Formula 115 by DC

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Celiac disease. Although there has been interest in using oral lipase for celiac disease, there is insufficient reliable information about the clinical effects of lipase for this purpose.
• Dyspepsia. It is unclear if oral lipase is beneficial for improving symptoms of postprandial distress syndrome. Details: A small clinical trial shows that taking a specific acid-resistant lipase (Amano Enzyme USA) 280 mg immediately before a high-fat meal does not reduce postprandial bloating and nausea when compared with placebo in individuals with postprandial distress syndrome (101900).
• Inflammatory bowel disease (IBD). Although there has been interest in using oral lipase for IBD, there is insufficient reliable information about the clinical effects of lipase for this purpose.
• Prematurity. It is unclear if adding a specific form of lipase, recombinant human bile salt-stimulated lipase (rhBSSL), to infant formula improves outcomes in premature infants. Some research suggests a potential increased risk for adverse effects. Details: Human breast milk contains rhBSSL, but it is inactivated when breast milk is pasteurized for donation. Clinical research in infants born before 32 weeks' gestation shows that adding rhBSSL as 8700 units per 100 mL formula or pasteurized breast milk, for 4 weeks does not increase growth velocity, body length, or head circumference over the next 12 months when compared with formula or pasteurized breast milk devoid of lipase. However, the infants who were small for gestational age (SGA), which made up approximately 15% of the study population, grew by an additional 1.9 grams/kg daily on average when compared with placebo (101940). More evidence is needed to rate lipase for these uses.

