REVESTIVE 5 mg Powder and solvent for solution for injection Ref.[9240] Active ingredients: Teduglutide

It is strongly recommended that every time Revestive is administered to a patient, the name and lot number of the product are recorded in order to maintain a link between the patient and the lot of the product.

Adults

Colo-rectal polyps

A colonoscopy with removal of polyps should be performed at the time of starting treatment with Revestive. Once yearly follow-up colonoscopies (or alternate imaging) are recommended during the first 2 years of Revestive treatment. Subsequent colonoscopies are recommended at a minimum of five year intervals. An individual assessment whether increased frequency of surveillance is necessary should be performed based on the patient characteristics (e.g., age, underlying disease). See also section 5.1. If a polyp is found, adherence to current polyp follow-up guidelines is recommended. In case of malignancy, Revestive therapy must be discontinued (see section 4.3).

Gastrointestinal neoplasia including hepatobiliary tract

In the rat carcinogenicity study, benign tumours were found in the small bowel and the extrahepatic bile ducts. Development of small intestinal polyps has also been observed in human SBS patients within several months after start of teduglutide treatment. Because of this, upper gastro-intestinal endoscopy or other imaging is recommended before and during the treatment with teduglutide. If a neoplasia is detected, it should be removed. In case of malignancy, teduglutide treatment must be discontinued (see sections 4.3 and 5.3).

Gallbladder and bile ducts

Cases of cholecystitis, cholangitis, and cholelithiasis have been reported in clinical studies. In case of gallbladder or bile duct-related symptoms, the need for continued Revestive treatment should be reassessed.

Pancreatic diseases

Pancreatic adverse events such as chronic and acute pancreatitis, pancreatic duct stenosis, pancreas infection and increased blood amylase and lipase have been reported in clinical studies. In case of pancreatic adverse events, the need for continued Revestive treatment should be reassessed.

Monitoring of small bowel, gallbladder and bile ducts, and pancreas

SBS patients are to be kept under close surveillance according to clinical treatment guidelines. This usually includes the monitoring of small bowel function, gallbladder and bile ducts, and pancreas for signs and symptoms, and, if indicated, additional laboratory investigations and appropriate imaging techniques.

Intestinal obstruction

Cases of intestinal obstruction have been reported in clinical studies. In case of recurrent intestinal obstructions, the need for continued Revestive treatment should be reassessed.

Fluid overload and Electrolyte Balance

To avoid fluid overload or dehydration, careful adjustment of parenteral support is required in patients taking Revestive. Electrolyte balance and fluid status should be carefully monitored throughout treatment, especially during initial therapeutic response and discontinuation of Revestive treatment.

Fluid overload:

Fluid overload has been observed in clinical trials. Fluid overload adverse events occurred most frequently during the first 4 weeks of therapy and decreased over time.

Due to increased fluid absorption, patients with cardiovascular disease, such as cardiac insufficiency and hypertension, should be monitored with regard to fluid overload, especially during initiation of therapy. Patients should be advised to contact their physician in case of sudden weight gain, face swelling, swollen ankles and/or dyspnoea. In general, fluid overload can be prevented by appropriate and timely assessment of parenteral nutrition needs. This assessment should be conducted more frequently within the first months of treatment.

Congestive heart failure has been observed in clinical trials. In case of a significant deterioration of the cardiovascular disease, the need for continued treatment with Revestive should be reassessed.

Dehydration:

Patients with SBS are susceptible to dehydration that may lead to acute renal failure. In patients receiving Revestive, parenteral support should be reduced carefully and should not be discontinued abruptly. The patient’s fluid status should be evaluated following parenteral support reduction and corresponding adjustment performed, as needed.

Concomitant medicinal products

Patients receiving oral concomitant medicinal products requiring titration or with a narrow therapeutic index should be monitored closely due to potential increased absorption (see section 4.5).

Special clinical conditions

Revestive has not been studied in patients with severe, clinically unstable concomitant diseases, (e.g., cardiovascular, respiratory, renal, infectious, endocrine, hepatic, or CNS), or in patients with malignancies within the last five years (see section 4.3). Caution should be exercised when prescribing Revestive.

Hepatic impairment

Revestive has not been studied in patients with severe hepatic impairment. The data from use in subjects with moderate hepatic impairment do not suggest a need for restricted use.

Discontinuation of treatment

Due to the risk of dehydration, discontinuation of treatment with Revestive should be managed carefully.

Paediatric population

See also general precautions for adults under this section.

Colo-rectal polyps/Neoplasia

Prior to initiating treatment with Revestive, faecal occult blood testing should be done for all children and adolescents. Colonoscopy/sigmoidoscopy is required if there is evidence of unexplained blood in the stool. Subsequent faecal occult blood testing should be done annually in children and adolescents while they are receiving Revestive.

Colonoscopy/sigmoidoscopy is recommended for all children and adolescents after one year of treatment, every 5 years thereafter while on continuous treatment with Revestive, and if they have new or unexplained gastrointestinal bleeding.

Excipients

Revestive contains less than 1 mmol sodium (23 mg) per dose. This means that it is essentially ‘sodium-free’.

