2 months is associated with a relapse rate of about 39%, compared with a rate of 68% in a control group that received no oral treatment (104128). The validity of this finding is limited by the lack of a placebo control. E. angustifolia and E. purpurea were taken in doses of 200 mg each in children under 20 kg and 400 mg each in children over 20 kg. More evidence is needed to rate echinacea for these uses.

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POSSIBLY EFFECTIVE

• Pregnancy-related iron deficiency. Oral lactoferrin seems to improve hemoglobin levels similarly to oral or parenteral iron therapy in patients with pregnancy-related iron deficiency. Details: A meta-analysis of 4 clinical studies in patients with pregnancy-related iron deficiency anemia shows that taking bovine lactoferrin 200-250 mg daily for 4-8 weeks during the second or third trimester is equally effective to ferrous sulfate 150-520 mg for improving hemoglobin levels (97788). Another meta-analysis of 6 mostly small, low-quality clinical studies in pregnant patients with iron deficiency anemia, iron deficiency, or hereditary thrombophilia shows that taking lactoferrin improves hemoglobin and serum iron, but not serum ferritin, when compared with ferrous sulfate (110773). However, the validity of these findings is limited by the heterogeneity of the included studies and lack of information about lactoferrin and iron doses.
• Sepsis. Oral lactoferrin seems to reduce the risk of late-onset sepsis in some premature infants. However, the optimal dosing regimen and patient population is unclear. Details: A meta-analysis of 12 clinical studies in premature infants shows that lactoferrin 150-200 mg/kg daily reduces the risk of late-onset sepsis by 20%, largely due to reductions in fungal infections specifically (104868). In contrast, other meta-analyses have reported conflicting findings (97783,104856) and some suggest that any benefits may be relegated to certain sub-groups of premature infants, including infants fed with bovine formula (104856,104868) or those with very low birth weight or extremely low birth weight (104856,104868,104869). These groups seemed to obtain greater benefits than other premature infants or those fed exclusively or almost exclusively with breast milk. Early data from one meta-analysis also suggests that lactoferrin may be more effective at preventing late-onset sepsis when combined with probiotics (104868). Fixed doses of 100-250 mg daily and weight-based doses up to 300 mg/kg daily have been studied (97783,104856,104868,104869,104870). However, many individual clinical studies, including 3 large studies, have failed to demonstrate clear benefits of lactoferrin. These clinical trials, one in very premature infants and the others in very low birthweight infants, show that lactoferrin 150 mg/kg daily, 200 mg/kg daily, or 100 mg daily does not reduce late-onset sepsis when compared with control (104857,104858,110771). Two of these trials had very few infants exclusively fed bovine formula, which may have limited potential benefits. Subgroup analyses from these trials also suggest that extremely low birth weight and/or extremely premature infants may have benefited from lactoferrin (104857,104858).

