NURSING CONSIDERATIONS IN MIDGUT NET

NURSING CONSIDERATIONS IN MIDGUT NET FOLLOW-UP VISIT OF A PATIENT WITH A FUNCTIONAL MIDGUT NET Not an actual patient or healthcare provider. Copyright Burlingham/Shutterstock.com. The case study presented in this brochure is based on a fictional patient. Individual results may vary. Indication for Sandostatin LAR Sandostatin LAR (octreotide) is indicated for the treatment of patients with symptoms associated with functional gastro-entero-pancreatic endocrine tumors (eg, carcinoid tumors with features of the carcinoid syndrome) and for the treatment of patients with advanced neuroendocrine tumors of the midgut or of unknown primary origin where non-midgut sites of origin have been excluded. 1

Consider the following patient* MEET MARIA 63 -Y E A R- OL D WOMA N L IVING W ITH C ARC I N O ID S YN DROME Not an actual patient. Copyright pixelheadphoto digitalskillet/ Shutterstock.com. Diagnosis: Functional, localized midgut NET of the small intestine Surgical History1: Surgical resection 15 months ago Ongoing Monitoring1-3 : Abdominal imaging (CT or MRI) Biochemical monitoring of CgA and 5-HIAA Echocardiogram as clinically indicated Current Symptoms2,4: Diarrhea (~8x daily) Current Treatment4 : Sandostatin LAR (octreotide) 20 mg every 4 weeks SANDOSTATIN LAR IS OFTEN PRESCRIBED FOR PATIENTS TO HELP Impor tant Note s: Maria has b e Sandostatin en on for 3 month LAR therapy s. flushing sym While her p controlled, s toms are h diarrhea up e still has t has been fee o 8x daily and li Maria did n ng weak. o about the ex t tell her doctor c during her la essive diarrhea she was em st visit because barrassed. 5-HIAA, 5-hydroxyindoleacetic acid; CgA, chromogranin A; CT, computed tomography; MRI, magnetic resonance imaging; NET, neuroendocrine tumor. CONTROL SYMPTOMS ASSOCIATED WITH CARCINOID SYNDROME.4 IN CASES LIKE MARIA S WHERE SYMPTOMS ARE STILL SIGNIFICANT WITH TREATMENT, A DOSE INCREASE TO 30 MG EVERY 4 WEEKS MAY BE CONSIDERED.4 2 * The information on this page is a representative patient snapshot, not a complete patient profile. Please see recommended monitoring during Sandostatin LAR treatment on page 5. Please see important dosing information on page 5.

TALKING TO THE PATIENT It is important for Maria to understand that she must be open and honest with all members of her healthcare team. The amount of diarrhea she is experiencing is taking a toll on her body and leaving her feeling weak.5 Let Maria know that by informing the doctor, he may recommend increasing her dose of Sandostatin LAR to 30 mg every 4 weeks to help control her diarrhea.4 Maria can also benefit from further education regarding nutritional decisions to help with symptom control and ensure she is eating the right foods to maintain adequate nutritional status. N UTR I T I O NA L INTERV ENTIONS FO R C ARC I N O ID S YN DROME * For a patient like Maria, who is having excessive diarrhea, nutritional status should be a primary concern. Dietary recommendations can be made to help maintain body weight and ensure adequate protein. Patients should be encouraged to speak to a nutritionist about dietary needs. Fat Intake: 25%-30% of total calories6 1-1.5 g of protein per kilo ideal body weight6 5-10 servings of carbohydrates6 DAILY NUTRITIONAL NEEDS* Water Intake: 2 quarts daily (electrolyte beverage replacements if needed)6 3 * These are general guidelines. Patients with carcinoid syndrome may have multiple medical issues, and nutritional needs should be assessed on a case-by-case basis. Vitamins and Minerals: if indicated7

