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EnteraGam

Prescription Medical Food

Generic name: serum-derived bovine immunoglobulin/protein isolate; SBI
Dosage Form: powder, for oral solution
Manufacturer:
Entera Health

Indications and Usage

Clinical dietary management of enteropathy due to limited or impaired capacity to ingest, digest, absorb, or metabolize certain nutrients.

  • EnteraGam is indicated for the clinical dietary management of enteropathy (intestinal conditions or diseases) in patients who have a limited or impaired capacity to ingest, digest, absorb, or metabolize certain nutrients. Utilization of nutrition depends on proper ingestion and digestion of foodstuffs along with optimal gut metabolism and absorption of nutrients. Some patients, due to chronic conditions, diseases or specific drug therapies, have an impaired ability to ingest, digest, absorb, or metabolize food and certain nutrients, including water.
  • In nonclinical studies and clinical trials of children and adults, EnteraGam has been shown to nutritionally support the management of enteropathies associated with malnutrition, diarrhea-predominant irritable bowel syndrome (IBS-D), and human immunodeficiency virus (HIV). Therefore, pediatric and adult patients with impaired capacity to process nutrients due to malnutrition or another enteropathy can utilize EnteraGam for nutritional support (see Nutritional Requirements in Enteropathy).

Clinical dietary management of enteropathy in patients with chronic loose or frequent stools [e.g., diarrhea-predominant irritable bowel syndrome (IBS-D) and HIV-associated enteropathy].

  • EnteraGam is indicated for the clinical dietary management of enteropathy in patients with chronic loose or frequent stools (e.g., IBS-D and HIV-associated enteropathy). In subjects with IBS-D, EnteraGam was shown clinically to improve stool consistency and frequency as well as other GI symptoms (e.g., abdominal discomfort, loose stools, bloating, urgency, flatulence and incomplete evacuation), all evidence for enteropathy in this condition.
  • In subjects with enteropathy associated with human immunodeficiency virus (HIV) infection, EnteraGam was shown to clinically improve stool consistency, frequency, abdominal pain, urgency, incontinence, and night time bowel movements. These symptoms are commonly reported in patients who experience HIV-associated enteropathy.
  • EnteraGam, as a medical food, must be used under physician supervision. EnteraGam is dispensed by prescription.

Dosage and Administration

Recommended Dosing

Take one (1) EnteraGam packet daily. If necessary, one packet can be divided into two doses and taken once in the morning and once in the evening. EnteraGam can be taken with or without food. As directed by the physician, the dose can be increased up to 4 packets per day. EnteraGam has been safely consumed for up to one year in clinical studies in adults.

EnteraGam powder from one packet should be dissolved in at least 4 oz (120 mL) of water or other liquids as preferred and stirred until fully mixed. The powder should not be shaken to dissolve as this may degrade the product. Foods such as pudding or yogurt may be used instead of liquid to blend the product. EnteraGam powder from packets should not be stored mixed in liquids over time as the product may degrade. Consume each dose immediately after mixing.

Pediatric Patients

Children 2 years and older can be administered one half (1/2) packet of EnteraGam once daily or in divided doses in liquids or food according to the physician’s instructions. EnteraGam has been safely consumed for up to 8 months in clinical studies in pediatric populations.

Dosage Forms and Strengths

EnteraGam packets contain light-colored powder (5 g of SBI per packet including other ingredients of 5 g dextrose and trace amounts of sunflower lecithin [10 g net weight]). The retail product is supplied in a carton containing 30 packets. A professional sample carton containing 3 packets is also available.

Contraindications

EnteraGam is contraindicated for patients with a hypersensitivity (allergy) to beef or any components in EnteraGam.

Warnings and Precautions

EnteraGam contains beef protein; therefore, patients who have an allergy to beef or any component of EnteraGam should not take this product.

Adverse Reactions

Clinical Trial Experience

  • Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a product cannot be directly compared to rates in the clinical trials of another product and may not reflect the rates observed in-market when prescribed to patients with comorbidities or taking multiple pharmaceutical agents. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to product use and for approximating rates of side effects.
  • There are no serious adverse events (SAEs) associated or related with the use of 0.18 to 10.0 g of SBI per day in EnteraGam found in clinical trials with a total of over 300 subjects or patients. Infants ranging in age from 6 to 25 months were administered between 0.18 and 1.0 g of SBI per day in EnteraGam for up to 8 months (refer to Table 1). Adults ranging in age from 18 to 70 years were administered 5 to 10 g per day of SBI in EnteraGam for a duration of 2 days up to 48 weeks (refer to Table 1). The most commonly reported AEs in clinical studies (incidence 2-5%) included mild nausea, constipation, stomach cramps, headache, and increased urination.

