Octreotide (Solution, Lyophilisate) Instructions for Use

ATC Code

H01CB02 (Octreotide)

Active Substance

Octreotide (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Somatostatin analogue

Pharmacotherapeutic Group

Pituitary and hypothalamic hormones and their analogues; hypothalamic hormones; somatostatin and its analogues

Pharmacological Action

Octreotide-depot is a long-acting dosage form of octreotide for intramuscular administration, which maintains stable therapeutic concentrations of octreotide in the blood for 4 weeks. Octreotide is a means of pathogenetic therapy for tumors that actively express somatostatin receptors. Octreotide is a synthetic octapeptide, a derivative of the natural hormone somatostatin, possessing similar pharmacological effects but with a significantly longer duration of action. The drug suppresses pathologically increased secretion of growth hormone (GH), as well as peptides and serotonin produced in the gastro-entero-pancreatic endocrine system.

In healthy individuals, Octreotide, like somatostatin, suppresses GH secretion induced by arginine, physical exercise, and insulin hypoglycemia; suppresses the secretion of insulin, glucagon, gastrin, and other peptides of the gastroenteropancreatic endocrine system induced by food intake; and suppresses insulin and glucagon secretion stimulated by arginine; suppresses thyrotropin secretion induced by thyroliberin. The inhibitory effect on GH secretion of octreotide, unlike somatostatin, is significantly more pronounced than on insulin secretion. The administration of octreotide is not accompanied by a phenomenon of hormone hypersecretion via the negative feedback mechanism.

In patients with acromegaly, the administration of the depot form of octreotide provides, in the vast majority of cases, a sustained decrease in GH concentration and normalization of the concentration of insulin-like growth factor 1/somatomedin C (IGF-1).

In most patients with acromegaly, the depot form of octreotide significantly reduces the severity of symptoms such as headache, increased sweating, paresthesia, fatigue, bone and joint pain, and peripheral neuropathy. It has been reported that treatment with the depot form of octreotide in individual patients with GH-secreting pituitary adenomas led to a reduction in tumor size.

In secreting endocrine tumors of the gastrointestinal tract (GIT) and pancreas, the use of the depot form of octreotide provides constant control of the main symptoms of these diseases.

The depot form of octreotide at a dose of 30 mg every 4 weeks slows tumor growth in patients with secreting and non-secreting widespread (metastatic) neuroendocrine tumors of the jejunum, ileum, cecum, ascending colon, transverse colon, and appendix, or metastases of neuroendocrine tumors without a primarily identified focus. The drug was effective in increasing time to progression, both for secreting and non-secreting neuroendocrine tumors.

In carcinoid tumors, the use of octreotide can lead to a reduction in the severity of disease symptoms, primarily such as flushing and diarrhea. In many cases, clinical improvement is accompanied by a decrease in plasma serotonin concentration and urinary excretion of 5-hydroxyindoleacetic acid.

In tumors characterized by hypersecretion of vasoactive intestinal peptide (VIPomas), the use of octreotide leads in most patients to a reduction in the severe secretory diarrhea characteristic of this condition, which, in turn, leads to an improvement in the patient’s quality of life. Simultaneously, there is a reduction in associated electrolyte balance disorders, for example, hypokalemia, allowing for the discontinuation of enteral and parenteral administration of fluids and electrolytes. According to computed tomography, in some patients, there is a slowing or halt in tumor progression, and even a reduction in its size, especially liver metastases. Clinical improvement is usually accompanied by a decrease (to normal values) in the plasma concentration of vasoactive intestinal peptide (VIP).

In glucagonomas, the use of octreotide in most cases leads to a noticeable reduction in the necrolytic migratory rash characteristic of this condition. Octreotide does not have any significant effect on the severity of diabetes mellitus, often observed in glucagonomas, and usually does not lead to a reduced need for insulin or oral hypoglycemic drugs. In patients suffering from diarrhea, Octreotide causes its reduction, accompanied by weight gain. With the use of octreotide, a rapid decrease in plasma glucagon concentration is often noted; however, this effect is not sustained during long-term treatment. At the same time, symptomatic improvement remains stable for a long time.