LIKELY INEFFECTIVE

• Fetal and premature infant mortality. Oral lactoferrin does not reduce the risk of all-cause mortality in premature infants. Details: Many meta-analyses and large clinical trials show that taking lactoferrin does not reduce the risk of mortality from any cause in premature infants (104856,104857,104858,104868,110771).
• Necrotizing enterocolitis (NEC). Most research shows that oral lactoferrin does not reduce the incidence of NEC in premature infants. Details: Many meta-analyses and large clinical studies show that lactoferrin does not reduce the incidence of NEC in premature infants (104856,104857,104858,104868,110771). Exploratory data from one meta-analysis suggest that lactoferrin combined with probiotics may reduce the incidence of NEC when compared with control (104868). However, since probiotics alone have demonstrated benefit for the prevention of NEC in clinical trials, it is unclear if lactoferrin confers any additional benefit.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Oral lactoferrin has only been studied in combination with other ingredients; its effect when used alone is unclear. Details: A large clinical study in adult females with acne shows that taking an oral supplement containing lactoferrin, zinc, niacinamide, and prebiotics once daily for 12 weeks, in addition to applying a topical combination retinoid-based cream, modestly improves the number of acne lesions (i.e., non-inflammatory, inflammatory, and total) when compared with the topical combination retinoid-based cream alone (112915). It is unclear if these effects are due to lactoferrin, other ingredients, or the combination.
• Anemia of chronic disease. Oral lactoferrin might improve hemoglobin levels in some patients with anemia of chronic disease. However, the optimal patient population is unclear. Details: One nonrandomized clinical study evaluated bovine lactoferrin in patients with anemia of chronic disease. In pregnant patients with anemia related to beta-thalassemia or hereditary thrombophilia, taking a specific bovine lactoferrin 100 mg capsule (Lattoglobina, Aqma Italia) twice daily with meals, starting at 6-8 weeks' gestation and continuing until delivery, improves hemoglobin levels by 50% and 15%, respectively, when compared with baseline. In non-pregnant patients, taking this same product twice daily for 30 days improves hemoglobin levels by 18% in patients with hereditary thrombophilia, but not in those with beta-thalassemia. The study may have been inadequately powered to detect a difference from baseline (104865).
• Antibiotic-associated diarrhea. It is unclear if oral lactoferrin is beneficial for preventing antibiotic-associated diarrhea in children or adults. Details: A very small clinical study in long-term care patients shows that adding lactoferrin at an unspecified dose to 600 mL of gastronomy tube solution daily for 56 days reduces the risk for antibiotic-associated diarrhea when compared with placebo (97782). Conversely, a clinical study in children aged 1-18 years receiving antibiotic therapy for an acute respiratory or urinary tract infection shows that those taking bovine lactoferrin 100 mg twice daily are more than twice as likely to develop antibiotic-associated diarrhea during or for the two weeks following antibiotic therapy when compared with those taking placebo (106729). However, the validity of these findings is limited by differences in baseline characteristics between groups.
• Atopic dermatitis (eczema). Oral lactoferrin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in adults with atopic dermatitis shows that taking a combination of lactoferrin 250 mg and a whey derived immunoglobulin-rich fraction 250 mg daily for 56 days improves symptoms in 13 of 22 patients, compared with 4 of 13 patients taking placebo (97789).
• Bacterial vaginosis. Oral lactoferrin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with recurrent bacterial vaginosis shows that adding a specific combination capsule (Respecta, Giellepi Spa Health Science) containing bovine lactoferrin 50 mg and 5 billion colony-forming units of Lactobacillus acidophilus GLA-14 and Lactobacillus rhamnosus HN001 on a varying schedule over 6 months, in conjunction with metronidazole 500 mg twice daily for the first 7 days, reduces the proportion of patients with vaginal discharge by 63%, itching by 57%, and a recurrent episode by 50% when compared with placebo. Patients took 2 capsules daily for 5 days, then 1 capsule daily for 10 days, followed by 1 capsule daily for 10 days of each month, beginning on the first day of the menstrual cycle. It is unclear if these effects are due to lactoferrin, other ingredients, or the combination (104872).
• Chemotherapy-induced anemia. It is unclear if oral lactoferrin is beneficial for chemotherapy-induced anemia. Details: An open-label clinical study in adults with advanced cancer and chemotherapy-induced anemia who are receiving treatment with recombinant human erythropoietin shows that taking oral lactoferrin (Lattoglobina, Grunenthal-Formenti) 200 mg daily for 12 weeks is as effective as intravenous ferric gluconate 125 mg weekly for improving hemoglobin and iron levels (97781).
• Cognitive function. Oral lactoferrin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in healthy adults shows that taking a product containing a combination of lactoferrin 10 mg, probiotics, prebiotics, minerals, and glutathione (Puraflor, GSK Consumer Healthcare, Milano, Italy) daily for 4 weeks does not affect cognitive performance during acute stress when compared with placebo (110923). It is unclear if this effect is due to lactoferrin, other ingredients, or the combination.
• Common cold. It is unclear if oral lactoferrin is beneficial for preventing the common cold. Details: A clinical study in healthy adults shows that taking bovine lactoferrin 200 mg or 600 mg daily for 12 weeks does not reduce the frequency or duration of self-reported symptoms of the common cold when compared with placebo (104859). Another clinical study in adults with frequent colds shows that taking a combination of bovine lactoferrin 400 mg and whey protein immunoglobulin-rich fraction 200 mg daily for 90 days reduces the number of colds by 57% when compared with placebo. There was no effect on cold severity (97786). It is not clear if this effect is due to lactoferrin, whey protein fraction, or the combination.
• Coronavirus disease 2019 (COVID-19). It is unclear if oral lactoferrin is beneficial for the treatment or prevention of COVID-19. Details: A small clinical study in adults hospitalized with mild-to-moderate COVID-19 receiving hydroxychloroquine, vitamin C, zinc, and acetylcysteine shows that taking lactoferrin 200 mg once or twice daily does not improve symptoms when compared with placebo (106731). Similarly, a large clinical study in adults hospitalized with moderate-to-severe COVID-19 receiving standard therapy shows that taking a specific product containing bovine lactoferrin (Mosaic, Pharmaguida) 400 mg twice daily for 30 days does not reduce intensive care unit admission or death, nor improve illness severity scores or discharge within 2 weeks when compared with placebo (112913). However, observational research with this product in outpatient adults with asymptomatic to moderately symptomatic COVID-19 suggests that taking 200-1000 mg daily is associated with a median of 15 days to a negative SARS-CoV-2 test, compared with 24 days in a historical control group (106732). The validity of these findings is limited by the retrospective nature of the study and differences in symptom severity between the groups at baseline. There is also interest in oral lactoferrin for prevention of COVID-19. A large clinical study conducted in healthcare workers in Peru who were screened and tested for COVID-19 shows that taking bovine lactoferrin 600 mg once daily for 65 days does not reduce the number of SARS-CoV-2 cases when compared with placebo (112914). However, the study was stopped prematurely due to vaccine availability; it may not have been powered to detect a difference between groups.
• Diarrhea. It is unclear if oral lactoferrin is beneficial for reducing the incidence of diarrhea in children or adults. Details: A large clinical study in weaned children 12-18 months of age shows that taking bovine lactoferrin 500 mg twice daily for 6 months does not reduce the incidence of diarrhea when compared with placebo (97787). However, a clinical study in infants with anemia who were exclusively breast-fed from 4-6 months before weaning and transitioning to infant formula from 6-9 months shows that fortification of each 100 grams of formula with 38 mg of bovine lactoferrin for 3 months improves vomiting and nausea when compared with formula without fortification. Similarly, fortification of each 100 grams of formula with 76 mg of bovine lactoferrin for 3 months improves diarrhea-related illness, diarrhea, vomiting, and nausea when compared with formula without fortification (106726). Lactoferrin has also been evaluated in adults. A large clinical study in healthy adults working at kindergartens or nursery schools in the winter shows that taking bovine lactoferrin 600 mg daily for 12 weeks is associated with a 1-day duration of diarrhea, compared with 2 days in those taking placebo (106728).
