Oczyesa 20 mg Prolonged-release solution for injection in pre-filled pen

Oczyesa is indicated for maintenance treatment in adult patients with acromegaly who have responded to and tolerated treatment with somatostatin analogues.

Posology

The recommended dose is 20 mg octreotide every 4 weeks administered by a single subcutaneous injection.

For patients transitioning from octreotide or lanreotide, patients should be instructed to take their first dose of Oczyesa at the end of the daily or monthly dosing interval of the previous treatment.

Oczyesa may be administered up to 1 week before or 1 week after the scheduled 4-week dose in exceptional circumstances (e.g. missed dose, non-adherence to treatment, etc.).

Monitoring of insulin-like growth factor-1 (IGF-1) levels and assessment of symptoms should be made periodically as per the clinician's discretion. Discontinuation of Oczyesa and switching patients to another somatostatin analogue should be considered if IGF-1 levels are not maintained after treatment with dose of 20 mg monthly or the patient cannot tolerate treatment with Oczyesa.

Missed dose

If a dose is missed, the next dose of Oczyesa should be administered as soon as possible.

Special populations

Elderly

No dose adjustment is required for elderly patients.

Hepatic impairment

In patients with liver cirrhosis, the half-life of the medicinal product may be increased. Monitoring of liver function in these patients is recommended (see section 5.2).

Renal impairment

Oczyesa can be used in patients with mild, moderate, or severe renal impairment. Clinical response and tolerability should be monitored (see section 5.2).

Paediatric population

The safety and efficacy of octreotide in children below 18 years of age have not been established. No data are available.

Method of administration

Subcutaneous use.

Prior to initiation of Oczyesa, patients should be trained on proper injection technique. For complete administration instructions with illustrations, see then instructions for use at the end of the package leaflet.

Oczyesa should be injected subcutaneously in the abdomen, thigh or buttock.

Patients should be instructed to rotate the injection site within or between injection areas.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

Tumour expansion

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.

Women of childbearing potential

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

Thyroid function should be monitored in patients receiving prolonged treatment with octreotide.

Hepatic function

Hepatic function should be monitored during octreotide therapy.

Cardiovascular-related events

Common cases of bradycardia 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).

Gallbladder-related events

Cholelithiasis has been reported during treatment with octreotide and may be associated with cholecystitis and biliary duct dilatation (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 before, and at about 6- to 12-month intervals during octreotide therapy is recommended.

Glucose metabolism

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 (see section 4.8). Hypoglycaemia has also been reported (see section 4.8).

Insulin requirements of patients with Type 1 diabetes mellitus therapy may be reduced by administration of octreotide. In non-diabetics and Type 2 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 (see section 4.8).

Nutrition

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 Oczyesa in patients who have a history of vitamin B12 deprivation.

Cardiovascular medicinal products

Dose adjustment of medicinal products that have bradycardic effects, such as beta blockers, calcium channel blockers, or agents to control fluid and electrolyte balance, may be necessary when Oczyesa is administered concomitantly (see section 4.4).

Insulin and antidiabetic medicinal products

Dose adjustments of insulin and antidiabetic medicinal products may be required when octreotide is administered concomitantly (see section 4.4).

Bromocriptine

Concomitant administration of octreotide and bromocriptine increases the bioavailability of bromocriptine.

Ciclosporin and cimetidine

Octreotide injections have been found to reduce the intestinal absorption of ciclosporin and to delay that of cimetidine.

Thyroid hormones replacement therapy

Octreotide may affect thyroid function (see sections 4.4 and 4.5). Therefore, regular monitoring of thyroid function and clinical monitoring is recommended during concomitant treatment with thyroid hormone replacement therapy as this may lead to thyroid imbalance.

Effects on metabolism of other medicinal products

Limited published data indicate that somatostatin analogues might decrease the metabolic clearance of compounds known to be metabolised by cytochrome P450 enzymes, which may be due to the suppression of GH. Since it cannot be excluded that octreotide may have this effect, other medicinal products mainly metabolised by CYP3A4 and which have a low therapeutic index should therefore be used with caution (e.g. quinidine, terfenadine).

Women of childbearing potential

Female patients of childbearing potential should be advised to use adequate contraception, if necessary, during treatment with octreotide (see section 4.4).

Pregnancy

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 100-1 200 micrograms/day of subcutaneous short-acting octreotide or 10-40 mg/month of intramuscular long-acting 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 Oczyesa during pregnancy (see section 4.4).

Breast-feeding

It is unknown whether octreotide is excreted in human milk. Animal studies have shown excretion of octreotide in breast milk. Patients should not breast-feed during Oczyesa 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 section 5.3).

Octreotide 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 Oczyesa (see section 4.8).

