Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Amryt Pharmaceuticals DAC, 45 Mespil Road, Dublin 4, Ireland
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
As growth hormone (GH)-secreting pituitary tumours may sometimes expand, causing serious complications (e.g. visual field defects), it is essential that all patients be carefully monitored. If evidence of tumour expansion appears, alternative procedures may be advisable.
The therapeutic benefits of a reduction in GH levels and normalisation of IGF-1 concentration in female acromegalic patients could potentially restore fertility. Female patients of childbearing potential should be advised to use adequate contraception, if necessary, during treatment with octreotide (see section 4.6).
Thyroid function should be monitored in patients receiving prolonged treatment with octreotide.
Hepatic function should be monitored during octreotide therapy.
Bradycardia and nodal arrhythmia have been reported (see section 4.8). 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 4.5).
Cholelithiasis has been reported during treatment with octreotide and may be associated with cholecystitis (see section 4.8). Additionally, cases of cholangitis have been reported as a complication of cholelithiasis in patients receiving octreotide injections in the post-marketing setting.
Ultrasonic examination of the gallbladder at about 6- to 12-month intervals during Mycapssa therapy is recommended.
Because of its inhibitory action on GH, glucagon, and insulin, octreotide may affect glucose regulation. Post-prandial glucose tolerance may be impaired. As reported for patients treated with subcutaneous octreotide, in some instances, the state of persistent hyperglycaemia may be induced as a result of chronic administration. Hypoglycaemia has also been reported.
Insulin requirements of patients with type I diabetes mellitus therapy may be reduced by administration of octreotide. In non-diabetics and type II diabetics with partially intact insulin reserves, octreotide administration can result in postprandial increases in glycaemia. It is therefore recommended to monitor glucose tolerance and antidiabetic treatment.
Octreotide may alter absorption of dietary fats in some patients.
Depressed vitamin B12 levels and abnormal Schilling’s tests have been observed in some patients receiving octreotide therapy. Monitoring of vitamin B12 levels is recommended during therapy with Mycapssa in patients who have a history of vitamin B12 deprivation.
This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially sodium-free.
Concomitant administration of Mycapssa with esomeprazole has been found to decrease the bioavailability of Mycapssa. Medicinal products that alter the pH of the upper gastrointestinal tract (e.g. other proton pump inhibitors, H2-receptor antagonists, and antacids) may alter the absorption of Mycapssa and lead to a reduction in bioavailability. Concomitant administration of Mycapssa with proton pump inhibitors, H2-receptor antagonists, or antacids may require increased doses of Mycapssa.
Concomitant administration of Mycapssa with metoclopramide reduced the Cmax and AUC of octreotide by an average of approximately 5% and 11%, respectively. Mycapssa should be titrated as indicated to clinical/biochemical effect.
Concomitant administration of Mycapssa with loperamide reduced the Cmax and AUC of octreotide by an average of approximately 9% and 3%, respectively. Mycapssa should be titrated as indicated to clinical/biochemical effect.
Multiple mechanisms such as cytochrome P450 enzymes inhibition due to suppression of growth hormone, delayed gastric emptying or possibly enhanced permeability in some cases, are involved which may result in drug-drug interactions. Therefore, drug-drug interactions may vary between medicinal products. As a consequence, other medicinal products which have a narrow therapeutic index should therefore be used with caution and doses adjusted as necessary.
In a clinical study, it was shown that transient permeability enhancer (TPE) excipients in the formulation increase the intestinal absorption of octreotide via paracellular transport, using the lactulose to mannitol ratio test (see section 5.1). No interaction studies with other drugs that are transported via the paracellular route (e.g. alendronate or desmopressin) were conducted.
Dose adjustment of medicinal products such as beta blockers, calcium channel blockers, or agents to control fluid and electrolyte balance may be necessary when Mycapssa is administered concomitantly (see section 4.4).
Concomitant administration of hydrochlorothiazide (HCTZ) and Mycapssa resulted in a 9% decrease in Cmax and 19% decrease in AUC(0-5) of HCTZ. Dose adjustment of HCTZ may be necessary.
Dose adjustments of insulin and antidiabetic medicinal products may be required when Mycapssa is administered concomitantly (see section 4.4).
Concomitant administration of metformin and Mycapssa resulted in no significant changes in the early exposure to metformin.
Octreotide has been found to reduce the intestinal absorption of ciclosporin (71% decrease in Cmax and 63% decrease in AUC) Dose adjustment of ciclosporin may be necessary.
Octreotide injections have been found to delay the intestinal absorption of cimetidine. Dose adjustment of cimetidine may be necessary.
Concomitant administration of octreotide injections and bromocriptine increases the bioavailability of bromocriptine. Dose adjustments of bromocriptine may be necessary.
Concomitant administration of lisinopril and Mycapssa increases the bioavailability of lisinopril (50% increase in Cmax and 40% increase in AUC(0-12)). Dose adjustment of lisinopril may be necessary when Mycapssa is administered concomitantly.
Concomitant administration of digoxin and Mycapssa has been found to decrease the rate of digoxin absorption.
Concomitant administration of levonorgestrel and Mycapssa decreases the bioavailability of levonorgestrel (38% decrease in Cmax and 24% decrease in AUC(0-5)), which may diminish the effectiveness of oral contraceptives containing progestogens (see section 4.6).
Concomitant administration of warfarin and Mycapssa resulted in no significant changes in the early exposure to warfarin.