Post-marketing Surveillance

  • Since 2001, in an estimated population of over 200,000 people consuming SBI, the AE rate is less than 0.1%. Common AEs are mild nausea and constipation. There has been one report of mild, itchy skin rash in a patient consuming a product containing SBI. No serious adverse events (SAEs) have been reported to the manufacturer or the FDA. Some patients have taken SBI for up to 4 years without experiencing AEs.

Drug Interactions

No significant interactions of EnteraGam with commonly prescribed medications or therapies have been observed.

Use in Specific Populations

Pregnancy

EnteraGam has not been studied in pregnant or nursing women. The choice to administer EnteraGam during pregnancy is at the clinical discretion of the prescribing physician.

Labor and Delivery

EnteraGam has not been studied in pregnant or nursing women. The choice to administer EnteraGam during labor and delivery is at the clinical discretion of the prescribing physician.

Nursing Mothers

EnteraGam has not been studied in pregnant or nursing women. The choice to administer EnteraGam in nursing mothers is at the clinical discretion of the prescribing physician.

Pediatric Use

Infants ranging in age from 6 to 25 months were exposed to 0.18 to 1.0 g of SBI per day in EnteraGam for up to 8 months with no reported AEs.

Geriatric Use

Clinical studies with EnteraGam did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger subjects.

Overdosage

No specific information is available on the treatment of overdosage with EnteraGam.

Description

  • EnteraGam packets contain 5 g of a specially formulated light-colored bovine serum-derived protein powder; SBI. SBI is composed of >50% immunoglobulin G (IgG) as well as other proteins and peptides which reflect the composition of plasma and are similar to other serum proteins found in colostrum and milk.

  • Other ingredients in EnteraGam packets are dextrose (5 g) and a trace amount sunflower lecithin. EnteraGam packets do not contain any milk products such as lactose, casein, or whey. EnteraGam packets are gluten-free, dye-free, and soy-free. EnteraGam packets are manufactured in accordance with current Good Manufacturing Practice (cGMP) for medical foods.

Nutritional Requirements in Enteropathy

Background

EnteraGam is an FDA-regulated Medical Food. The term medical food, as defined by the Orphan Drug Act (21 U.S.C. 360ee (b) (3)) of 1988, is “a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.” Medical foods are required to be composed of ingredients which are generally recognized as safe (GRAS) and/or approved food additives. Medical foods must also demonstrate the management of specific chronic conditions or diseases through clinical investigation to substantiate their indications. One important requirement for medical foods is that they provide for a “distinct nutritional requirement” as a result of a chronic condition or disease.

Distinct Nutritional Requirement for Oral Immunoglobulins in Enteropathy

Intestinal disorders (also known as enteropathy) are frequently found in association with several human disease conditions, including IBS-D or HIV infection, and are caused by pathological changes in the lining of the intestinal tract. Such changes disrupt the homeostasis or balance of the GI tract, which leads to symptoms of abdominal discomfort, bloating, and abnormal bowel function (e.g., urgency, diarrhea, constipation).

While the pathophysiological mechanisms that cause enteropathy are not well understood, there is a developing body of evidence to suggest the involvement of genetic predispositions, diet, stress, and exposure to external antigens (foreign substances), toxins, or other environmental insults (including infection). There are dozens of mutated genes, for example, which have been implicated in irritable bowel syndrome (IBS), a specific enteropathy which affects 10-20% of the population. These mutations can affect intestinal permeability, metabolism of tryptophan, and the synthesis and metabolism of bile acids, which result in imbalances of neurotransmitters and alterations in motility.

Modifications in tryptophan, serotonin, and bile acid metabolism, as well as alterations in the host microbiome, have been implicated in causing or exacerbating many of the symptoms endured by patients with diarrhea-predominant IBS (IBS-D). Changes in tryptophan metabolism have also been reported in HIV patients. Besides the potential genetic contribution, alterations of the intestinal microbiota (bacteria) and gut permeability can limit or impair digestive and absorptive function, leading to changes in fluid balance, vitamin production and absorption, and maldigestion of carbohydrates and fats. Malabsorption of key micronutrients (e.g., vitamins and minerals) and macronutrients (e.g., protein, carbohydrate, fat) during chronic diarrhea can lead to malnutrition or chronic undernutrition and play a central role in patients with enteropathy. A simple dietary change does not correct the problems which occur in enteropathy.