DIARRHEA MANAGEMENT Maria withheld important information from the doctor about the frequency of her diarrhea because she was embarrassed. Nurses should share information with the physician that was miscommunicated or withheld by the patient. In Maria s case, a dose increase of Sandostatin LAR to 30 mg every 4 weeks may help with the frequency of diarrhea that Maria is experiencing. 4 Education on dietary adjustments should be made as well. DIETARY ADJUSTMENTS CAN HELP CONTROL DIARRHEA WHAT TO AVOID 6 * WHAT CAN HELP 8,9 Foods/drinks high in amines Aged cheeses (cheddar, Camembert, Stilton) Alcoholic beverages Smoked, salted, or pickled fish and meat (herring, salami, sausage, corned beef) Yeast extracts and Brewer s yeast Broad beans, sauerkraut, shrimp paste, some soybean products, miso soup, soy sauce, tofu Chocolate (in large amounts) Peanuts, coconuts, brazil nuts Some types of pizza Raspberries, bananas, avocados Caffeinated beverages (coffee, soda) Large meals Fatty or spicy foods High-fiber foods Raw fruits and vegetables Starchy, easily digestible carbohydrates Potatoes with skin removed White carbohydrates (ie, white bread, pasta, rice) Cornflour, tapioca, croissants Low-fiber foods Cooked fruits and vegetables Remove skin, seeds, and stalks from vegetables Healthy, low-fat sources of protein Smaller, more frequent meals Room temperature beverages PATIENTS SHOULD BE ADVISED TO TALK WITH THEIR DOCTOR BEFORE MAKING ANY SIGNIFICANT CHANGES TO THEIR DIET. * The foods listed here may trigger a reaction and therefore it may be beneficial to avoid or eat sparingly. 4

TREATMENT WITH SANDOSTATIN LAR HOW IT WORKS Sandostatin LAR is a somatostatin analogue. Somatostatin is the hormone in the brain that inhibits secretion of peptides and serotonin produced within the gastroenteropancreatic endocrine system. Somatostatin also inhibits increased secretion of growth hormone. 4 Administration of Sandostatin LAR in patients with carcinoid syndrome may result in improvement of symptoms, particularly of flushing and diarrhea. In many cases, this is accompanied by a fall in plasma serotonin and reduced urinary excretion of 5-HIAA. Administration of Sandostatin LAR also works at the tumor site to inhibit growth in advanced NET of midgut or unknown primary tumor location. 4 IMPORTANT DOSING INFORMATION It is recommended to start treatment with the administration of 20-mg Sandostatin LAR at 4-week intervals. Patients on treatment with subcutaneous Sandostatin (octreotide acetate) should continue at the previously effective dosage for 2 weeks after the first injection of Sandostatin LAR. 4 For patients in whom symptoms and biological markers are well controlled after 3 months of treatment, the dose may be reduced to 10-mg Sandostatin LAR every 4 weeks. 4 For patients in whom symptoms are only partially controlled after 3 months of treatment, the dose may be increased to 30-mg Sandostatin LAR every 4 weeks. 4 The recommended dose of Sandostatin LAR for patients with advanced NET of the midgut or unknown primary tumor location is 30 mg every 4 weeks. Treatment with Sandostatin LAR for tumor control should be continued in the absence of tumor progression. 4 RECOMMENDED MONITORING DURING SANDOSTATIN LAR THERAPY Thyroid function, hepatic function, glucose tolerance, and antidiabetic treatment should be monitored during treatment with Sandostatin LAR. 4 Ultrasonic examination of the gallbladder should occur prior to therapy initiation and at 6-month intervals to check for gallstones. 4 Patients with a history of vitamin B 12 deprivation should have B 12 levels monitored during therapy. 4 LEARN MORE ABOUT SANDOSTATIN LAR AT WWW.SANDOSTATIN.COM. 5

NURSING CONSIDERATIONS If patients are still experiencing diarrhea, the following should be reviewed with them during their Sandostatin LAR follow-up visit: Current symptoms 4 - Frequency and severity Reasons for Sandostatin LAR dose changes, if any 4 Treatment schedule 4 - Sandostatin LAR injection by a healthcare professional every 4 weeks Goals of treatment 4 - Nutritional interventions 6 Current medication list Additional Issues to Address With Patients Chronic diarrhea can put patients at risk for other problems. Assess for: Electrolyte imbalances 10 Altered nutritional status 10 Dehydration 11 Impaired skin integrity 8,12 Focus on impaired skin integrity Frequent loose stools can cause skin breakdown around the anus, and patients with poor nutritional status are at an increased risk of having impaired skin integrity. 8,12 Patients may be embarrassed to talk about this topic, so it is important for the nurse to address this information. To help ease discomfort and avoid skin breakdown, offer patients the following advice 8 : Use unscented wet wipes instead of toilet paper Take a warm bath daily Wear loose-fitting, cotton underwear. Nylon can further irritate the area Consider using a barrier cream or ointment to help soothe the area and prevent further irritation 6

PATIENT SUPPORT GROUPS Encourage your patients to find a support group with other patients with NET, either online or in their area, if they haven t done so already. A support group is a place where they can share their feelings and concerns, hear others stories, and even help those who are just beginning their own journey. It may be harder for patients to find live support groups specific to NET. Support groups dedicated to cancer in general should also be considered for the patient and their loved ones. Not an actual patient or healthcare provider. Copyright Rawpixel.com/Shutterstock.com. 7