Female patients of childbearing potential should be advised to use adequate contraception, if necessary, during treatment with octreotide (see section 4.4).
Concomitant administration of Mycapssa with levonorgestrel decreases levonorgestrel bioavailability (see section 4.5). Decreased bioavailability may potentially diminish the effectiveness of oral contraceptives containing progestogens. Women should be counselled to use an alternative non-hormonal method of contraception or a back-up method when Mycapssa is used with oral contraceptives.
There are 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 post-marketing 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 subcutaneous octreotide or 10-40 mg/month of long-acting release octreotide. 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 section 5.3).
As a precautionary measure, it is preferable to avoid the use of Mycapssa during pregnancy (see section 4.4).
It is unknown whether octreotide is excreted in human breast milk. Animal studies have shown excretion of octreotide in breast milk. A risk to the newborns cannot be excluded. Mycapssa should not be used during breast-feeding.
It is not known whether octreotide has an effect on human fertility. Late descent of the testes was found for male offspring 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 section 5.3).
Mycapssa 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 Mycapssa.
The most frequent adverse reactions reported during treatment with Mycapssa are mostly mild to moderate gastrointestinal disorders, with abdominal pain, diarrhoea, and nausea reported most frequently. The overall frequency of gastrointestinal adverse reactions is known to decrease over time with continued treatment.
The adverse drug reactions (ADRs) listed below have been accumulated from clinical studies and post-marketing safety experience with octreotide.
Adverse drug reactions are listed by System Organ Class according to the following classification: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); and not known (cannot be estimated from the available data).
Table 1. Tabulated list of adverse reactions:
| System organ class | Very common | Common | Uncommon | Postmarketing safety experience (frequency not known) |
|---|---|---|---|---|
| Nervous system disorders | Headache** | Dizziness | Burning sensation, carpal tunnel syndrome, disturbance in attention, dysgeusia, hypoaesthesia, memory impairment, paraesthesia, presyncope, sinus headache, somnolence, tremor | |
| Eye disorders | Lacrimation increased | |||
| Ear and labyrinth disorders | Vertigo | |||
| Cardiac disorders | Bradycardia** | Nodal arrhythmia, tachycardia* | Cardiac disorder, arrhythmias* | |
| Vascular disorders | Flushing, hypotension | |||
| Respiratory, thoracic and mediastinal disorders | Dyspnoea* | Nasal mucosal disorder, throat irritation | ||
| Gastrointestinal disorders | Abdominal pain, diarrhoea nausea, constipation**, flatulence** | Dyspepsia, vomiting, abdominal bloating*, steatorrhoea*, faeces soft**, faeces discoloured**, abdominal discomfort, abdominal distension, gastritis, gastrooesophageal reflux disease | Acute pancreatitis, change of bowel habit, dry mouth, faecal incontinence, faecal volume increased, frequent bowel movements, gastrointestinal disorder, gastrointestinal motility disorder, haemorrhoidal haemorrhage, odynophagia, oesophageal achalasia, parotid gland enlargement, rectal tenesmus | |
| Hepatobiliary disorders | Cholelithiasis** | Cholecystitis**, biliary sludge*, hyperbilirubinaemia* | Bile duct obstruction, jaundice, post cholecystectomy syndrome, biliary colic, gallbladder disorder, hepatic steatosis | Acute hepatitis without cholestasis*, cholestatic hepatitis*, cholestasis*, cholestatic jaundice* |
| Skin and subcutaneous tissue disorders | Pruritus**, rash**, alopecia* | Allergic dermatitis, hyperhidrosis, hypertrichosis | Urticaria* | |
| Musculoskeletal and connective tissue disorders | Arthralgia | Back pain, bone pain, flank pain, groin pain, joint swelling, muscle spasms, musculoskeletal discomfort, musculoskeletal pain, myalgia, pain in extremity, soft tissue swelling | ||
| General disorders and administration site conditions1 | Asthenia, fatigue, peripheral swelling | Feeling abnormal, feeling of body temperature change, malaise, pain, tenderness, thirst | ||
| Investigations | Elevated liver function tests2 | Blood creatine phosphokinase increased, blood creatinine increased, blood lactate dehydrogenase increased, blood urea increased, cardiac murmur, heart rate irregular, insulin- like growth factor increased, lipase increased, thyroxine increased, weight decreased, weight increased | Blood growth hormone increased |
* These adverse reactions were not observed with Mycapssa. Their frequencies were established based on data from injectable octreotide
** Very common or common adverse reactions reported more frequently for injectable octreotide versus Mycapssa
1 Injection site reactions were reported as very common ADR for injectable octreotide. Since Mycapssa is for oral administration only, this ADR is not included in the table
2 For injectable octreotide, elevated transaminase levels were reported as common ADR, and increased alkaline phosphatase levels and gamma glutamyl transferase levels were reported post-marketing (frequency not known)
Somatostatin analogues have been shown to inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder abnormalities or sludge. If gallstones do occur, they are usually asymptomatic; symptomatic stones should be treated either by dissolution therapy with bile acids or by surgery.
Bradycardia is an adverse reaction with somatostatin analogues. ECG changes observed with octreotide include QT prolongation, axis shifts, early repolarisation, low voltage, R/S transition, early R wave progression, and non-specific ST-T wave changes. The relationship of these events to octreotide is not established because many of these patients have underlying cardiac diseases (see section 4.4).
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.
Not applicable.
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