It is widely recognized that colostrum and breast milk, the sole source of nutrition for the neonate, contain a number of proteins including immunoglobulins which, along with early exposure to external antigens and bacteria, are critical for establishing the intestinal microbiota, normal immune function, integrity of the gut barrier, and digestive processes in the GI tract. Studies evaluating specially-formulated bovine immunoglobulin preparations have revealed a similar need for immunoglobulins in maintaining gut homeostasis in enteropathy.

In a clinical study in infants with malnutrition where serum-derived bovine immunoglobulin/protein isolate (SBI), a specially formulated bovine IgG-containing preparation, replaced 25% and 50% of the milk protein of the control diet composed of rice, whole milk powder, vegetable oil, and sugar, there were trends toward better carbohydrate and nitrogen absorption as well as nitrogen retention, a statistically significant decrease in fecal fat and energy loss. These results demonstrate a significantly greater apparent absorption of fat and energy in infants who were malnourished, a condition which causes enteropathy. In an adult clinical study comparing SBI to soy protein at the same level, only SBI demonstrated within group statistically significant management of IBS-D, another type of enteropathy.

Finally, SBI administered daily to adult patients with HIV-associated enteropathy provided nutritional support as evidenced by an increase in D-xylose absorption, a marker for nutrient uptake. These results demonstrate that SBI, a specially formulated bovine- IgG preparation, provides for a distinct nutritional requirement created by enteropathies in different clinical populations.

Nonclinical studies corroborate the clinical findings with regard to addressing a distinct dietary requirement for immunoglobulin-containing preparations for the management of enteropathy resulting from a variety of causes. In a review of data from 75 trials in 43 publications involving over 12,000 piglets, which are prone to developing enteropathy during the critical weaning period, the addition of plasma protein concentrates to normal feed provided high levels of immunoglobulins similar to levels found in SBI. Nutritional status improved by increasing nutrient ingestion, digestion, absorption and metabolism of feed and certain nutrients when compared to a range of other proteins added to feed (i.e., from dairy, fish, soy and other vegetable sources).

Other models of environmental stress including viral infection and GI toxin exposure demonstrated that bovine plasma containing high levels of immunoglobulin managed enteropathy in weanling pigs compared to soy protein at the same level as well as in rats when added and compared to normal feed, respectively.

Taken together, results from clinical and nonclinical studies reveal a distinct dietary requirement for immunoglobulins for the purpose of nutritional support in maintaining homeostasis to the disrupted gut environment in enteropathy.

Mode of Action

EnteraGam, specially formulated with SBI, has been shown to have a multi-faceted mode of action providing nutritive benefits such as increases in lean body mass, increased utilization and decreased catabolism of protein, decreased fecal fat and energy loss, as well as increased nutrient absorption. EnteraGam has been shown to bind microbial components, manage GI immune balance, maintain gut barrier function, and improve nutrient utilization to provide the distinct nutrition required to manage enteropathy (e.g., IBS-D or HIV infection).

Kinetics

Absorption
Protein digestion and amino acid absorption of SBI (10 g) was evaluated in 12 healthy adult subjects who consumed pudding containing SBI versus pudding alone. No absorbed, intact bovine immunoglobulin was detected in plasma. Partial digestion occurs as SBI travels down the digestive tract and increases in amino acid levels in systemic circulation demonstrate the nutritive value of SBI as an immunoglobulin-containing protein isolate. Some of the proteins in SBI were digested in the GI tract leading to heightened leucine levels, especially at 60 to 120 minutes after administration. Overall area under the curve (AUC) for leucine in the SBI group was significantly higher (p < 0.05) compared to the non-SBI group. Plasma amino acids had returned to fasting levels by 90 minutes after pudding alone, but remained above baseline levels until 120 to 150 minutes after SBI-containing pudding was administered. There is no metabolism in hepatic or renal organs. This data suggests that EnteraGam only acts locally within the GI tract to manage enteropathy.

Food Effect
EnteraGam has been fed alone and in combination with a variety of foods. There are no food effects on the activity of EnteraGam.

Distribution
EnteraGam has only been detected in the GI tract.

Metabolism and Elimination
Up to 50% of orally-administered immunoglobulins have been shown to survive initial digestive processes in the stomach. Transit time from oral ingestion of bovine immunoglobulins occurs between 6 and 40 hours depending on the health of the individual. In infants with diarrhea, approximately 5-12% of orally- administered immunoglobulins are excreted in feces. Other studies in adults with compromised GI tracts show that approximately 10-20% of orally-administered immunoglobulins are excreted in the feces.

Analysis of feces from healthy adults using immunological methods, however, found that only minute amounts (< 0.01%) of orally-administered immunoglobulins were excreted, indicating that most was digested as any protein source. Differences in survival through the GI tract may be due to variation in transit time because of co-administration with proton pump inhibitors, gastrointestinal infection, hydration state, or disease resulting in diarrhea.