• Gastroenteritis-associated nausea and vomiting. It is unclear if oral lactoferrin prevents the development of gastroenteritis-associated nausea and vomiting in children or adults. Details: A large clinical study in children aged 3-6 years shows that consuming yogurt fortified with bovine lactoferrin 100 mg 3-5 days weekly for 15 weeks reduces the odds of school absence due to vomiting by 19% when compared with consuming the yogurt less than 3 days per week. However, consuming the yogurt did not reduce absences due to gastroenteritis, the presumed cause of vomiting (104862). A large clinical study in healthy adults working at kindergartens or nursery schools in the winter shows that taking bovine lactoferrin 200 or 600 mg daily for 12 weeks is associated with a 12% prevalence of acute gastrointestinal symptoms, compared with a prevalence of 22% in those taking placebo (106728).
• Gingivitis. Oral lactoferrin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in adults with mild gingivitis shows that taking bovine lactoferrin 60 mg, bovine lactoperoxidase 7.8 mg, and glucose oxidase 7.8 mg daily for 12 weeks improves gingival health and plaque index scores when compared with placebo. A lower dose product containing bovine lactoferrin 20 mg, bovine lactoperoxidase 2.6 mg, and glucose oxidase 2.6 mg daily for 12 weeks improves plaque index scores, but not gingival health scores, when compared with placebo. It is unclear if these effects are due to lactoferrin, other ingredients, or the combination (104867).
• Helicobacter pylori. Research on the use of oral lactoferrin as an adjunct for H. pylori eradication is inconclusive and conflicting. Details: Monotherapy with human recombinant lactoferrin, even at high doses of 5 grams daily, does not suppress or eradicate H. pylori infection (13317). However, research on its use as an adjunct to standard therapy is conflicting. Some studies suggest that lactoferrin improves efficacy when added to a triple therapy regimen of rabeprazole, clarithromycin, and tinidazole (13316,13332). However, research using lactoferrin with a triple therapy regimen of esomeprazole, clarithromycin, and amoxicillin found no difference in eradication rates. It is possible that lactoferrin activity on the bacterial cell wall interferes with the cell wall activity of amoxicillin (13315). Other research shows that using lactoferrin in addition to a sequential therapy regimen of esomeprazole, amoxicillin, metronidazole, and clarithromycin or a triple therapy regimen of esomeprazole, amoxicillin, and clarithromycin is associated with eradication rates of 95% or 86%, respectively, compared with eradication rates of 83% and 70%, respectively, with the use of either regimen alone (106730). However, using lactoferrin in addition to a sequential therapy regimen (esomeprazole, amoxicillin, tinidazole, and clarithromycin) and probiotics does not increase eradication more than sequential therapy and probiotics alone (97790).
• Hepatitis C. It is unclear if oral lactoferrin is beneficial for hepatitis C. Details: Some clinical research shows that lactoferrin decreases serum levels of hepatitis C virus RNA and alanine aminotransferase (ALT) in adults with hepatitis C (13320,13321). Some experts recommend starting lactoferrin 1 to 3 months before starting interferon to identify lactoferrin responders (13321,13322,13323,13324). Lactoferrin doses of 1.8 or 3.6 grams daily appear to be necessary for efficacy (13323,13324); lower doses don't seem to have any effect (13313,13314).
• Infant development. Oral lactoferrin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in healthy, full-term, exclusively formula-fed infants shows that taking a formula fortified with bovine lactoferrin 0.6 grams/L and bovine milk fat globule membrane 5 grams/L for 12 months improves cognitive development scores by about 8% after 12 months, but not after 18 months, when compared with control formula. This study may have been inadequately powered to detect a difference between groups at 18 months. It is unclear if any effect is due to lactoferrin, milk fat globule membrane, or the combination (104866).
• Iron deficiency anemia. It is unclear if oral lactoferrin is beneficial for the treatment or prevention of iron deficiency anemia in infants and children. Details: An open-label clinical study in children aged 1-10 years with cerebral palsy and iron deficiency anemia shows that taking bovine lactoferrin (Pravotin, Hygint) 100 mg twice daily for 4 weeks improves hemoglobin by 1.4 grams/dL, compared with 0.8 grams/dL in those taking iron hydroxide polymaltose complex providing elemental iron 3 mg/kg twice daily. Lactoferrin also improves serum ferritin, but not the rest of the serum iron profile (106725). Conversely, a small open-label clinical study in children aged 1-18 years with iron deficiency anemia in Egypt shows that the improvement in hemoglobin, serum iron, ferritin, or transferrin saturation is less with lactoferrin 100 mg daily, or twice daily if over age 3, when compared with iron bisglycinate chelate 0.75 mg/kg daily or iron polymaltose complex 6 mg/kg daily for a month. However, improvement in hemoglobin and iron studies was similar when comparing 30% iron saturated lactoferrin (100 mg lactoferrin and 30 mg iron) daily, or twice daily if over age 3 years, with iron bisglycinate chelate or iron polymaltose complex (110189). Lactoferrin has also been evaluated for the prevention of iron deficiency anemia. A clinical study in healthy, full-term formula-fed infants aged 6 weeks to 6 months shows that feeding a low-iron infant formula supplemented with lactoferrin has no effect on iron status or incidence of iron deficiency when compared with the low-iron formula alone (106724).
• Preterm labor. It is unclear if vaginal lactoferrin is beneficial for preventing preterm labor. Details: Observational research in patients diagnosed with bacterial vaginosis in the first trimester of pregnancy and a previous history of preterm labor has found that using a lactoferrin vaginal tablet 300 mg daily for 21 days is associated with a 44% reduced incidence of preterm birth when compared with no intervention. The validity of this study is limited by the use of a retrospective chart review (105405).
• Psoriasis. It is unclear if topical lactoferrin is beneficial in psoriasis. Details: A small open-label clinical study in patients with mild to moderate stable plaque-type psoriasis shows that applying lactoferrin 10% or 20% ointment topically daily in addition to taking bovine lactoferrin 100 mg orally daily (Lattoglobina, Grünenthal-Formenti) for 4 weeks improves symptoms of psoriasis, such as redness and scaling, by up to 37% when compared with use of oral lactoferrin alone (97784).
• Respiratory tract infections. It is unclear if oral lactoferrin is beneficial for treating or preventing respiratory tract infections. Details: A clinical study in healthy children aged 12-32 months shows that taking bovine lactoferrin 48 mg daily for 13 weeks does not reduce symptoms of respiratory tract infections when compared with placebo (104861). However, a clinical study in infants with anemia who were exclusively breast-fed from 4-6 months before weaning and transitioning to infant formula from 6-9 months shows that fortification of each 100 grams of formula with 38 mg of bovine lactoferrin for 3 months improves rhinorrhea, wheezing, and skin rash when compared with formula without fortification. Similarly, fortification of each 100 grams of formula with 76 mg of bovine lactoferrin for 3 months improves respiratory-related illness and wheezing when compared with formula without fortification (106726). There is also interest in oral lactoferrin for prevention of respiratory tract infections. However, two meta-analyses that each included 6 clinical studies in infants, children, and adults who consumed a bovine lactoferrin supplement or bovine lactoferrin enhanced formula, with some studies included in both analyses, have conflicting results. One meta-analysis of 1194 patients shows that lactoferrin reduces the risk of developing a respiratory infection by 43% when compared with placebo or various controls (110774). Conversely, the second meta-analysis of 1157 patients shows that lactoferrin does not reduce the risk of developing a respiratory infection in adults but may reduce the risk by 22% in infants and children when compared with placebo or unenhanced formula (110775). The validity of the findings from these meta-analyses is limited by the heterogeneity of the included studies, which enrolled patients of a broad age range and utilized widely varying dosing regimens. Furthermore, some studies are of poor quality.
• Vaginal candidiasis. Oral lactoferrin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with recurrent vaginal candidiasis shows that taking a specific combination capsule (Respecta, Giellepi Spa Health Science) containing bovine lactoferrin 50 mg and 5 billion colony-forming units of Lactobacillus acidophilus GLA-14 and Lactobacillus rhamnosus HN001 on a varying schedule over 6 months, in conjunction with clotrimazole 100 mg daily for the first 7 days, reduces the proportion of patients with vaginal discharge by 63%, itching by 100%, and a recurrent infection by 71% when compared with placebo. Patients took 2 capsules daily for 5 days, then 1 capsule daily for 10 days, followed by 1 capsule daily for 10 days of each month, beginning during the premenstrual phase. It is unclear if these effects are due to lactoferrin, other ingredients, or the combination (104863).
• Ventilator-associated pneumonia (VAP). It is unclear if oral lactoferrin is beneficial for preventing VAP. Details: A clinical study in critically ill, mechanically ventilated adults shows that taking lactoferrin 500 mg four times daily for up to 28 days does not reduce the incidence of VAP or other infections, or increase antibiotic-free days, when compared with placebo (104873). More evidence is needed to rate lactoferrin for these uses.