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EFFECTIVE

• Pancreatic insufficiency. Oral prescription pancreatic enzyme products improve digestion in patients with exocrine pancreatic insufficiency due to various causes. It is unclear if non-prescription pancreatic enzyme products would be beneficial; their use is not recommended. Details: Prescription pancreatic enzyme products are effective for improving fat, protein, and total energy absorption in patients with exocrine pancreatic insufficiency due to cystic fibrosis, chronic pancreatitis, pancreas resection or removal, or other conditions (67622,67634,67676,67688,67694,67699,67714) (98667,98674,98676,98677,99115,99116,99118,99119,99120,99122)(99124,99125,99126,99127). Improvement in fat absorption and digestion occurs in as little as 1 week. Symptoms such as gas and abdominal discomfort are also improved in most patients (98667,98674,98677). Various prescription products have been approved by the US Food and Drug Administration (FDA) for this indication (95743). These prescription pancreatic enzyme products are typically used at a starting dose of 500-1000 lipase units/kg body weight per meal to a maximum of 2500 lipase units/kg body weight per meal or 10,000 lipase units/kg body weight daily or 4000 lipase units/gram of fat daily (99130). Despite being beneficial for most patients with exocrine pancreatic insufficiency, there is some evidence that prescription pancreatic enzyme products might not be beneficial in all patients. In patients with pancreatic insufficiency following gastrectomy for gastric cancer, research on prescription pancreatic enzyme products shows conflicting results (67617,95744). Also, a small study shows that taking a prescription pancreatic enzyme product for 26-30 days does not improve time to recovery from pancreatic insufficiency related to acute pancreatitis (99117). However, the small size of most of these studies limit the reliability of the results. One large clinical study shows that taking prescription pancreatic enzyme products for pancreatic insufficiency following pancreatoduodenectomy does not improve body weight or serum albumin levels. However, the dose used in this study was lower than recommended in the US guidelines, and adherence to the prescribed regimen was poor (102322). There is no strong evidence that supplemental forms of pancreatic enzyme products help with digestion in patients with pancreatic insufficiency. Non-prescription pancreatic enzyme products are not recommended for this use.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Atopic dermatitis (eczema). It is unclear if oral pancreatic enzyme products are beneficial in children with atopic dermatitis. Details: A small clinical study in children with refractory atopic dermatitis and food allergies shows that taking a specific prescription pancreatic enzyme product (Creon, Solvay Pharma) 37,500 or 75,000 protease units with each meal and 18,750 or 37,500 protease units with each snack for 6 weeks reduces the severity of atopic dermatitis when compared with baseline (102321). The validity of this finding is limited by the lack of a comparator group.
• HIV/AIDS. It is unclear if oral pancreatic enzyme products are beneficial in children with HIV. Details: Nutrient malabsorption is common in individuals with HIV/AIDS, possibly leading to malnutrition. Preliminary clinical research in children aged 1-14 years with HIV shows that taking a prescription pancreatic enzyme product (Creon 10,000) 1000 lipase units per gram of digested fat for 2 weeks reduces fecal fat loss when compared with baseline. Although improvement occurred in all of the children, a complete response, resulting in no steatorrhea, occurred in only 33% (99123). The validity of these findings is limited by the lack of a comparator group.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral pancreatic enzyme products are beneficial in patients with NAFLD following pancreaticoduodenectomy. Details: NAFLD is a common complication post-pancreaticoduodenectomy (PD). A small clinical study in patients who developed NAFLD after PD shows that taking a prescription pancreatic enzyme product (LipaCreon, marketed as Creon in the US) 1800 mg daily for 6 months improves the liver-to-spleen attenuation ratio on computed tomography when compared with baseline, suggesting a reduction in hepatic fat content. Liver function was also improved, and most patients showed improvement in symptoms such as diarrhea (99113). The validity of these findings is limited by the lack of a comparator group. Although another preliminary clinical study shows that taking this prescription product for 12 months is as effective for preventing NAFLD after PD as taking specific non-prescription pancreatic enzyme products, including Politose (Takeda Pharmaceutical Co. Ltd) 1800 mg daily or Toughmac-E (Ono Pharmaceutical Co. Ltd) 3 grams daily for 10-12 months (99112), this study was underpowered and was not necessarily designed to detect between-group differences.
• Pancreatic cancer. It is unclear if oral pancreatic enzyme products improve nutrition status and health in patients with clinically overt exocrine pancreatic insufficiency resulting from pancreatic cancer. Details: Exocrine pancreatic insufficiency can be a complication of pancreatic cancer. One clinical study in patients with unresectable pancreatic cancer shows that taking a prescription pancreatic enzyme product (Norzyme, Nordmark Arzneimittel GmbH & Co. KG; not available in the US) 6-9 capsules daily for 8-24 weeks does not increase body weight, global assessment, quality of life, or survival when compared with placebo (99114). Another preliminary clinical study shows that taking a high-dose pancreatic enzyme product providing 48,000 lipase units per meal for 8 weeks during chemotherapy does not improve body mass index, nutritional parameters, or survival when compared with no treatment (99111). However, in both studies, clinically overt exocrine pancreatic insufficiency was absent in most of the patients. In a study in which clinically overt exocrine pancreatic insufficiency was more prevalent, taking a prescription pancreatic enzyme product (Panzytrat 25,000, Nordmark GmbH; not available in the US) 50,000 lipase units per meal three times daily for 8 weeks appears to increase body weight by about 5% when compared with placebo (67708). More evidence is needed to rate pancreatic enzyme products for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cancer. Although there has been interest in using oral papain for cancer, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Dental caries. It is unclear if topical papain gel is beneficial for reducing procedure time or pain in children having caries removed by a dentist. Details: A small clinical study in children 3-9 years of age with dental caries shows that application of a specific papain gel (Brix3000, Brix Medical Science) 3000 U/mg during atraumatic restorative treatment (ART) by a dentist actually increases the time required to remove caries tissue, with no effect on pain, when compared with ART alone (107434).
• Diabetic foot ulcers. Although there has been interest in using topical papain for diabetic foot ulcers, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Exercise-induced muscle soreness. Oral papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy males shows that taking a combination enzyme tablet containing papain 50 mg, trypsin 75 mg, bromelain 50 mg, amylase 10 mg, lipase 10 mg, lysosome 10 mg, and chymotrypsin 2 mg, four times in one day before downhill running, improves recovery of contractile muscle function and decreases muscle soreness when compared with placebo (67838). It is unclear if these findings are due to papain, other ingredients, or the combination.
• Herpes zoster (shingles). Although there has been interest in using oral papain for shingles, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Insect bite. It is unclear if topical papain is beneficial in individuals with fire ant stings. Details: A small clinical study in individuals with fire ant stings shows that applying gauze soaked with a specific papain-containing meat tenderizer (Adolph's meat tenderizer) to the sting for 20 minutes does not reduce pain or itching when compared with placebo (67845).
• Intestinal parasite infection. Although there has been interest in using oral papain for intestinal parasite infections, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Jellyfish stings. It is unclear if topical papain is beneficial in individuals with jellyfish stings. Details: A small clinical study in individuals with jellyfish stings shows that submerging affected skin into a solution with a papain-containing meat tenderizer (Adolph's meat tenderizer), starting two minutes after a jellyfish sting and continuing for at least 20 minutes, is less effective than hot water alone in decreasing pain caused by the jellyfish sting (67835).
• Pressure ulcers. Although there has been interest in using topical papain for pressure ulcers, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Radiation dermatitis. Oral papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients receiving pelvic radiotherapy shows that taking three capsules of a specific combination product (Wobe-Mugos E, Mucos Pharma) containing papain 100 mg, trypsin 40 mg, and chymotrypsin 40 mg per capsule, four times daily, beginning 3 days prior to radiotherapy and continuing until the last day of therapy, does not attenuate skin deterioration when compared with placebo (67834). However, another small, open-label clinical study in patients with uterine carcinoma shows that taking three capsules of the same combination product four times daily, beginning 7 days before radiotherapy and continuing for 9 weeks, reduces skin reactions when compared with control (67831). It is unclear if these findings are due to papain, other ingredients, or the combination.
• Radiation-induced cystitis. Oral papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with uterine carcinoma receiving radiotherapy shows that taking three capsules of a specific combination product (Wobe-Mugos E, Mucos Pharma) containing papain 100 mg, trypsin 40 mg, and chymotrypsin 40 mg per capsule, four times daily, beginning 7 days before radiotherapy and continuing for 9 weeks, reduces genitourinary symptoms when compared with control (67831).
• Radiation-induced nausea and vomiting. Oral papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients receiving pelvic radiotherapy shows that taking three capsules of a specific combination product (Wobe-Mugos E, Mucos Pharma), containing papain 100 mg, trypsin 40 mg, and chymotrypsin 40 mg per capsule, four times daily, beginning 3 days prior to radiotherapy and continuing until the last day of therapy, does not reduce radiation-related nausea or vomiting when compared with placebo (67834).
• Tonsillopharyngitis. Oral papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Two small clinical studies in patients with pharyngitis and/or tonsillitis shows that use of throat lozenges containing papain 2 mg, lysozyme 5 mg, and bacitracin 200 IU daily for 4 days reduces pain and inflammation of the throat and lymph nodes when compared with placebo or disinfectant alone (964,968). It is unclear if these findings are due to papain, other ingredients, or the combination.
• Traumatic oral ulcers. Although there has been interest in using topical papain for traumatic oral ulcers, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Venous leg ulcers. Although there has been interest in using topical papain for venous leg ulcers, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Wound healing. Topical papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with purulent wounds shows that applying papain 1% solution plus dimethylsulfoxide (DMSO) followed by phonophoresis, a process by which ultrasound is used to increase topical drug delivery, improves wound healing when compared to baseline (67843). The validity of this finding is limited by the lack of a comparator group. Also, it is unclear if these findings are due to papain, DMSO, or the combination. More evidence is needed to rate papain for these uses.