In gastrinomas/Zollinger-Ellison syndrome, Octreotide, used as monotherapy or in combination with histamine H₂-receptor blockers and proton pump inhibitors, can reduce gastric hydrochloric acid production and lead to clinical improvement, including regarding diarrhea. A reduction in the severity of other symptoms, probably associated with tumor peptide synthesis, including flushing, is also possible. In some cases, a decrease in plasma gastrin concentration is noted. In patients with insulinomas, Octreotide reduces the concentration of immunoreactive insulin in the blood. In patients with operable tumors, Octreotide can provide restoration and maintenance of normoglycemia in the preoperative period. In patients with inoperable benign and malignant tumors, glycemic control may improve even without a simultaneous prolonged decrease in blood insulin concentration.

In patients with rare tumors hypersecreting growth hormone-releasing factor (somatoliberinomas), Octreotide reduces the severity of acromegaly symptoms. This appears to be due to the suppression of growth hormone-releasing factor secretion and GH itself. Subsequently, a reduction in the size of the pituitary gland, which was enlarged before treatment, is possible.

In patients with hormone-resistant prostate cancer (HRPC), the pool of neuroendocrine cells expressing somatostatin receptors with affinity for octreotide (SS2 and SS5 types) increases, which determines the tumor’s sensitivity to octreotide. The use of the drug Octreotide-depot in combination with dexamethasone against the background of androgen blockade (medical or surgical castration) in patients with HRPC restores sensitivity to hormonal therapy and leads to a decrease in prostate-specific antigen (PSA) in more than 50% of patients.

In patients with HRPC with bone metastases, this therapy is accompanied by a pronounced and long-lasting analgesic effect. At the same time, in all patients responding to combination therapy with the drug Octreotide-depot, the quality of life and median relapse-free survival are significantly improved.

Pharmacokinetics

Data on the pharmacokinetics of the drug Octreotide-depot are not provided.

Indications

In the therapy of acromegaly

• When adequate control of disease manifestations is achieved with s.c. administration of octreotide;
• In case of insufficient effect from surgical treatment and radiation therapy;
• For preparation for surgical treatment;
• For treatment between courses of radiation therapy until a sustained effect develops;
• In inoperable patients.

In the therapy of endocrine tumors of the GIT and pancreas:

• Carcinoid tumors with manifestations of carcinoid syndrome;
• Insulinomas;
• VIPomas;
• Gastrinomas (Zollinger-Ellison syndrome);
• Glucagonomas (for controlling hypoglycemia in the preoperative period, as well as for maintenance therapy);
• Somatoliberinomas (tumors characterized by hypersecretion of growth hormone-releasing factor);
• Treatment of patients with secreting and non-secreting widespread (metastatic) neuroendocrine tumors of the jejunum, ileum, cecum, ascending colon, transverse colon, and appendix, or metastases of neuroendocrine tumors without a primarily identified focus.

In the therapy of hormone-resistant prostate cancer:

• As part of combination therapy against the background of surgical or medical castration.

In the prevention of the development of acute postoperative pancreatitis

• During extensive abdominal surgeries and thoracoabdominal interventions (including for gastric cancer, esophageal cancer, colon cancer, pancreatic cancer, primary and secondary tumor lesions of the liver).

ICD codes

Dosage Regimen

Solution

The drug is intended for s.c. and i.v. administration.

The initial dose is 50 mcg/day s.c. once or twice daily. After that, the number of injections and the dose can be gradually increased, based on tolerance, clinical response, and the effect on the levels of hormones produced by the tumor (in the case of carcinoid tumors – the effect on urinary excretion of 5-hydroxyindoleacetic acid). The drug is usually used 2-3 times/day.