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LIKELY SAFE ...when used orally and appropriately, short-term. Various liquid extracts of Echinacea purpurea have been used safely for up to 10 days, including EchinaGuard (Madaus AG) 20 drops every 2 hours for 1 day, then three times daily (10320), or Echinilin (Inovobiologic Inc.) 40 mL in divided doses for 1 day, then 15 mL in divided doses daily thereafter (12355,20062). Other liquid extracts have been used safely for relatively longer periods, including Echinaforce (A. Vogel Bioforce AG) 2.4 grams daily for 4 months or 1.6 grams daily for 6 months (7087,18225), and Echinacin (Madaus AG) 5 mL twice daily for 10 days, or 4 mL twice daily for 8 weeks (3282,10802). Specific solid dosage forms of echinacea that have been used safely for up to 10 days include Echinacea purpurea above-ground parts (EchinaFresh, Enzymatic Therapy) 300 mg daily (11970), and mixtures of Echinacea purpurea and Echinacea angustifolia herb in divided doses of 6 grams to 10.5 grams for 1 day then 3 grams to 5.1 grams daily (10800,17519,20059). A specific Echinacea angustifolia extract (ExtractumPharma ZRT) has also been used with apparent safety at a dose of 40 mg once or twice daily for up to 7 days (20064,103233). An Echinacea purpurea product (Natures Resource) has been used safely at a dose of 1.8 grams daily for 8 weeks (17521), and echinacea (Puritan's Pride) has been used safely at 8 grams daily for 28 days (20066).