Resistance
There are no reported incidences of resistance to orally-administered bovine-derived immunoglobulin protein isolates.

Cross-Reactivity
Serological studies have shown that bovine immunoglobulins, particularly IgG, contain cross-reactive antibodies to lipopolysaccharides (endotoxin) from gram-negative bacteria. Immunoglobulins in SBI have been shown to neutralize endotoxins and other microbial antigens.

Special Populations
There have been no transit time studies of orally-delivered immunoglobulins in geriatric patients. Several studies in infants have been performed demonstrating that immunoglobulin transit times through the GI tract of infants occur between 6 and 72 hours after ingestion.

CYP450 Interactions

Since orally-administered SBI has been shown only to be present in the GI tract, there is no interaction with the cytochrome P450 (CYP450) enzyme system in the liver. Therefore, CYP450 polymorphisms are not a factor when administering EnteraGam.

Clinical Safety in the Management of Enteropathies

SBI in EnteraGam has been self-affirmed as Generally Recognized as Safe (GRAS) with no questions regarding safety from the FDA for doses up to 50 g/day. Table 1 presents a safety summary of current clinical studies.

Table 1. Clinical Safety in the Management of Enteropathies (note from Leigh: tables may need to be recreated due to formatting issues, sorry)

Population Studied Safety Summary

Healthy Adults

12 healthy adults ingested a single dose of 10 g SBI, followed by 2.5 g SBI twice a day for 14 days. SBI was generally well-tolerated by the subjects during the single bolus dose and over 14 days of ingestion. Reported AEs (subjects) included: increased urination (3), stomach cramps (3), fatigue (2), and headache (2), as well as sore throat, softened stools, nausea, constipation, and irritability (1 each).>

IBS-D

34 adult subjects were administered either 5 or 10 g of SBI for 6 weeks. SBI was well-tolerated with no SAEs reported. Three subjects withdrew from the study due to nausea. No statistically significant differences between groups with respect to hematology and clinical chemistry laboratory results were observed.

HIV-associated Enteropathy

Eight HIV+ adults were administered 2.5 g SBI twice a day for 8 weeks. SBI was well-tolerated with no SAEs reported. Five patients continued on therapy for up to a year. The most commonly reported AEs included worsening or reoccurrence of diarrhea (5 AEs reported by 4 subjects), constipation (2 subjects), and worsening neuropathy (3 AEs reported by 2 subjects). AEs that were reported by 1 subject each included sinus infection, throat infection, gastroesophageal reflux disease, flatulence, worsening lower back pain, groin pain, nausea, bronchitis, acute ear infection, and infection on finger. No AEs were reported to be related to SBI and no subjects discontinued due to an AE.

Malnutrition (Pediatric) Study 1 and 2

10 children (9-25 months of age) were provided a diet with either 25 or 50% protein replacement of milk protein with serum-derived bovine protein containing immunoglobulins during 3 randomly ordered, 7 day dietary periods. There were no reported AEs due to serum-derived bovine protein containing immunoglobulins.

107 infant children (6-7 months of age) received serum-derived bovine protein containing immunoglobulins in the 8 month study. There were no reported AEs due to serum-derived bovine protein containing immunoglobulins

AE = adverse event; HIV = human immunodeficiency virus; IBS-D = irritable bowel syndrome-diarrhea predominant; SAEs = Serious adverse events; SBI = serum-derived bovine immunoglobulin/protein isolate

Clinical Management of Enteropathies

Patients with enteropathy (chronic intestinal disorder) have a “distinct nutritional requirement” for specially formulated dietary immunoglobulins to maintain homeostasis in the gastrointestinal tract. Table 2 describes clinical findings for SBI in the management of IBS-D, HIV-associated enteropathy as evidence, required to substantiate indications for medical foods, that SBI manages enteropathy in these patient populations. In addition, Table 2 also summarizes the nutritive value of SBI in infants and children with malnutrition, which is known to cause enteropathy.