In acromegaly, the drug is administered s.c. at an initial dose of 50-100 mcg, at intervals of 8 or 12 hours. Further dose selection is based on the results of monthly monitoring of blood growth hormone concentration, analysis of clinical symptoms, and drug tolerance. In most cases, the daily dose is 200-300 mcg. The maximum dose is 1500 mcg/day. If after 3 months of treatment there is no sufficient reduction in growth hormone and improvement in the clinical picture of the disease, therapy should be discontinued.

In endocrine tumors of the gastroenteropancreatic system, the drug is administered s.c. at an initial dose of 50 mcg 1-2 times/day. Subsequently, depending on the achieved effect, influence on the concentration of hormones produced by the tumor (in the case of carcinoid tumors – influence on the excretion of 5-hydroxyindoleacetic acid in the urine), and tolerance, the dose can be gradually increased to 100-200 mcg 3 times/day.

For the prevention of complications after pancreatic surgery, the drug is administered s.c., the first dose of 100 mcg 1 hour before laparotomy, after surgery – 100 mcg 3 times/day for the next 7 days. In exceptional cases, higher doses may be required. Maintenance doses of the drug should be selected individually.

If therapy at the maximum tolerated dose is not effective within 1 week, therapy should be discontinued.

For stopping bleeding from esophageal varices, the drug is administered i.v. by drip at a rate of 25 mcg/h for 5 days.

For the treatment of acute pancreatitis, the drug is administered s.c. at a dose of 100 mcg 3 times/day for 5 days. Administration of up to 1200 mcg/day using the i.v. route is possible.

Injection Rules

When administering s.c., multiple injections of the drug into the same site within a short period of time should be avoided.

When administering the drug i.v., immediately before use, the contents of the single-use vial or multi-use vial must be diluted in physiological saline. The dilution volume will depend on the infusion system used and should be adjusted to ensure continuous administration of octreotide at the recommended rate. After the drug has been diluted, the resulting solution should be used within 24 hours. Unused solution must be discarded.

Before i.v. administration of the solution, it must be checked for clarity, presence of particles, sediment, color change, and leakage, in all cases where the solution and packaging material allow. Do not use the drug if it is cloudy, contains particles, sediment, if its color has changed, or if traces of leakage are visible.

Lyophilisate

The drug Octreotide-depot should be administered only by deep intramuscular (i.m.) injection into the gluteal muscle. For repeated injections, the left and right sides should be alternated. The suspension should be prepared immediately before injection. On the day of injection, the vial with the drug and the ampoule with the solvent can be kept at room temperature.

In the treatment of acromegaly in patients for whom s.c. administration of octreotide provides adequate control of disease manifestations, the recommended initial dose of the drug Octreotide-depot is 20 mg every 4 weeks for 3 months. Treatment with the drug Octreotide-depot can be started the day after the last s.c. administration of octreotide. Subsequently, the dose is adjusted based on serum GH and IGF-1 concentrations, as well as clinical symptoms. If after 3 months of treatment an adequate clinical and biochemical effect has not been achieved (in particular, if the GH concentration remains above 2.5 mcg/l), the dose can be increased to 30 mg administered every 4 weeks.

In cases where after 3 months of treatment with the drug Octreotide-depot at a dose of 20 mg, a sustained decrease in serum GH concentration below 1 mcg/l, normalization of IGF-1 concentration, and disappearance of reversible symptoms of acromegaly are observed, the dose of the drug Octreotide-depot can be reduced to 10 mg. However, in these patients receiving a relatively small dose of the drug Octreotide-depot, serum GH and IGF-1 concentrations, as well as disease symptoms, should continue to be carefully monitored.

In patients receiving a stable dose of the drug Octreotide-depot, GH and IGF-1 concentrations should be determined every 6 months.

In patients for whom surgical treatment and radiation therapy are insufficiently effective or completely ineffective, as well as in patients requiring short-term treatment in the intervals between courses of radiation therapy until its full effect develops, a trial course of treatment with s.c. injections of octreotide is recommended to assess its effectiveness and overall tolerance, and only after that switch to the use of the drug Octreotide-depot according to the above scheme.