POSSIBLY SAFE ...when used topically, short-term. A specific cream (Linola Plus Cream, Dr. August Wolff GmbH & Co.) containing echinacea extract (WO 3260) has been applied to the skin safely 2-3 times daily for up to 12 weeks (97499). There is insufficient reliable evidence about the safety of echinacea when used parenterally.

CHILDREN: POSSIBLY SAFE
when used orally, short-term. Some clinical research shows that an extract of the above-ground parts of Echinacea purpurea (EC31J2, Echinacin Saft, Madaus AG) in a dose of 3.75 mL twice daily (for ages 2 years to 5 years) or 7.5 mL twice daily (for ages 6 years to 11 years) is safe when used for up to 10 days (4989). However, about 7% of children experienced a rash after taking echinacea, which might have been caused by an allergic reaction (4989). There is concern that allergic reactions could be severe in some children. The Medicines and Healthcare Products Regulatory Agency in the United Kingdom recommends against the use of oral echinacea products in children under 12 years of age due to this risk of allergic reaction (18207). In contrast, another clinical study in children 4-12 years old shows that a specific Echinacea purpurea product (Echinaforce Junior, A. Vogel) does not cause allergic or urticarial reactions more frequently than vitamin C (105719).

PREGNANCY: POSSIBLY SAFE
when used orally, short-term. There is preliminary evidence that mothers can safely use echinacea in the form of E. purpurea or E. angustifolia solid dosage forms, 250-1000 mg daily, or tinctures, up to 30 drops daily, for 5 days to 7 days during the first trimester without adversely affecting the fetus (7056,13418,15123). There is insufficient reliable information available about the safety of echinacea when used for longer than 7 days.

LACTATION:
Insufficient reliable information available; avoid using.

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LIKELY SAFE ...when used orally in amounts commonly found in foods. Lactoferrin has Generally Regarded as Safe (GRAS) status in the US (13312).