SANDOSTATIN LAR IMPORTANT SAFETY INFORMATION Contraindications Known hypersensitivity to octreotide or to any of the excipients (see list of excipients). Special warnings and precautions for use General As GH-secreting pituitary tumors may sometimes expand, causing serious complications (e.g., visual field defects), it is essential that all patients be carefully monitored. If evidence of tumor expansion appears, alternative procedures may be advisable. Thyroid function should be monitored in patients receiving prolonged treatment with octreotide. Hepatic function should be monitored during octreotide therapy. Cardiovascular related events Common cases of bradycardia have been reported. Dose adjustment of medicinal products such as beta blockers, calcium channel blockers, or agents to control fluid and electrolyte balance, may be necessary (see section Interaction with other medicinal products and other forms of interaction). Gallbladder and related events Octreotide inhibits secretion of cholecystokinin, resulting in reduced contractility of the gallbladder and an increased risk of sludge and stone formation. Development of gallstones has been reported in 15 to 30% of long-term recipients of s.c. Sandostatin. The prevalence in the general population (aged 40 to 60 years) is about 5 to 20%. Long-term exposure to Sandostatin LAR of patients with acromegaly or gastro-entero-pancreatic tumors suggests that treatment with Sandostatin LAR does not increase the incidence of gallstone formation, compared with s.c. treatment. Ultrasonic examination of the gallbladder before and at about 6-monthly intervals during Sandostatin LAR therapy is however recommended. If gallstones do occur, they are usually asymptomatic; symptomatic stones should be treated either by dissolution therapy with bile acids or by surgery. Glucose metabolism Because of its inhibitory action on growth hormone, glucagon, and insulin release, Sandostatin LAR may affect glucose regulation. Post-prandial glucose tolerance may be impaired. As reported for patients treated with s.c. Sandostatin, in some instances, the state of persistent hyperglycemia may be induced as a result of chronic administration. Hypoglycemia has also been reported. In patients with concomitant Type I diabetes mellitus, Sandostatin LAR is likely to affect glucose regulation, and insulin requirements may be reduced. In non-diabetics and type II diabetics with partially intact insulin reserves, Sandostatin s.c. administration may result in increases in post-prandial glycaemia. It is therefore recommended to monitor glucose tolerance and antidiabetic treatment. In patients with insulinomas, octreotide, because of its greater relative potency in inhibiting the secretion of GH and glucagon than that of insulin, and because of the shorter duration of its inhibitory action on insulin, may increase the depth and prolong the duration of hypoglycemia. These patients should be closely monitored. 8

SANDOSTATIN LAR IMPORTANT SAFETY INFORMATION (cont) Nutrition Octreotide may alter absorption of dietary fats in some patients. Depressed vitamin B 12 levels and abnormal Schilling s tests have been observed in some patients receiving octreotide therapy. Monitoring of vitamin B 12 levels is recommended during therapy with Sandostatin LAR in patients who have a history of vitamin B 12 deprivation. Sodium content Sandostatin LAR contains less than 1 mmol (23 mg) sodium per dose, i.e., is essentially sodium-free. Interaction with other medicinal products and other forms of interaction Dose adjustment of medicinal products such as beta blockers, calcium channel blockers, or agents to control fluid and electrolyte balance may be necessary when Sandostatin LAR is administered concomitantly (see Special warnings and precautions for use). Dose adjustments of insulin and antidiabetic medicinal products may be required when Sandostatin LAR is administered concomitantly (see Special warnings and precautions for use). Octreotide has been found to reduce the intestinal absorption of ciclosporin and to delay that of cimetidine. Concomitant administration of octreotide and bromocriptine increases the bioavailability of bromocriptine. Limited published data indicate that somatostatin analogs might decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that octreotide may have this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g. quinidine, terfenadine) should therefore be used with caution. Pregnancy, breastfeeding and fertility Pregnancy There is a limited amount of data (less than 300 pregnancy outcomes) from the use of octreotide in pregnant women, and in approximately one third of the cases the pregnancy outcomes are unknown. The majority of reports were received after postmarketing use of octreotide and more than 50% of exposed pregnancies were reported in patients with acromegaly. Most women were exposed to octreotide during the first trimester of pregnancy at doses ranging from 100-1200 micrograms/day of Sandostatin s.c. or 10-40 mg/month of Sandostatin LAR. Congenital anomalies were reported in about 4% of pregnancy cases for which the outcome is known. No causal relationship to octreotide is suspected for these cases. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see Preclinical safety data). As a precautionary measure, it is preferable to avoid the use of Sandostatin LAR during pregnancy (see Special warnings and precautions for use). 9