In the treatment of endocrine tumors of the GIT and pancreas in patients for whom s.c. administration of octreotide provides adequate control of disease manifestations, the recommended initial dose of the drug Octreotide-depot is 20 mg every 4 weeks. S.c. administration of octreotide should be continued for another 2 weeks after the first administration of the drug Octreotide-depot.

In patients who have not previously received Octreotide s.c., it is recommended to start treatment with s.c. administration of octreotide at a dose of 0.1 mg 3 times/day for a relatively short period (approximately 2 weeks) to assess its effectiveness and overall tolerance. Only after that, the drug Octreotide-depot is prescribed according to the above scheme.

If therapy with the drug Octreotide-depot for 3 months provides adequate control of clinical manifestations and biological markers of the disease, it is possible to reduce the dose of the drug Octreotide-depot to 10 mg administered every 4 weeks. In cases where only partial improvement has been achieved after 3 months of treatment with the drug Octreotide-depot, the dose of the drug can be increased to 30 mg every 4 weeks. During treatment with the drug Octreotide-depot, on certain days, an increase in clinical manifestations characteristic of endocrine tumors of the GIT and pancreas is possible. In these cases, additional s.c. administration of octreotide at the dose used before starting treatment with the drug Octreotide-depot is recommended. This may occur mainly in the first 2 months of treatment, until therapeutic plasma concentrations of octreotide are achieved.

For secreting and non-secreting widespread (metastatic) neuroendocrine tumors of the jejunum, ileum, cecum, ascending colon, transverse colon, and appendix, or metastases of neuroendocrine tumors without a primarily identified focus the recommended dose of the drug Octreotide-depot is 30 mg every 4 weeks. Therapy with the drug Octreotide-depot should be continued until signs of tumor progression appear.

In the treatment of hormone-resistant prostate cancer, the recommended initial dose of the drug Octreotide-depot is 20 mg every 4 weeks for 3 months. Subsequently, the dose is adjusted based on the dynamics of serum PSA concentration, as well as clinical symptoms. If after 3 months of treatment an adequate clinical and biochemical effect (reduction in PSA) has not been achieved, the dose can be increased to 30 mg administered every 4 weeks.

Treatment with the drug Octreotide-depot is combined with the use of dexamethasone, which is administered orally according to the following scheme: 4 mg per day for 1 month, then 2 mg per day for 2 weeks, then 1 mg per day (maintenance dose).

Treatment with the drug Octreotide-depot and dexamethasone in patients who previously received medical antiandrogen therapy is combined with the use of a gonadotropin-releasing hormone (GnRH) analogue. In this case, an injection of the GnRH analogue (depot form) is administered once every 4 weeks.

In patients receiving the drug Octreotide-depot, PSA concentrations should be determined every month.

In patients with impaired renal function, hepatic function, and in elderly patients, there is no need to adjust the dosing regimen of Octreotide-depot.

For the prevention of acute postoperative pancreatitis, Octreotide-depot is administered as a single dose of 10 or 20 mg no earlier than 5 days and no later than 10 days before the planned surgical intervention.

Rules for the preparation of the suspension and administration of the drug

The drug is administered intramuscularly only. The suspension for intramuscular injection is prepared using the supplied solvent immediately before administration. The drug must be prepared and administered only by specially trained medical personnel.

Before the injection, the ampoule with the solvent and the vial with the drug should be removed from the refrigerator and brought to room temperature (requires 30-50 minutes). Keep the vial with Octreotide-depot strictly vertical. By tapping the vial lightly, ensure that all the lyophilisate is at the bottom of the vial.

Open the package with the syringe, attach a needle size 1.2 mm x 50 mm to the syringe for drawing up the solvent. Open the ampoule with the solvent and draw the entire contents of the ampoule with the solvent into the syringe, set the syringe to a dose of 2.0 ml. Remove the plastic cap from the vial containing the lyophilisate. Disinfect the rubber stopper of the vial with an alcohol swab. Insert the needle into the vial with the lyophilisate through the center of the rubber stopper and carefully introduce the solvent along the inner wall of the vial, without the needle touching the contents of the vial.