POSSIBLY SAFE ...when used orally in medicinal amounts. Bovine lactoferrin has been safely used at doses of up to 600 mg daily for up to 12 months (13313,13314,13315,13316,13320,13321,13322,13323,97786,104859,104860). Recombinant human lactoferrin has been used with apparent safety at a dose of 5 grams daily for up to 14 days (13317,13318,13319). There is insufficient reliable information available about the safety of lactoferrin when used topically.

CHILDREN: POSSIBLY SAFE
when used enterally in infants and children up to 6 years of age. Lactoferrin has been used safely as a part of enteral feeds in preterm infants at a dose of 250 mg daily or up to 300 mg/kg daily for up to 30 days (97783,97787,104857,104858,104870). Formula fortified with bovine lactoferrin 0.6 grams/L and bovine milk fat globule membrane 5 grams/L has also been used safely in infants for up to 12 months (104866). Bovine and recombinant human lactoferrin 1000 mg daily for up to 6 months has been used with apparent safety in weaned infants up to 18 months of age (97783,97787). Bovine lactoferrin 336-500 mg per week has been used with apparent safety in children 1-6 years of age for 13-15 weeks (104861,104862). There is insufficient reliable information available about the safety of lactoferrin in children over 6 years of age.

PREGNANCY: LIKELY SAFE
when used orally in amounts commonly found in foods. Lactoferrin has Generally Regarded as Safe (GRAS) status in the US (13312).

PREGNANCY: POSSIBLY SAFE
when used orally in medicinal amounts. Lactoferrin has been used with apparent safety during the second or third trimester of pregnancy at doses of up to 250 mg daily for up to 8 weeks (97788). Also, bovine lactoferrin has been used with apparent safety throughout all trimesters of pregnancy at doses of up to 200 mg daily (104865). There is insufficient reliable information available about the safety of intravaginal lactoferrin during pregnancy and lactation; avoid using.

LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods. Lactoferrin has Generally Regarded as Safe (GRAS) status in the US (13312). There is insufficient reliable information available about the safety of lactoferrin when used medicinally during lactation; avoid using.

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CAFFEINE Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Echinacea can increase plasma levels of caffeine by inhibiting its metabolism.  Details Echinacea seems to increase plasma concentrations of caffeine by around 30% (12155). This is likely due to inhibition of cytochrome P450 1A2 (CYP1A2) by echinacea.

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Echinacea might inhibit the metabolism of CYP1A2 and increase plasma levels of some drugs.  Details Echinacea appears to inhibit CYP1A2 enzymes in humans. Additionally, echinacea seems to increase plasma concentrations of caffeine, a CYP1A2 substrate, by around 30% (12155). Theoretically, echinacea might increase levels of other drugs metabolized by CYP1A2.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Echinacea may induce hepatic CYP3A4 and inhibit intestinal CYP3A4. This may increase or decrease levels of drugs metabolized by CYP3A4.  Details Several clinical trials have shown that taking echinacea for up to one month does not significantly affect the metabolism of various CYP3A4 substrates, including midazolam, docetaxel, etravirine, lopinavir-ritonavir, and darunavir-ritonavir (13712,48618,88164,88165). However, other clinical research shows that echinacea may increase the clearance of midazolam, suggesting that echinacea might induce CYP3A4 (48618). The discrepancy is thought to be due to differing effects of echinacea on intestinal versus hepatic CYP3A4 enzymes. Echinacea appears to induce hepatic CYP3A4 but inhibit intestinal CYP3A4 (12155). In some cases, these effects might cancel each other out, but in others, drug levels may be increased or decreased depending on the level of effect at hepatic and intestinal sites. The effect of echinacea on CYP3A4 activity may differ depending on the CYP3A4 substrate (6450,11026,88162,88167).

DARUNAVIR (Prezista) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, echinacea may interfere with the metabolism of darunavir; however, a small clinical study found no effect.  Details Darunavir is metabolized by cytochrome P450 3A4 (CYP3A4) and is administered with the CYP3A4 inhibitor ritonavir to increase its plasma concentrations. Echinacea has variable effects on CYP3A4, but administration of an E. purpurea root extract (Arkocapsulas Echinacea, Arkopharma) 500 mg four times daily for 14 days did not affect darunavir/ritonavir pharmacokinetics in 15 HIV-infected patients (88163,93578).

DOCETAXEL (Taxotere) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, echinacea may interfere with the metabolism of docetaxel; however, a small clinical study found no effect.  Details Docetaxel is metabolized by cytochrome P450 3A4 (CYP3A4). Echinacea has variable effects on CYP3A4, but taking E. purpurea whole plant extract (Echinaforce, A. Vogel Biopharma AG) 20 drops three times daily for 2 weeks did not alter the pharmacokinetics of docetaxel in one clinical study (88164).

