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warnings and cautions
5 WARNINGS AND PRECAUTIONS Fibrosing colonopathy is associated with high-dose use of pancreatic enzyme replacement. Exercise caution when doses of ULTRESA exceed 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day). ( 5.1 ) To avoid irritation of oral mucosa, do not chew ULTRESA or retain in mouth. ( 5.2 ) Exercise caution when prescribing ULTRESA to patients with gout, renal impairment, or hyperuricemia. ( 5.3 ) There is theoretical risk of viral transmission with all pancreatic enzyme products including ULTRESA. ( 5.4 ) Exercise caution when administering pancrelipase to a patient with a known allergy to proteins of porcine origin. ( 5.5 ) 5.1 Fibrosing Colonopathy Fibrosing colonopathy has been reported following treatment with different pancreatic enzyme products. 4, 5 Fibrosing colonopathy is a rare, serious adverse reaction initially described in association with high-dose pancreatic enzyme use, usually with use over a prolonged period of time and most commonly reported in pediatric patients with cystic fibrosis. The underlying mechanism of fibrosing colonopathy remains unknown. Doses of pancreatic enzyme products exceeding 6,000 lipase units/kg of body weight per meal have been associated with colonic stricture in children less than 12 years of age. 1 Patients with fibrosing colonopathy should be closely monitored because some patients may be at risk of progressing to stricture formation. It is uncertain whether regression of fibrosing colonopathy occurs. It is generally recommended, unless clinically indicated, that enzyme doses should be less than 2,500 lipase units/kg of body weight per meal (or less than 10,000 lipase units/kg of body weight per day) or less than 4,000 lipase units/g fat ingested per day [see Dosage and Administration ( 2.2 ) ]. Doses greater than 2,500 lipase units/kg of body weight per meal (or greater than 10,000 lipase units/kg of body weight per day) should be used with caution and only if they are documented to be effective by 3-day fecal fat measures that indicate a significantly improved coefficient of fat absorption. Patients receiving higher doses than 6,000 lipase units/kg of body weight per meal should be examined and the dosage either immediately decreased or titrated downward to a lower range. 5.2 Potential for Irritation to Oral Mucosa Care should be taken to ensure that no drug is retained in the mouth. ULTRESA should not be crushed or chewed or mixed in foods having a pH greater than 4.5. These actions can disrupt the protective enteric coating resulting in early release of enzymes, irritation of oral mucosa, and/or loss of enzyme activity [see Dosage and Administration ( 2.1 ) and Patient Counseling Information ( 17.1 ) ] For patients who are unable to swallow intact capsules, the contents may be sprinkled on soft acidic food with pH 4.5 or less such as applesauce or yogurt. The ULTRESA-soft food mixture should be swallowed immediately and followed with water or juice to ensure complete ingestion. 5.3 Potential for Risk of Hyperuricemia Caution should be exercised when prescribing ULTRESA to patients with gout, renal impairment, or hyperuricemia. Porcine-derived pancreatic enzyme products contain purines that may increase blood uric acid levels. 5.4 Potential for Viral Exposure from the Product Source ULTRESA is sourced from pancreatic tissue from swine used for food consumption. Although the risk that ULTRESA will transmit an infectious agent to humans has been reduced by testing for certain viruses during manufacturing and by inactivating certain viruses during manufacturing, there is a theoretical risk for transmission of viral disease, including diseases caused by novel or unidentified viruses. Thus, the presence of porcine viruses that might infect humans cannot be definitely excluded. However, no cases of transmission of an infectious illness associated with the use of porcine pancreatic extracts have been reported. 5.5 Allergic Reactions Caution should be exercised when administering pancrelipase to a patient with a known allergy to proteins of porcine origin. Rarely, severe allergic reactions including anaphylaxis, asthma, hives, and pruritus, have been reported with other pancreatic enzyme products with different formulations of the same active ingredient (pancrelipase). The risks and benefits of continued ULTRESA treatment in patients with severe allergy should be taken into consideration with the overall clinical needs of the patient.
6 ADVERSE REACTIONS The most serious adverse reactions reported with different pancreatic enzyme products of the same active ingredient (pancrelipase) that are described elsewhere in the label include fibrosing colonopathy, hyperuricemia and allergic reactions [see Warnings and Precautions ( 5.1 , 5.3 and 5.5 ) ]. The most common adverse reactions (≥7% of patients treated with ULTRESA) are headache, pharyngolaryngeal pain, and epistaxis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact APTALIS Pharma US, Inc. / Forest Laboratories, LLC at 1-800-472-2634 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The short-term safety of ULTRESA was assessed in two clinical trials conducted in 40 patients with exocrine pancreatic insufficiency (EPI) due to cystic fibrosis (CF). Study 1 was conducted in 31 patients, ages 8 years to 37 years; Study 2 was conducted in 9 patients, ages 7 years to 11 years. Study 1 was a randomized, double-blind, placebo-controlled, crossover study of 31 patients, ages 8 to 37 years, with EPI due to CF. In this study, patients were randomized to receive ULTRESA at doses not to exceed 2,500 lipase units per kilogram per meal or matching placebo for 6 to 7 days of treatment, followed by crossover to the alternate treatment for an additional 6 to 7 days. The mean daily dose of ULTRESA was 6,270 lipase units per kilogram body weight per day. The mean exposure to ULTRESA during this study was 5.4 days. The most common adverse reactions (≥7%) were headache, pharyngolaryngeal pain, and epistaxis. Table 1 enumerates adverse reactions that occurred in at least 2 patients (greater than or equal to 7%) treated with ULTRESA at a higher rate than with placebo in Study 1. TABLE 1 Adverse Reactions Occurring in at Least 2 Patients (≥ 7%) in Cystic Fibrosis (Study 1) Adverse Reaction ULTRESA n=30 n (%) Placebo n=31 n (%) Headache 2 (7%) 1 (3%) Pharyngolaryngeal Pain 2 (7%) 1 (3%) Epistaxis 2 (7%) 0 Study 2 was an open-label study of 9 patients, ages 7 years to 11 years, with EPI due to CF. After a screening period of up to 15 days on individually-titrated doses of ULTRESA not to exceed 2,500 lipase units per kilogram per meal, patients entered a washout phase (no treatment) of up to 7 days before returning to a treatment phase of up to 12 days on the same individually-titrated dose of ULTRESA. Two patients discontinued during the washout phase leaving 7 patients in the treatment phase. The mean daily dose of ULTRESA was 6,361 lipase units per kilogram body weight per day during the last 4 days of the screening phase, and was 6,846 lipase units per kilogram body weight per day during the treatment phase. The mean duration of the treatment phase was 5.7 days. Adverse reactions that occurred during treatment with ULTRESA were nasal congestion (14%), neck pain (14%), beta-hemolytic streptococcal infection (11%), ear pain (11%), and lymphadenopathy (11%). 6.2 Postmarketing Experience Postmarketing data for ULTRESA has been available since 2003. The safety data is similar to that described below. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Pancreatic enzyme products (delayed and immediate-release) with different formulations of the same active ingredient (pancrelipase) have been used for the treatment of patients with exocrine pancreatic insufficiency due to cystic fibrosis and other conditions, such as chronic pancreatitis. The long-term safety profile of these products has been described in the medical literature. The most serious adverse events included fibrosing colonopathy, distal intestinal obstruction syndrome (DIOS), recurrence of pre-existing carcinoma, and severe allergic reactions including anaphylaxis, asthma, hives, and pruritus. The most commonly reported adverse events were gastrointestinal disorders, including abdominal pain, diarrhea, flatulence, constipation and nausea, and skin disorders including pruritus, urticaria and rash.