Remove the syringe from the vial. The vial must remain motionless until the solvent has completely soaked the lyophilisate and a suspension has formed (approximately 3-5 minutes). After that, without inverting the vial, check for the presence of dry lyophilisate on the walls and bottom of the vial. If dry residues of the lyophilisate are found, leave the vial until complete soaking.

After you have made sure that there are no residues of dry lyophilisate, the contents of the vial should be gently mixed with circular motions for 30-60 seconds until a homogeneous suspension is formed. Do not invert or shake the vial, as this may cause flaking and render the suspension unusable.

Quickly insert the needle through the rubber stopper into the vial. Then lower the needle bevel down and, tilting the vial at a 45-degree angle, slowly draw the entire suspension into the syringe. Do not invert the vial during aspiration. A small amount of the drug may remain on the walls and bottom of the vial. The residue on the walls and bottom of the vial is accounted for.

Immediately after drawing up the suspension, replace the needle with the pink hub with a needle with a green hub (0.8 x 40 mm), carefully turn the syringe over and remove air from the syringe.

The suspension of Octreotide-depot should be administered immediately after preparation. The suspension of Octreotide-depot must not be mixed with any other medication in the same syringe.

Disinfect the injection site with an alcohol swab. Insert the needle deep into the gluteal muscle, then slightly pull back the syringe plunger to ensure that no blood vessel has been punctured. Administer the suspension intramuscularly slowly with constant pressure on the syringe plunger.

If a blood vessel is entered, the injection site and needle should be changed. If the needle becomes clogged, replace it with another needle of the same diameter.

For repeated injections, the left and right sides should be alternated.

Adverse Reactions

Local reactions with intramuscular administration of Octreotide-depot may include pain, less frequently swelling and rash at the injection site (usually mild and short-lived).

Gastrointestinal side effects include anorexia, nausea, vomiting, spasmodic abdominal pain, abdominal distension, excessive gas formation, loose stools, diarrhea, steatorrhea. Although fecal fat excretion may increase, to date there is no evidence that long-term treatment with octreotide can lead to the development of deficiency of certain nutrients due to malabsorption. In rare cases, phenomena resembling acute intestinal obstruction may occur: progressive abdominal distension, severe pain in the epigastric region, abdominal wall rigidity. Long-term use of Octreotide-depot may lead to the formation of gallstones.

Pancreatic side effects rare cases of acute pancreatitis developing within the first hours or days of octreotide use have been reported. With long-term use, cases of pancreatitis associated with cholelithiasis have been noted.

Hepatic side effects: there are isolated reports of the development of liver function disorders (acute hepatitis without cholestasis with normalization of transaminase levels after discontinuation of octreotide); slow development of hyperbilirubinemia, accompanied by an increase in alkaline phosphatase, GGT and, to a lesser extent, other transaminases.

Metabolic side effects since Octreotide-depot has a suppressive effect on the formation of GH, glucagon, and insulin, it can affect glucose metabolism. A decrease in glucose tolerance after meals is possible. With long-term subcutaneous use of Octreotide, persistent hyperglycemia may develop in some cases. Hypoglycemic conditions have also been observed.

Other in rare cases, temporary hair loss after octreotide administration, occurrence of bradycardia, tachycardia, shortness of breath, skin rash, anaphylaxis have been reported. There are isolated reports of the development of hypersensitivity reactions.

Contraindications

• Hypersensitivity to octreotide or other components of the drug.

With caution the drug should be prescribed for cholelithiasis, diabetes mellitus, during pregnancy and lactation.

Use in Pregnancy and Lactation

There is no experience with the use of Octreotide-depot during pregnancy and breastfeeding.

Therefore, during pregnancy, the drug should be prescribed only if the potential benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding is not recommended while using the drug during lactation.

Use in Hepatic Impairment

In patients with impaired liver function, there is no need to adjust the dosing regimen of Octreotide-depot.