ETOPOSIDE (VePesid) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Echinacea may increase levels of etoposide.  Details In one report, concomitant use of etoposide and echinacea was associated with more severe thrombocytopenia than the use of etoposide alone, suggesting inhibition of etoposide metabolism (20082). Etoposide is a cytochrome P450 3A4 (CYP3A4) substrate. Echinacea has variable effects on CYP3A4, but some studies have reported inhibition of the enzyme (6450,11026,12155,88162,88167).

ETRAVIRINE (Intelence) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, echinacea may interfere with the metabolism of etravirine; however, a small clinical study found no effect.  Details Etravirine is metabolized by cytochrome P450 3A4 (CYP3A4). Echinacea has variable effects on CYP3A4, but taking E. purpurea root extract (Arkocapsulas Echinacea, Arkopharma) 500 mg three times daily for 14 days did not alter the pharmacokinetics of etravirine in HIV-infected patients (88165,93578).

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Echinacea has immunostimulant activity which may interfere with immunosuppressant therapy.  Details Theoretically, echinacea may interfere with immunosuppressant therapy because of its immunostimulant activity (3279,6388,6389,12639).

LOPINAVIR/RITONAVIR (Kaletra) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, echinacea may interfere with the metabolism of lopinavir; however, a small clinical study found no effect.  Details Lopinavir is metabolized by cytochrome P450 3A4 (CYP3A4) and is administered with the CYP3A4 inhibitor ritonavir to increase its plasma concentrations. Echinacea has variable effects on CYP3A4, but taking E. purpurea (Echinamide, Natural Factors Nutritional Products, Inc.) 500 mg three times daily for 14 days did not alter the pharmacokinetics of lopinavir/ritonavir in healthy volunteers (48618,93578).

MIDAZOLAM (Versed) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = B Theoretically, echinacea may increase the metabolism of intravenous midazolam.  Details Echinacea induces hepatic CYP3A4 and might decrease plasma levels of midazolam by about 20%, reducing the effectiveness of intravenous midazolam (12155). Echinacea also appears to inhibit intestinal CYP3A4, which could theoretically increase the bioavailability of oral midazolam. This may cancel out the decrease in availability caused by induction of hepatic CYP3A4, such that overall plasma levels after oral administration of midazolam are not affected by echinacea.

WARFARIN (Coumadin) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = B Echinacea seems to increase the clearance of warfarin, although the effect may not be clinically significant.  Details Preliminary clinical research in healthy male volunteers suggests that taking echinacea increases the clearance of the active S-isomer of warfarin after a single dose of warfarin, but there was not a clinically significant effect on the INR (20083).

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General ...Orally, echinacea is well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, constipation, diarrhea, heartburn, nausea and vomiting, rashes, and stomach upset.
Serious Adverse Effects (Rare):
Orally: Severe allergic reactions and hepatitis have been reported.

Dermatologic ...Itching, urticaria, tingling, and allergic rashes have been reported with various echinacea preparations (8225,12355,17519,20059,20077,101592,111530,111540). In a study of children aged 2-11 years, rash occurred in about 7% of children treated with an extract of the above-ground parts of E. purpurea (EC31J2, Echinacin Saft, Madaus AG), compared with about 3% of those treated with placebo (4989,95652). There is concern that allergic reactions could be severe in some children. The Medicines and Healthcare Products Regulatory Agency in the United Kingdom (UK) recommends against the use of oral echinacea products in children under 12 years of age due to this risk of allergic reaction (18207). However, another study in children 4-12 years old shows that a specific E. purpurea product (Echinaforce Junior, A. Vogel) did not cause allergic or urticarial reactions more frequently than vitamin C (105719).

Gastrointestinal ...Gastrointestinal adverse effects include nausea and vomiting, abdominal pain, stomach upset, heartburn, diarrhea, and constipation (10802,11970,12355,13419,17519,20059,48680,105719,106626). An unpleasant taste, dry mouth, and burning, tingling or numbness of the tongue also occur (11970,12355,17519,20059,20070,20077).

Hematologic ...A 51-year-old female presented with leukopenia after taking echinacea 450 mg three times daily for 2 months, along with ginkgo biloba, multivitamins, and calcium. Her leukocyte count recovered upon stopping these supplements, but dropped again when she restarted echinacea alone about a year later. The problem resolved when echinacea was stopped permanently (48533). A 32-year-old male presented with severe thrombotic thrombocytopenic purpura (TTP) about 2 weeks after using an extract of E. pallida to treat a cold. He required admission to an intensive care unit and extensive plasmapheresis. The authors speculate that immunostimulant effects of echinacea induced or exacerbated the TTP (48572).