Table 2. Clinical Dietary Management of Enteropathies with SBI

Population Studied Impact of Dietary Management with SBI
IBS-D
Randomized, double- blind, placebo-controlled, single site, 6 week study N=66 patients diagnosed with IBS-D Placebo, SBI 5 g/day or SBI 10 g/day
  • 10 g/day SBI group had a reduction in days with loose stools (p = 0.01), abdominal pain (p < 0.01), urgency (p = 0.050), bloating (p < 0.05), flatulence (p < 0.01), and any symptom (p < 0.01).
  • 5 g/day SBI group experienced reductions in days with flatulence (p = 0.035), incomplete evacuation (p < 0.050), and any symptom (p = 0.014).
HIV-associated Enteropathy
Open-label pilot study, 8 HIV+ male adult patients, w/ HIV- associated enteropathy; median CD4+ cell count 372 cells/dL, SBI – 2.5 g twice a day for 48 weeks, (SBI for 8 weeks followed by 4 weeks washout and SBI for 48 weeks)
  • Median bowel movements/day and stool consistency decreased at 8 weeks (p = 0.008).
  • Improvements in median GI symptoms questionnaire scores (cramping, urgency, incontinence, and nocturnal diarrhea at 8 weeks (p = 0.008).
  • Durable bowel movements/day, stool consistency and questionnaire responses, after a 4 week washout, were reported at 2.0 (2.0, 3.0), 2.5 (1.0, 3.8), and 6.0 (2.0,12.8), respectively, for those that continued SBI for an additional 48 weeks (p = 0.062 compared to baseline).
  • Marked improvement of GI-related symptoms within 3 weeks of initiating SBI in all 8 patients.
  • Duodenal absorption of D-xylose increased in 7/8 subjects as reflected in urinary excretion. In those with improvement, absorption levels increased from 33.8 mg (28.7,38.2) to 40.9 mg (19.8,44.4) at week 8 (p = 0.19).
  • Increased CD4+ T-lymphocyte density (an average of ~140 cells/mm2) within lamina propria after 8 weeks of SBI from 213 to 322 cells/mm2 (p = 0.016).
  • MCP-1 levels were unchanged at week 8 but decreased in 5/5 subjects at week 48 (379.5 ng/mL [225, 502]) (p = 0.06).
  • I-FABP initially rose in 7/8 subjects after 8 weeks from 3514 ng/mL to 4042 ng/mL (p = 0.039) and then fell below baseline in 4 of the 5 who continued receiving SBI to 2442 ng/mL at week 48 (p = 0.12 compared to baseline, p = 0.06 compared to week 8).
  • MMP-9/TIMP-1 ratios in subjects were significantly lower than controls at baseline (0.13 versus 0.42 [p = 0.007]), respectively, and tended to increase at the end of study to 0.33 (p = 0.08).
  • MCP-1 levels were negatively correlated to CD4+ lamina propria density (r = -0.59, p = 0.019) with all time points examined.
  • MMP-9/TIMP-1 ratios were negatively correlated with CD8+ lamina propria density (r = -0.70, p = 0.0039).
  • Baseline serum I-FABP levels were negatively correlated with subsequent rise in lamina propria CD4+ T-lymphocytes (r = -0.74, p = 0.046).
  • Pro-inflammatory gammaproteobacteria tended to decrease and Clostridium (genus) tended to decrease.
  • Changes in gut microbiota correlated with local lymphocyte populations that increased significantly with 8 weeks of SBI therapy.
Malnutrition (Pediatric) Study 1: Randomized, controlled study
N=10 (9-25 months of age) recovering from severe malnutrition. Diet contained either control, or 25% or 50% milk protein replacement with serum-derived bovine protein containing immunoglobulins during 3 randomly ordered, 7 day dietary periods.
  • The mean number of daily bowel movements, mean apparent absorption and retention of nitrogen, and mean apparent absorption of carbohydrate were similar for each diet.
  • Fractional absorption of dietary lipid and of total energy increased significantly in relation to the amount of serum-derived bovine protein containing immunoglobulins in the diet.
Malnutrition (Pediatric) Study 2: Randomized, controlled, community based intervention study
N=259 (6-7 months of age). Diet containing serum-derived bovine protein containing immunoglobulins, WPC, serum-derived bovine protein containing immunoglobulins + MMN or WPC + MMN daily for 8 months.
  • No differences in growth or rates of morbidity were found for any group in those children who completed 8 months of observation.
  • Children receiving MMN had lower rates of anemia, and children who received WPC+MMN had less of a decline in serum ferritin. No differences in other biochemical indicators of micronutrient status were noted.
  • Supplementation with MMN reduced anemia and iron deficiency in this population, but the MMN content and source of protein in the supplements did not affect other indicators of micronutrient status, growth, or morbidity.
  • Trends toward increased MMN uptake and lean muscle mass in the presence of serum-derived bovine protein containing immunoglobulins but not WPC.