Use in Renal Impairment

In patients with impaired renal function, there is no need to adjust the dosing regimen of Octreotide-depot.

Geriatric Use

In elderly patients, there is no need to adjust the dosing regimen of Octreotide-depot.

Special Precautions

In pituitary tumors secreting GH, careful monitoring of patients is necessary, as an increase in tumor size with the development of serious complications such as visual field constriction is possible. In these cases, the need for other treatment methods should be considered.

In 15-30% of patients receiving subcutaneous Octreotide for a long time, gallstones may appear. The prevalence in the general population (age 40-60 years) is 5-20%. Experience with long-term treatment of patients with acromegaly and gastrointestinal and pancreatic tumors with prolonged-action Octreotide indicates that prolonged-action Octreotide, compared to short-acting Octreotide, does not lead to an increased frequency of gallstone formation. Nevertheless, it is recommended to perform gallbladder ultrasound before starting treatment with Octreotide-depot and approximately every 6 months during treatment. Gallstones, if detected, are usually asymptomatic. In the presence of clinical symptoms, conservative treatment (e.g., with bile acid preparations) or surgical intervention is indicated.

In patients with type 1 diabetes mellitus, Octreotide-depot may affect glucose metabolism and, consequently, reduce the need for administered insulin. For patients with type 2 diabetes mellitus and patients without concomitant carbohydrate metabolism disorders, subcutaneous injections of Octreotide may lead to postprandial glycemia. In this regard, it is recommended to regularly monitor blood glucose concentration and, if necessary, adjust hypoglycemic therapy.

In patients with insulinomas, during treatment with octreotide, an increase in the severity and duration of hypoglycemia may be noted (this is associated with a more pronounced suppressive effect on the secretion of GH and glucagon than on insulin secretion, as well as with a shorter duration of the inhibitory effect on insulin secretion). Systematic monitoring of these patients is indicated.

Before prescribing octreotide, patients should undergo a baseline gallbladder ultrasound. During treatment with Octreotide-depot, repeat gallbladder ultrasounds should be performed, preferably at 6-12 month intervals.

If gallstones are detected before the start of treatment, the potential benefits of Octreotide-depot therapy should be weighed against the possible risk associated with the presence of gallstones.

Currently, there is no evidence that Octreotide-depot adversely affects the course or prognosis of pre-existing cholelithiasis.

Management of patients in whom gallstones form during treatment with Octreotide-depot

A) Asymptomatic gallstones. The use of Octreotide-depot can be discontinued or continued – according to the benefit/risk assessment. In any case, no other measures are required, except for continuing examinations, making them more frequent if necessary.

B) Symptomatic gallstones. The use of Octreotide-depot can be discontinued or continued according to the benefit/risk assessment. In any case, the patient should be treated as in other cases of clinically manifest cholelithiasis. Drug treatment includes the use of combinations of bile acid preparations (for example, chenodeoxycholic acid at a dose of 7.5 mg/kg/day in combination with ursodeoxycholic acid at the same dose) under ultrasound control – until the stones completely disappear.

Effect on the ability to drive vehicles and mechanisms

Currently, there are no data on the effect of Octreotide-depot on the ability to drive a car and operate machinery requiring increased attention and speed of mental and motor reactions.

Overdose

To date, no cases of overdose with Octreotide-depot have been reported.

Drug Interactions

Octreotide reduces the intestinal absorption of cyclosporine and slows the absorption of cimetidine.

With simultaneous use of octreotide and bromocriptine, the bioavailability of the latter increases.

There are literature data indicating that somatostatin analogs may reduce the metabolic clearance of substances metabolized by cytochrome P450 isoenzymes, which may be caused by GH suppression. Since such effects of octreotide cannot be excluded, drugs metabolized by cytochrome P450 system isoenzymes and having a narrow therapeutic range (quinidine and terfenadine) should be prescribed with caution.

Storage Conditions

The drug should be stored in a dry, light-protected place, out of the reach of children, at a temperature of 2°C (35.6°F) to 8°C (46.4°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.