Hepatic ...Although uncommon, cases of echinacea-induced hepatitis have been reported. One case report describes acute cholestatic autoimmune hepatitis in a 45-year-old male who had been taking an echinacea root extract 1500 mg daily for about 2 weeks. He presented with significantly elevated liver function tests (LFTs), elevated immunoglobulin G (IgG) levels, and a positive test for anti-smooth muscle antibodies, indicating an autoimmune process. Elevated LFTs and IgG levels returned to normal within one month of stopping echinacea (17518). Another case report describes acute cholestatic hepatitis in a 44-year-old male who had taken echinacea root tablets 600 mg daily for 5 days to treat flu-like symptoms. He presented with elevated LFTs, prothrombin time, and international normalized ratio (INR). His condition gradually improved after stopping echinacea, and his LFTs normalized within 3 months (91528).
Seven cases of hepatitis associated with echinacea use were reported to the Australian Adverse Drug Reactions Advisory Committee between 1979 and 2000, but specific details are lacking (8225).
One case report describes acute liver failure in a 2 year-old child who had been given about 100 mg of echinacea daily for 2 weeks. The patient presented with jaundice, diarrhea, lethargy, anorexia, and significantly elevated LFTs. A liver biopsy showed hepatocyte swelling, spotty necrosis, and inflammatory infiltrate with eosinophils. A full recovery was made over a 2-week period (88166).

Immunologic ...Allergic reactions, including urticaria, runny nose, dyspnea, bronchospasm, acute asthma, angioedema, and anaphylaxis, have been reported with various echinacea preparations (638,1358,8225). Atopic individuals and those sensitive to other members of the Asteraceae family (ragweed, chrysanthemums, marigolds, daisies) seem to be at higher risk for these reactions (1358,8225).
A case report describes a 36-year-old female who presented with muscle weakness, electrolyte abnormalities, renal tubular acidosis, fatigue, and dry mouth and eyes after taking echinacea, kava, and St. John's Wort for 2 weeks., She also had a positive antinuclear antibody (ANA) test, with elevated anti-dsDNA antibodies SSA and SSB. Sjogren syndrome was diagnosed; the authors hypothesize that it may have been triggered by the immunostimulant effects of echinacea (10319). A 55-year-old male with a history of pemphigus vulgaris in remission for about a year experienced a flare of the disease after taking an echinacea supplement for one week. After stopping echinacea, medical treatment resulted in partial control of the disease (12171). Another case report describes a 58-year-old male who presented with marked eosinophilia and elevated immunoglobulin E (IgE) levels while taking an echinacea supplement. He required prednisone therapy until he stopped taking echinacea 3 years later, at which time his eosinophils and IgE normalized (48623). A 41-year-old male experienced four episodes of erythema nodosum, each occurring after he had taken echinacea for early symptoms of influenza. After stopping echinacea, he had no further exacerbations of erythema nodosum, suggesting that it had been triggered by the immunostimulant effects of echinacea (7057).

Musculoskeletal ...Reports of arthralgia and myalgia have been associated with echinacea (13418).

Neurologic/CNS ...Headache has been reported in people taking various echinacea preparations orally (3282,11970,17519,20059,20064). Dizziness has also been reported (3282,8225,11970). In one study using an alcoholic extract of the above-ground parts of E. purpurea (EC31J0, Echinacin, Madaus AG), somnolence and a tendency to aggressiveness were reported (3282).

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General ...Orally, bovine and human recombinant lactoferrin are well tolerated when used in typical doses. However, hjgher doses of 7.2 grams daily increase the risk of side effects and decrease tolerability.
Topically, there is a limited amount of information on the adverse effects of lactoferrin.
Intravaginally, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Constipation, diarrhea, epigastric pain, and nausea.
Topically: Burning sensation.
Serious Adverse Effects (Rare):
Orally: Bowel obstruction, intestinal perforation.

Dermatologic ...Orally, at higher doses of 7. 2 grams daily, lactoferrin has been reported to cause skin rash (13323). Topically, burning sensation has been reported (97784).

Gastrointestinal ...Orally, lactoferrin has been reported to cause diarrhea in some patients. At higher doses of 7.2 grams daily, anorexia and constipation have been reported (13323). However, gastrointestinal effects of lactoferrin, including epigastric pain, constipation, nausea, and diarrhea, are less common than with other sources of iron such as ferrous sulfate (97788). In neonates, single cases of jaundice, bloody stool, bowel obstruction, and intestinal perforation have been reported in clinical trials (104857,104858).

Neurologic/CNS ...Orally, at higher doses of 7. 2 grams daily, lactoferrin has been reported to cause fatigue and chills (13323).

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