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 studies with other formulations of octreotide were diarrhoea, abdominal pain, nausea, flatulence, headache, cholelithiasis, hyperglycaemia and constipation. Other commonly reported adverse reactions were dizziness, localised 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 hypoglycaemia.

Tabulated list of adverse reactions

The following adverse reactions, listed in Table 1, have been accumulated from clinical studies and post-marketing safety experience with octreotide.

Adverse reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: 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 ranked in order of decreasing seriousness.

Table 1. Tabulated list of adverse reactions

a The adverse reactions and frequencies were established based on data from other octreotide products.

b Injection site erythema, swelling, mass, pruritus, induration, pain, nodule, bruising, discomfort, rash, haematoma, oedema, paresthesia, dermatitis, haemorrhage, inflammation, extravasation and hypertrophy.

Description of selected adverse reactions

Gallbladder-related adverse reactions

Octreotide has been shown to inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder abnormalities, and may result in complications. If gallstones do occur, they are usually asymptomatic. Symptomatic gallstones should be treated either by dissolution therapy with bile acids or by surgery.

In ACROINNOVA 1 (Study 1), chronic cholecystitis was reported by 1 patient (2.1%).

In ACROINNOVA 2 (Study 2), cholelithiasis was reported by 6 patients (4.4%), cholecystitis acute and cholecystitis were reported by 1 patient (0.7%) each.

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 reactions is known to decrease over time with continued treatment with octreotide.

Hypersensitivity and anaphylactic reactions

Hypersensitivity and allergic reactions have been reported during post-marketing experience with octreotide. When these occur, they mostly affect the skin, rarely the mouth and airways. Isolated cases of anaphylactic shock have been reported.

Injection site reactions

Most injection site reactions were transient, and mild or moderate. None of these were severe. The most common injection site reactions were injection site erythema, injection site swelling, injection site pruritus, injection site induration, injection site pain, injection site nodule and injection site mass.

Metabolism and nutrition disorders

Although measured faecal fat excretion may increase, there is no evidence to date that long-term treatment with octreotide has led to nutritional deficiency due to malabsorption.

Cardiac disorders

Bradycardia is a common adverse reaction with somatostatin analogues. ECG changes such as QT prolongation, axis shifts, early repolarisation, low voltage, R/S transition, early R wave progression, and non-specific ST-T wave changes have been observed with octreotide. The relationship of these events to octreotide is not established because many of these patients have underlying cardiac diseases (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medical 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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

A limited number of accidental overdoses of octreotide injections in adults and children have been reported. In adults, the doses ranged from 2 400-6 000 micrograms/day administered by continuous infusion (100-250 micrograms/hour) or subcutaneously (1 000 micrograms three times a day). The adverse events reported were arrhythmia, hypotension, cardiac arrest, brain hypoxia, pancreatitis, hepatic steatosis, diarrhoea, weakness, lethargy, weight loss, hepatomegaly, and lactic acidosis.

No unexpected adverse events have been reported in cancer patients receiving subcutaneous octreotide at doses of 3 000-30 000 micrograms/day in divided doses.

Paediatric population

In children, the doses ranged from 50-3 000 micrograms/day administered by continuous infusion (2.1-500 micrograms/hour) or subcutaneously (50-100 micrograms). The only adverse event reported was mild hyperglycaemia.

The management of overdose is symptomatic.

Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, somatostatin and analogues, ATC code: H01CB02

Mechanism of action

Octreotide is a synthetic octapeptide derivative of naturally occurring somatostatin with similar pharmacological effects, but with a considerably prolonged duration of action. It inhibits pathologically increased secretion of GH and of peptides and serotonin produced within the gastro-entero-pancreatic (GEP) endocrine system.

In animals, octreotide is a more potent inhibitor of GH, glucagon and insulin release than somatostatin is, with greater selectivity for GH and glucagon suppression.

In healthy subjects, octreotide has been shown to inhibit:

• release of GH stimulated by arginine, exercise- and insulin-induced hypoglycaemia,

• post-prandial release of insulin, glucagon, gastrin, other peptides of the GEP endocrine system, and arginine-stimulated release of insulin and glucagon,

• thyrotropin-releasing hormone (TRH)-stimulated release of thyroidstimulating hormone (TSH).

Unlike somatostatin, octreotide inhibits GH secretion preferentially over insulin and its administration is not followed by rebound hypersecretion of hormones (i.e. GH in patients with acromegaly).

Pharmacodynamic effects

Octreotide substantially reduces and, in many cases, normalizes IGF-1 and GH levels in patients with acromegaly.

Single doses of octreotide given subcutaneously have been shown to inhibit gallbladder contractility and to decrease bile secretion in healthy volunteers. In clinical studies, the incidence of gallstone or biliary sludge formation was markedly increased (see sections 4.4 and 4.8).