Caution is needed when administering Revestive to persons with a known hypersensitivity to tetracycline (see section 4.3).

No clinical pharmacokinetic drug-drug interaction studies have been performed. An in vitro study indicates that teduglutide does not inhibit cytochrome P450 drug metabolising enzymes. Based upon the pharmacodynamic effect of teduglutide, there is a potential for increased absorption of concomitant medicinal products (see section 4.4).

Pregnancy

There are no data from the use of Revestive in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Revestive during pregnancy.

Breast-feeding

It is unknown whether teduglutide is excreted in human milk. In rats, mean teduglutide concentration in milk was less than 3% of the maternal plasma concentration following a single subcutaneous injection of 25 mg/kg. A risk to the breast-fed newborn/infant cannot be excluded. As a precautionary measure it is preferable to avoid the use of Revestive during breast-feeding.

Fertility

There are no data on the effects of teduglutide on human fertility. Animal data do not indicate any impairment of fertility.

Revestive has minor influence on the ability to drive and use machines. However, cases of syncope have been reported in clinical studies (see section 4.8). Such events might impact the ability to drive and use machines.

Summary of the safety profile

Adverse reactions were retrieved from 2 placebo-controlled clinical studies with teduglutide in 109 patients with SBS treated with doses of 0.05 mg/kg/day and 0.10 mg/kg/day for up to 24 weeks. Approximately 52% of the patients treated with teduglutide experienced adverse reactions (versus 36% of the patients given placebo). The most commonly reported adverse reactions were abdominal pain and distension (45%), respiratory tract infections (28%) (including nasopharyngitis, influenza, upper respiratory tract infection, and lower respiratory tract infection), nausea (26%), injection site reactions (26%), headache (16%), and vomiting (14%). Approximately 38% of the treated patients with a stoma experienced gastrointestinal stoma complications. The majority of these reactions were mild or moderate.

No new safety signals have been identified in patients exposed to 0.05 mg/kg/day of teduglutide for up to 30 months in a long-term open-label extension study.

Tabulated list of adverse reactions

Adverse reactions are listed below by MedDRA system organ class and by frequency. Frequencies are defined as very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

All adverse reactions identified in post-marketing experience are italicised.

^* Includes the following preferred terms: Nasopharyngitis, Influenza, Upper respiratory tract infection, and Lower respiratory tract infection.
^† Includes the following preferred terms: Pancreatitis, Pancreatitis acute, and Pancreatitis chronic.
^‡ Locations include duodenum, jejunum, and ileum.
^§ Includes the following preferred terms: Injection site haematoma, Injection site erythema, Injection site pain, Injection site swelling and Injection site haemorrhage.

Description of selected adverse reactions

Immunogenicity

Consistent with the potentially immunogenic properties of medicinal products containing peptides, administration of Revestive may potentially trigger the development of antibodies. Based on integrated data from two trials in adults with SBS (a 6-month randomised placebo-controlled trial, followed by a 24-month open-label trial), the development of anti-teduglutide antibodies in subjects who received subcutaneous administration of 0.05 mg/kg teduglutide once daily was 3% (2/60) at Month 3, 17% (13/77) at Month 6, 24% (16/67) at Month 12, 33% (11/33) at Month 24, and 48% (14/29) at Month 30. In phase 3 studies with SBS patients who received teduglutide for ≥2 years, 28% of patients developed antibodies against E. coli protein (residual host cell protein from the manufacture). The antibody formation has not been associated with clinically relevant safety findings, reduced efficacy or changed pharmacokinetics of Revestive.

Injection site reactions

Injection site reactions occurred in 26% of SBS patients treated with teduglutide, compared to 5% of patients in the placebo arm. The reactions included injection site haematoma, injection site erythema, injection site pain, injection site swelling and injection site haemorrhage (see also section 5.3). The majority of reactions were moderate in severity and no occurrences led to drug discontinuation.

C-reactive protein

Modest increases of C-reactive protein of approximately 25 mg/l have been observed within the first seven days of teduglutide treatment, which decreased continuously under ongoing daily injections. After 24 weeks of teduglutide treatment, patients showed small overall increase in C-reactive protein of approximately 1.5 mg/l on average. These changes were neither associated with any changes in other laboratory parameters nor with any reported clinical symptoms. There were no clinically relevant mean increases of C-reactive protein from baseline following long-term treatment with teduglutide for up to 30 months.

Paediatric population

In two completed clinical trials, there were 87 paediatric subjects (aged 1 to 17 years) enrolled and exposed to teduglutide for a duration of up to 6 months. No subject discontinued the studies due to an adverse event. Overall, the safety profile of teduglutide (including type and frequency of adverse reactions, and immunogenicity) in children and adolescents (ages 1-17 years) was similar to that in adults.

In three completed clinical studies in paediatric subjects (aged 4 to <12 months corrected gestational age), the safety profile reported in these studies was consistent with the safety profile seen in the previous paediatric studies and no new safety issues were identified.

Limited long-term safety data is available for the paediatric population. No data are available for children under 4 months of age.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.