SANDOSTATIN LAR IMPORTANT SAFETY INFORMATION (cont) Breastfeeding It is unknown whether octreotide is excreted in human breast milk. Animal studies have shown excretion of octreotide in breast milk. Patients should not breastfeed during Sandostatin LAR treatment. Fertility It is not known whether octreotide has an effect on human fertility. Late descent of the testes was found for male offsprings of dams treated during pregnancy and lactation. Octreotide, however, did not impair fertility in male and female rats at doses of up to 1 mg/kg body weight per day (see Preclinical safety data). Effects on ability to drive and use machines Sandostatin LAR has no or negligible influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or using machines if they experience dizziness, asthenia/ fatigue, or headache during treatment with Sandostatin LAR. Undesirable effects and adverse drug reactions Summary of the safety profile The most frequent adverse reactions reported during octreotide therapy include gastrointestinal disorders, nervous system disorders, hepatobiliary disorders, and metabolism and nutritional disorders. The most commonly reported adverse reactions in clinical trials with octreotide administration were diarrhea, abdominal pain, nausea, flatulence, headache, cholelithiasis, hyperglycemia and constipation. Other commonly reported adverse reactions were dizziness, localized pain, biliary sludge, thyroid dysfunction (e.g., decreased thyroid stimulating hormone [TSH], decreased total T4, and decreased free T4), loose stools, impaired glucose tolerance, vomiting, asthenia, and hypoglycemia. Tabulated list of adverse reactions The following adverse drug reactions, listed in Table 1, have been accumulated from clinical studies with octreotide: Adverse drug reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: very common ( 1/10); common ( 1/100, <1/10); uncommon ( 1/1,000, <1/100); rare ( 1/10,000, <1/1,000); very rare (<1/10,000), including isolated reports. Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness. 10

SANDOSTATIN LAR IMPORTANT SAFETY INFORMATION (cont) Table 1 Adverse drug reactions reported in clinical studies Gastrointestinal disorders Very common: Nervous system disorders Very common: Endocrine disorders Hepatobiliary disorders Very common: Diarrhea, abdominal pain, nausea, constipation, flatulence. Dyspepsia, vomiting, abdominal bloating, steatorrhea, loose stools, discoloration of feces. Headache. Dizziness. Hypothyroidism, thyroid dysfunction (e.g., decreased TSH, decreased total T4, and decreased free T4). Cholelithiasis. Metabolism and nutrition disorders Very common: Uncommon: Cholecystitis, biliary sludge, hyperbilirubinemia. Hyperglycemia. Hypoglycemia, impaired glucose tolerance, anorexia. Dehydration. General disorders and administration site conditions Very common: Investigations Injection site reactions. Asthenia. Skin and subcutaneous tissue disorders Respiratory disorders Cardiac disorders Uncommon: Elevated transaminase levels. Pruritus, rash, alopecia. Dyspnea. Bradycardia. Tachycardia. 11

SANDOSTATIN LAR IMPORTANT SAFETY INFORMATION (cont) Table 2 Adverse drug reactions derived from spontaneous reports Post-marketing Spontaneously reported adverse reactions, presented in Table 2, are reported voluntarily and it is not always possible to reliably establish frequency or a causal relationship to drug exposure. Immune system disorders Skin and subcutaneous tissue disorders Hepatobiliary disorders Cardiac disorders Investigations Anaphylaxis, allergy/hypersensitivity reactions. Urticaria. Acute pancreatitis, acute hepatitis without cholestasis, cholestatic hepatitis, cholestasis, jaundice, cholestatic jaundice. Arrhythmias. Increased alkaline phosphatase levels, increased gamma glutamyl transferase levels. Description of selected adverse reactions Gastrointestinal disorders In rare instances, gastrointestinal side effects may resemble acute intestinal obstruction, with progressive abdominal distension, severe epigastric pain, abdominal tenderness and guarding. The frequency of gastrointestinal adverse events is known to decrease over time with continued treatment. Injection site reactions Injection site related reactions including pain, burning, redness, hematoma, hemorrhage, pruritus or swelling were commonly reported in patients receiving Sandostatin LAR ; however, these events did not require any clinical intervention in the majority of the cases. Metabolism and nutrition disorders Although measured fecal fat excretion may increase, there is no evidence to date that long-term treatment with octreotide has led to nutritional deficiency due to malabsorption. Pancreatic enzymes In very rare instances, acute pancreatitis has been reported within the first hours or days of Sandostatin s.c. treatment and resolved on withdrawal of the drug. In addition, cholelithiasis induced pancreatitis has been reported for patients on long term Sandostatin s.c. treatment. 12