Octreotide may cause clinically significant suppression of TSH (see sections 4.4 and 4.8).

Clinical efficacy and safety

The efficacy and safety of octreotide were established in two phase 3 studies in patients with acromegaly: a 24-week, randomised, double-blind, placebo-controlled, multi-centre study (study 1) and a 52-week, open-label, multi-centre study (study 2). Patients completing study 1 could roll over to study 2. Patients in both studies were on stable treatment with standard of care with injectable long-acting octreotide or lanreotide at time of enrolment.

Study 1

The study enrolled biochemically controlled patients who had IGF-1 levels below or equal to the upper limit of normal (ULN; mean of two measurements, adjusted for age and sex) at screening. Patients were randomised 2:1 to receive either octreotide or placebo for 24 weeks. At baseline, the mean age of patients was 55 years, 56% were women, and 96% were White.

The primary endpoint was the proportion of responders, i.e. patients with IGF-1 levels below or equal to the ULN at the end of the randomised, double-blind period (mean of the measurements at week 22 and week 24). Patients who discontinued treatment or were switched to rescue medication were regarded as non-responders in the analysis.

Study 1 met the primary endpoint of statistical superiority for octreotide over placebo (Table 2). Key secondary endpoints were also met, including the proportion of patients that were responders for both IGF-1 below or equal to ULN and GH below 2.5 mcg/L.

Table 2: Primary and key secondary efficacy endpoint outcomes

a Mantel-Haenszel estimate of the common risk difference accounting previous treatment (long-acting octreotide or lanreotide) with 95% confidence intervals (CI) and upper-tail p-values.

b No patients required dose reduction in the study.

Mean IGF-1 levels were stable below the ULN in patients receiving octreotide and increased above ULN in the placebo arm (Figure 1).

Figure 1: Mean IGF-1/1×ULN over time

In an ANCOVA analysis of the change from baseline to the mean of week 22/24 in IGF-1/ULN, the LS Mean change from baseline was 0.04 in the octreotide arm and 0.52 in the placebo arm. The mean difference between the treatment arms (placebo) was -0.48 (95% CI: -0.75, -0.22). The p-value was 0.0003.

The median time to loss of IGF-1 response was not reached for patients receiving octreotide and was 8.4 weeks for patients in the placebo arm.

The proportions of patients with GH levels < 1.0 mcg/L at week 24 were assessed as secondary endpoint in study 1. The proportion of patients with mean GH < 1.0 mcg/L at Week 24 was 59.9% in the octreotide arm and 37.5% in the placebo arm. The difference between the treatment arms (‑placebo) was 21.3% (95% CI: -2.6%, 45.1%). The p-value was 0.0404.

Study 1 included several patient-reported outcomes, including the acromegaly quality of life questionnaire (AcroQoL) and treatment satisfaction questionnaire for medication (TSQM). The AcroQoL Total Score and TSQM convenience score increased from baseline (i.e. during treatment with long-acting octreotide or lanreotide) to week 24 in both treatment arms, with a larger increase in the octreotide arm than in the placebo arm; the differences between octreotide and placebo were not significant.

Study 2

Long-term safety and efficacy of octreotide were assessed in 135 patients with acromegaly enrolled in study 2. Fifty-four (54) patients were roll-over patients from Study 1 (36 randomized to octreotide and 18 to placebo) and 81 patients (both biochemically controlled and uncontrolled) were directly enrolled in Study 2.

For roll-over- patients who received octreotide in study 1, the mean IGF-1 values remained stable and below 1×ULN during 52 weeks of octreotide treatment. For roll-over patients who received placebo in study 1, IGF-1 values returned to normal after switching to treatment with octreotide in study 2 (Figure 2).

Figure 2: Mean IGF-1/ULN during long-term treatment for roll-over patients

N=number of patients with evaluable data at the certain visit.

Population analyses of efficacy data in Study 1 and Study 2

A population PKPD model describing the impact of octreotide on IGF-1 was developed. The structural model used model-based exposure of octreotide and was an indirect response model with medicinal product effects on the zero-order production rate constant. Medicinal product effects of octreotide were described as an inhibitory E_max function.

Simulations of the effect of octreotide on IGF-1 using the model showed a similar IGF-1 response for Oczyesa 20 mg given every 4 weeks compared to subcutaneous short-acting octreotide 0.25 mg given three times per day. Furthermore, comparable effects on IGF-1 concentrations over time were observed for dosing intervals ranging from 3 to 5 weeks.

Absorption

Bioavailability of octreotide for Oczyesa was 92-98% of that for subcutaneous short-acting octreotide, and 4-5 times higher than for intramuscular long-acting octreotide, without any initial lag-phase.