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Proteolytic enzymes represent a wide group of enzymes that are used alone or in combination. See specific monographs for effectiveness information.

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There is insufficient reliable information available about the safety of lipase.

CHILDREN: POSSIBLY UNSAFE
when recombinant human bile salt-stimulated lipase (rhBSSL) is used orally by premature infants. Adding rhBSSL to infant formula or pasteurized breast milk increases the risk for serious gastrointestinal adverse effects in premature infants (101940).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

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LIKELY SAFE ...when prescription pancreatic enzyme products are used orally and appropriately under the guidance of a healthcare professional (98667,98674,98676,98677,99115,99116,99118,99120,99122,99124)(99125,99126,99127). Prescription pancreatic enzyme products are typically initiated at a dose of 500-1000 lipase units/kg body weight per meal to a maximum of 2500 lipase units/kg body weight per meal or 4000 lipase units/gram of fat daily. Doses higher than 2500 lipase units/kg body weight per meal are prescribed only if medically necessary (99130).

POSSIBLY UNSAFE ...when prescription pancreatic enzyme products are used orally at doses over 2500 lipase units/kg body weight per meal or 10,000 lipase units/kg body weight daily. Higher doses, especially those greater than 6000 lipase units/kg body weight per meal, have been associated with fibrosing colonopathy (99130). There is insufficient reliable information available about the safety of supplemental forms of pancreatic enzyme products.