SANDOSTATIN LAR IMPORTANT SAFETY INFORMATION (cont) Cardiac disorders In both acromegalic and carcinoid syndrome patients, ECG changes were observed such as QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, early R wave progression, and nonspecific ST-T wave changes. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac diseases (see Special warnings and precautions). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. Overdose A limited number of accidental overdoses of Sandostatin LAR have been reported. The doses ranged from 100 mg to 163 mg/month of Sandostatin LAR. The only adverse event reported was hot flushes. Cancer patients receiving doses of Sandostatin LAR up to 60 mg/month and up to 90 mg/2 weeks have been reported. These doses were in general well tolerated; however, the following adverse events have been reported: frequent urination, fatigue, depression, anxiety, and lack of concentration. The management of overdosage is symptomatic. List of excipients Vial Poly (DL-lactide-co-glycolide) 78.35% of nominal ll weight; sterile mannitol 17.0% of nominal fill weight. Prefilled syringe Kit without vial adapter/safety needle One prefilled syringe (solvent for parenteral use), containing: sodium carboxymethylcellulose 12.5 mg, mannitol 15 mg; water for injection qs ad 2.5 ml. Kit with vial adapter/safety needle One prefilled syringe (solvent for parenteral use), containing: sodium carboxymethylcellulose (14 mg), mannitol (12 mg), poloxamer 188 (4 mg); water for injection qs ad 2 ml. Pharmaceutical formulations may vary between countries. Please see the Summary of Product Characteristics. 13

References: 1. Kunz PL, Reidy-Lagunes D, Anthony LB, et al. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas. 2013;42(4):557-577. 2. Vinik AI, Woltering EA, O Dorisio TM, Go VLW, Mamikunian G. Diagnosing and treating gastroenteropancreatic tumors, including ICD-9 codes. In: Neuroendocrine Tumors: A Comprehensive Guide to Diagnosis and Management. 5th ed. Inglewood, CA: Inter Science Institute; 2012:1-56. 3. Grozinsky-Glasberg S, Grossman AB, Gross DJ. Carcinoid heart disease: from pathophysiology to treatment Something in the way it moves. Neuroendocrinology. 2015;101(4):263-273. 4. Sandostatin LAR [Summary of Product Characteristics]. Novartis; 2016. 5. U.S. National Library of Medicine. MedlinePlus. Diarrhea. https://www.medlineplus.gov/ency/article/003126.htm. Accessed January 30, 2017. 6. Warner ME. The Carcinoid Cancer Foundation. Nutritional concerns for the carcinoid patient: developing nutritional guidelines for persons with carcinoid disease. http://www.carcinoid.org/for-patients/general -information/nutrition/nutritional-concerns-for-the-carcinoid-patient-developing-nutrition-guidelines-for -persons-with-carcinoid-disease/. Accessed January 30, 2017. 7. The Carcinoid Cancer Foundation. Nutrition and diet for carcinoid patients: an interview with Jeffrey I. Mechanick, M.D. http://www.carcinoid.org/for-patients /general-information/nutrition/nutrition-and-diet-for-carcinoid-patients-an-interview-with-jeffrey-i-mechanick -m-d/. Accessed January 30, 2017. 8. Cancer Research UK. Tips on coping with diarrhea. http://www.cancerresearchuk.org/about-cancer/coping-with-cancer/coping-physically/bowel/types/diarrhoea/managing /tips-on-how-to-cope-with-diarrhoea. Accessed January 30, 2017. 9. Whyand T, Davies P, Caplin M. Food and Neuroendocrine Tumours (NETs). ENETS Centre of Excellence; 2014. 10. Greenberger NJ. Merck Manual. Diarrhea. http://www.merckmanuals.com/professional/ gastrointestinal-disorders/symptoms-of-gi-disorders/diarrhea. Accessed January 30, 2017. 11. Anthony L, Freda PU. From somatostatin to octreotide LAR: evolution of a somatostatin analogue. Curr Med Res Opin. 2009;25(12):2989-2999. 12. Litchford MD, Dorner B, Posthauer ME. Malnutrition as a precursor of pressure ulcers. Adv Wound Care. 2014;3(1):54-63. 14 Novartis Pharma AG CH-4002 Basel Switzerland Novartis 2017 3/17 G-SAS-1157175