AE = adverse event; CD = cluster of differentiation antigen; IBS-D = irritable bowel syndrome-diarrhea predominant; HIV = human immunodeficiency virus; I-FABP = Intestinal fatty acid binding protein; MCP- 1 = monocyte chemotactic protein-1; MMN = multiple micronutrients; MMP = matrix metalloproteinase; SBI = serum-derived bovine immunoglobulin/protein isolate; TIMP-1 = Tissue inhibitor of metalloproteinase 1; WPC = whey protein concentrate

Diarrhea Predominant Irritable Bowel Syndrome

A randomized, double-blind, placebo-controlled, single site study in which subjects with diarrhea- predominant irritable bowel syndrome (IBS-D) were administered either SBI (10 g/day), SBI (5 g/day), or placebo (10 g/day soy protein isolate) for 6 weeks. Subjects in the 5 g/day SBI group also received 5 g/day placebo so that all 3 groups received an equivalent amount of protein. Demographic characteristics of subjects included in the study were not significantly different. There was a one week assessment period and then subjects randomized into the study at baseline. Assessments included a modified IBS-36 questionnaire, daily symptoms scores, and hematology and clinical chemistry laboratory tests. A total of 66 subjects were enrolled in this study: 22 in the placebo group, 25 in the 10 g/day SBI group, and 19 in the 5 g/day SBI group.

Four subjects withdrew from the study due to nausea: 1 subject in the placebo group, 2 subjects in the 10 g/day SBI group, and 1 subject in 5 g/day SBI group. A total of 51 subjects completed the study: 16 subjects in the placebo group, 17 subjects in the 10 g/day SBI group, and 18 subjects in the 5 g/day SBI group. The rate of withdrawal was similar across groups.

Within group comparison for subjects in the 10 g/day SBI cohort showed statistically significant reductions in the number of days with symptoms from week 2 to week 6 for loose stools (p < 0.01), abdominal pain (p = 0.01), flatulence (p < 0.01), bloating (p < 0.05), urgency (p = 0.05), and any symptom (p < 0.01). Within group comparison for subjects in the 5 g/day SBI cohort showed statistically significant reductions from week 2 to week 6 in the number of days with flatulence (p = 0.035), incomplete evacuation (p < 0.05), and any symptom (p = 0.014).

The study was not powered to compare differences between groups. There were no statistically significant differences between groups with respect to hematology and clinical chemistry laboratory results. No serious AEs were reported.

Administration of SBI at a dose of 10 g/day for 6 weeks significantly decreased, from baseline to end of study, the number of symptom days for loose stools, abdominal pain, flatulence, bloating, urgency, and any symptom. Greater improvements in hard stools, and incomplete evacuation were also achieved with SBI. Results also demonstrate the safety and tolerability of SBI when supplemented daily for 6 weeks in subjects affected by the diarrhea predominant form of IBS.

HIV-associated Enteropathy

A small open-label study in which HIV-infected subjects with HIV-associated enteropathy were administered SBI (5 g/day) for 8 weeks with a 4-week washout period and an optional 9-month extension study. HIV-associated enteropathy was defined as chronic gastrointestinal symptoms including frequent loose or watery stools despite no identifiable, reversible cause. Assessments included gastrointestinal symptoms, disaccharide gut permeability/absorption studies to test gastrointestinal function, upper endoscopy for tissue immunofluorescent antibody assays to test mucosal immunity, plasma biomarkers of microbial translocation, inflammation and collagen kinetics, and intestinal microbial sequencing. Median peripheral blood CD4+ T-cell count was 372 cells/mL (193, 459) at baseline, was unchanged at 339 cells/mL (210, 468) after 8 weeks and 348 cells/mL (225, 397) after 48 weeks.

Eight men (5 white, 3 African-American) with a median age of 44.5 years (38.8, 47.8) on HAART for more than 1 year were enrolled in the study. Median bowel movements/day decreased from 5.8 (range: 5.0, 8.4) to 2 (2.0, 3.8) (p = 0.008) and stool consistency [1-constipated to 6-watery] decreased from a median of 5.3 (5, 6) to 3 (2.2, 3.8) (p = 0.008) at 8 weeks. Median GI symptoms questionnaire scores (cramping, urgency, incontinence, and nocturnal diarrhea [0 to 39 with normal < 4]) decreased from 17 (15.6, 21.8) to 8.0 (3.5, 11.9) (p = 0.008) at 8 weeks compared to baseline. For those five subjects who continued SBI to week 48, durable bowel movements/day, stool consistency and questionnaire responses were reported at 2 (2.0, 3.0), 2.5 (1.0, 3.8), and 6.0 (2.0, 12.8), respectively (all p = 0.062 compared to baseline).