CHILDREN: LIKELY SAFE
when prescription pancreatic enzyme products are used orally and appropriately under the guidance of a healthcare professional (99118,99119,99120,99121,99122,99124,99125,99126). Prescription pancreatic enzyme products are usually initiated at a dose of 500-1000 lipase units/kg body weight per meal to a maximum of 2500 lipase units/kg body weight per meal or 4000 lipase units/gram fat daily. Doses higher than 2500 lipase units/kg body weight per meal are prescribed only if medically necessary (99130).

CHILDREN: POSSIBLY UNSAFE
when prescription pancreatic enzyme products are used orally at doses over 2500 lipase units/kg body weight per meal or 10,000 lipase units/kg body weight daily. Higher doses, especially those greater than 6000 lipase units/kg body weight per meal, have been associated with fibrosing colonopathy (99130). There is insufficient reliable information available about the safety of supplemental forms of pancreatic enzyme products.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using unless essential for replacement therapy (15).

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LIKELY SAFE ...when used orally in amounts commonly found in foods. Papain has Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when used orally and appropriately for medicinal purposes, short-term. Papain has been used in combination with other proteolytic enzymes at a dose of up to 1200 mg daily for up to 9 weeks (964,965,968,67831,67834). ...when used topically as a diluted solution in appropriate doses for up to 20 minutes (67835,67843,67845).

POSSIBLY UNSAFE ...when used orally in large amounts. In excessive doses, papain can cause significant side effects including esophageal perforation (6). ...when raw papain is used topically. Raw papain or papaya latex is a severe irritant and vesicant (6).

PREGNANCY: POSSIBLY UNSAFE
when used orally. There is some concern that crude papain is teratogenic and embryotoxic (6).

LACTATION:
Insufficient reliable information available; avoid using.

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POSSIBLY SAFE ...when used orally and appropriately. Various proteolytic enzymes have been safely used orally in clinical research (716,964,965,968,969,6252,6253,10622,11457,18281,18284) (91104,91105,91106,91111,96449). Side effects are typically mild to moderate and most often include gastrointestinal effects. See specific monographs for more detailed information related to the safety of individual proteolytic enzymes. ...when used topically and appropriately. Various proteolytic enzymes have been safely used topically in clinical research (67835,67843,67845,91113). Some proteolytic enzymes might cause allergic reactions when used topically. See specific monographs for more detailed information related to the safety of individual proteolytic enzymes.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

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ACARBOSE (Precose, Prandase) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, pancreatic enzyme products may reduce the effects of acarbose.  Details The digestive enzymes present in pancreatic enzyme products may break down acarbose, reducing its effects (9).

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WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, papain might increase the effects and side effects of warfarin.  Details In one case report, a patient previously stable on warfarin was found to have an international normalization ratio (INR) of 7.4, which was attributed to ingestion of a supplement containing papain from papaya extract (613).

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...Orally, taking large amounts of lipase in combination with other pancreatic enzymes can cause diarrhea, abdominal pain, flatulence, and nausea. To improve fat absorption and reduce steatorrhea, patients often must take many capsules of pancreatic enzymes per day, which may reduce adherence (12722,12723).

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...Orally, excessive doses of pancreatin can cause nausea, vomiting, diarrhea, or other transient intestinal upset, and perianal soreness. Extremely high doses have been associated with high uric acid level in blood and urine, and colon strictures (15).
Topically, pancreatin preparations that are held in the mouth prior to swallowing can cause irritation of the mucosa, including ulceration and stomatitis (15). Pancreatin powder is irritating to the skin, eyes, mucus membranes, and respiratory tract. Hypersensitivity reactions, e.g., sneezing, lacrimation, and skin rash, have been reported (15). Inhalation of dust containing pancreatin has been associated with pulmonary hypersensitivity reactions, allergic rhinitis, bronchospasm, and asthma (11768,11769).

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...Orally, large amounts of papain can cause esophageal perforation (6). Ingestion of papaya latex (raw papain) can cause severe gastritis.
Topically, papaya latex can cause severe irritation and blisters (6). Topical use of papain can cause itching (966).
Severe allergic reactions have been reported in sensitive individuals (6,967). One case report suggests that there may be cross-sensitivity between papain, fig, and kiwi (963).

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