Maximum concentration of octreotide was reached in approximately 4 hours post dose. Thereafter, the octreotide concentration slowly decreased with a half-life of 9 to 12 days.

Comparable exposure was achieved with Oczyesa injected subcutaneously in the abdomen, thigh, or buttock.

Steady-state pharmacokinetics were achieved by the third injection of Oczyesa given every 4 weeks. Based on population pharmacokinetic modelling, the average octreotide concentration at steady state was 3.1 ng/mL, similar to subcutaneous short-acting octreotide given at a 0.25 mg dose injected 3-times daily (3.2 ng/mL), but with less daily variation.

Distribution

According to data obtained with subcutaneous short-acting octreotide injection, the volume of distribution is 0.27 L/kg. Plasma protein binding amounts to 65%. The amount of octreotide bound to blood cells is negligible.

Elimination

According to data obtained with subcutaneous short-acting octreotide injection, most of the peptide is eliminated via faeces, while approximately 32% of the dose is excreted unchanged in the urine.

The total body clearance is 160 mL/min.

Oczyesa exhibits absorption rate limited elimination of octreotide with an apparent terminal half-life of 217 to 279 hours (9 to 12 days).

Special populations

Elderly

No significant effect of age (ranging from 18-83 years) on octreotide pharmacokinetics was found with octreotide.

Renal impairment

No significant effect of creatinine clearance (CLCR) on clearance of octreotide was found analysing 191 study participants with normal renal function (CLCR ≥ 90 mL/min), 24 with mild renal impairment (CLCR 60-89 mL/min), and 1 subject with moderate renal impairment (CLCR 30-59 mL/min).

Impaired renal function did not affect the total exposure (AUC) with subcutaneous short-acting octreotide.

Hepatic impairment

The elimination capacity may be reduced in patients with liver cirrhosis, but not in patients with fatty liver disease.

Acute and repeated dose toxicology, genotoxicity, carcinogenicity and reproductive toxicology studies of octreotide acetate in animals revealed no specific safety concerns for humans.

Reproduction studies of octreotide in animals revealed no evidence of teratogenic, embryo/foetal or other reproduction effects due to octreotide at parental doses of up to 1 mg/kg/day. Some retardation of the physiological growth was noted in the offspring of rats which was transient and attributable to GH inhibition brought about by excessive pharmacodynamic activity (see section 4.6).

No specific studies were conducted in juvenile rats. In the pre- and post-natal developmental studies, reduced growth and maturation was observed in the first filial generation (F1) offspring of dams given octreotide during the entire pregnancy and lactation period. Delayed descent of the testes was observed for male F1 offspring, but fertility of the affected F1 male pups remained normal. Thus, the abovementioned observations were transient and considered to be the consequence of GH inhibition.

Carcinogenicity/chronic toxicity

No carcinogenicity studies have been conducted with octreotide hydrochloride. In rats receiving octreotide acetate at daily subcutaneous doses up to 1.25 mg/kg body weight, fibrosarcomas were observed, predominantly in a number of male animals, at the subcutaneous injection site after 52, 104 and 113/116 weeks. Local tumours also occurred in rats in the control group, however development of these tumours was attributed to disordered fibroplasia produced by sustained irritant effects at the injection sites, enhanced by the acidic lactic acid/mannitol vehicle. This non-specific tissue reaction appeared to be particular to rats. Neoplastic lesions were not observed either in mice receiving daily subcutaneous injections of octreotide at doses up to 2 mg/kg for 98 weeks, or in dogs treated with daily subcutaneous doses of octreotide for 52 weeks.

Glycerol dioleate

Soybean phosphatidylcholine

Ethanol anhydrous

Propylene glycol (E 1520)

Edetic acid

Ethanolamine

This medicinal product must not be mixed with other medicinal products.

30 months

Do not refrigerate.

Store in the original package in order to protect from oxygen and light.

1 mL pre-filled pen supplied as single-dose, sterile, ready-to-use syringe (glass, Type I) with plunger stopper (fluoropolymer-coated bromobutyl rubber), a non-visible needle (22 gauge) and a protective cap with needle shield (synthetic rubber), fitted in an autoinjector.

The pre-filled pen is contained in a sealed aluminium pouch. The package contains a small white cylinder, included for storage purposes only.

Pack size of 1 single-dose pre-filled pen.

Instructions for use

For single use only (do not reuse the Oczyesa pre-filled pen).

Do not use if the Oczyesa pre-filled pen appears damaged.

Do not use if the packaging (carton and pouch) or the seal is damaged.

Do not use this medicine if you notice visible particles or if it is cloudy.

For full instructions for use please refer to the package leaflet.

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.