Increased gastrointestinal absorption assessed by D-xylose urinary excretion increased in 7/8 subjects over the course of the 8-week intervention from a median of 33.8 mg (28.7, 38.2) at baseline to 40.9 mg (19.8, 44.4) at week 7 (p = 0.19) demonstrated the nutritive value in SBI. These 7 patients demonstrated SBI was well-tolerated, with a reduction in HIV-associated enteropathy as noted by a decrease in stool frequency, an increase in formed stool consistencies and a decrease in GI symptoms.

Immunohistochemistry enumeration of absolute lamina propria CD3+/CD4+ T-cell density revealed an increase from 213 (152, 243) to 322 cells/mm2 (228, 433) (p = 0.016) [a median increase of 139.5 cells/mm2 of CD3+/CD4+ lamina propria lymphocytes (66.1, 216)] after 8 weeks of SBI. By contrast, previous studies showed increases of 57 cells/mm2 (IQR: -9.0, 82) after 9 months of antiretroviral therapy. While the lamina propria CD3+/CD8+ density was unchanged [502 cells/mm2 (416, 650) and 598 cells/mm2 (361, 699) at baseline and week 8, respectively], the lamina propria CD4+/CD8+ ratio increased from 0.41 to 0.62 (p = 0.016). MCP-1 levels were unchanged from baseline [476.4 ng/mL (426.4, 598.1)] at week 8 but decreased in 5/5 subjects at week 48 [379.5 ng/mL (225, 502)] (p = 0.06).

Intestinal fatty acid-binding protein initially rose in 7/8 subjects after 8 weeks from 3514 ng/mL (2858, 4275) to 4042 ng/mL (3233, 5613) (p = 0.039) and then fell below baseline in 4 of the 5 who continued receiving SBI to 2442 ng/mL (1267, 2875) after 48 weeks (p = 0.12 compared to baseline, p = 0.06 compared to week 8). MMP-9/TIMP-1 ratios in subjects were significant lower than controls at baseline [0.13 (0.07, 0.33) versus 0.42 (0.23, 0.44), p = 0.007], respectively and then tended to increase at the end of study to 0.33 (0.13, 0.73) (p = 0.08). MCP-1 levels were negatively correlated to CD3+/CD4+ lamina propria density (r = -0.59, p = 0.019) with all time points examined together, suggesting that MCP-1 expression is associated with mucosal immunologic damage. Similarly, MMP-9/TIMP-1 ratios were negatively correlated with CD3+/CD8+ lamina propria density (r = -0.70, p = 0.0039) suggesting that factors promoting CD8+ T-cell infiltration into the lamina propria correlate with impaired collagen kinetics. Baseline serum I-FABP levels were negatively correlated with subsequent rise in lamina propria CD4+ T-lymphocytes (r = -0.74, p = 0.046). In addition, SBI demonstrated an effect on the composition of the gut microbiota in patients with HIV-associated enteropathy.

Pro-inflammatory gammaproteobacteria tended to decrease from 0.70% to 0.12%. Clostridium (genus) and Ruminococcus (also a genus in the Clostridia family) decreased from 6.5 (2.80, 10.65) to 3.4 (2.50, 5.89) and 0.89 (0.52, 1.29) to 0.30 (0.15, 0.47), respectively. Ruminococcus decreased in all eight subjects. Decreases in Clostridium in the stool were correlated with duodenal CD3+/CD4+ density (r = -0.63; p < 0.01). Changes in gut microbiota correlated with local lymphocyte populations that increased significantly with short-term administration of SBI. A total of 20 AEs were reported by 7 subjects. Most of the reported AEs were mild (7/20) or moderate (9/20) in severity, and judged by the investigator to be not related to study product (16/20).

The 4 events judged to be severe included worsening diarrhea, worsening diarrhea (due to ova/parasites), worsening lower back pain, and groin pain. Four events (reported in 3 subjects) judged to be possibly related to product included constipation (reported by 2 subjects), GERD (reported by 1 subject) and nausea (reported by 1 subject).

The most common AEs included worsening or recurrence of diarrhea (5 AEs reported by 4 subjects), constipation (2 subjects), and worsening neuropathy (3 AEs reported by 2 subjects). Adverse events that were reported by 1 subject each included sinus infection, throat infection, gastroesophageal reflux disease, flatulence, worsening lower back pain, groin pain, nausea, bronchitis, acute ear infection, and infection on finger.

Pediatric Malnutrition

Malnutrition from suboptimal food intake is known to cause enteropathy. A preliminary randomized, controlled study was conducted to assess the acceptability, safety, and digestibility of bovine serum proteins in young children. Masked study diets were provided sequentially to each of 10 young, Peruvian children (9 – 25 months of age) recovering from severe protein-energy malnutrition, during 3 randomly ordered, 7-day dietary periods. The control diet was prepared from rice, milk, vegetable oil, and sugar; the 2 study diets included serum-derived bovine protein (containing immunoglobulins) to replace either 25% or 50% of the milk protein of the control diet. All children consumed the entire amounts offered of each of the diets.

The mean number of daily bowel movements, mean apparent absorption and retention of nitrogen, and mean apparent absorption of carbohydrate were similar for each diet. Fractional absorption of dietary lipid and of total energy increased significantly in relation to the amount of serum-derived bovine protein in the diet. There was no difference between digestibility of the milk fat versus serum- derived bovine protein when provided in the diet. Therefore, the increase in fractional absorption is likely due to increased serum-derived bovine protein content in the diet.

Numerical improvements in nitrogen retention were also noted with increased serum-derived bovine protein diet which means improved absorption was also a potential explanation for the improvement. These results demonstrate the distinct nutritive value of the serum-derived bovine immunoglobulin containing diet. Each diet was well-tolerated by the children in the study, and there was no evidence of any adverse effects of serum proteins. Another randomized, controlled, community-based intervention study was conducted to evaluate the effects of serum-derived bovine protein (containing immunoglobulins) and/or multiple micronutrients on children’s growth, morbidity, and micronutrient status in a low-income peri-urban Guatemalan community.

A total of 259 children who were initially 6 to 7 months of age received 1 of 4 maize-based dietary products daily for 8 months: whey protein concentrate (control group), whey protein concentrate plus multiple micronutrients, or serum-derived bovine protein containing immunoglobulins, and serum-derived bovine protein containing immunoglobulins plus multiple micronutrients. Two hundred and twenty-five (225; 86.9%) children completed = 60 days of observation, 184 (71.0%) completed = 180 days of observation, and 132 (51.0%) finished the full 8 months of observation. All diets were well-tolerated. There were no significant differences in the number of dropouts for all groups at any time point. There were no significant differences in growth or rates of morbidity were found for any group in those children who completed 8 months of observation.

Children who received multiple micronutrients had lower rates of anemia. Those who received whey protein concentrate plus multiple micronutrients showed less of a decline in serum ferritin than those who did not, but there were no differences in other biochemical indicators of micronutrient status between groups. Administration of multiple micronutrients reduced anemia and iron deficiency in this population, but the multiple micronutrients content and source of protein in the product did not affect other indicators of micronutrient status, growth, or morbidity. There was a notable trend toward increased micronutrient uptake and lean body mass in the group receiving micronutrient and serum- derived bovine protein containing immunoglobulins.

References

1 21 USC Section 360ee(b)(3).

How Supplied/Storage and Handling

EnteraGam packets contain a light-colored powder available as 5 g SBI including other ingredients 5 g dextrose and trace amounts of sunflower lecithin in 10 g net weight individual retail packets. Read more: Inactive ingredients

†Product: 53703-100-03
# Size: 30 packets per box

EnteraGam packets contain a light-colored powder available as 5 g SBI including other ingredients 5 g dextrose and trace amounts of sunflower lecithin in 10 g net weight individual sample packets. (Not for resale).

†Product: 53703-100-01
# Size: 3 packets per box

Store packets at 20-25°C (68-77°F): excursions permitted between 15-30°C (59-86°F). [see USP Controlled Room Temperature].

†Entera Health, Inc. does not represent this product code to be a National Drug Code (NDC) number. Instead, Entera Health has assigned a product code formatted according to standard industry practice to meet the formatting requirements of pharmacy and health insurance computer systems.

Patient Counseling Information

Patients should be informed of the following information before initiating therapy with EnteraGam and periodically during the course of ongoing therapy:

Instructions for Use

  • Pour packet ingredients into cup or glass
  • Add at least 4 oz of water (or other liquid as preferred)
  • Avoid hot liquids
  • Stir until fully mixed (do not shake)
  • Drink all of the contents immediately
  • Alternatively, product can be mixed with foods such as yogurt
  • Take one packet daily or in divided doses with or without food according to your healthcare provider’s instructions

Pregnancy and Nursing

  • EnteraGam has not been studied in pregnant or nursing women. The choice to administer EnteraGam during pregnancy is at the clinical discretion of the prescribing physician.

Warnings and Precautions

  • EnteraGam contains beef protein so anyone allergic to beef should not take this product. If the patient experiences shortness of breath, immediately discontinue the product and contact your healthcare professional.

Manufactured and Distributed by:

Entera Health, Inc.
Ankeny, Iowa 50021
ENT005C0414 Rev 04/14


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