What is the stability data for compounded octreotide syringes and continuous infusions? What data is available on concentrations, diluents, storage, stability and syringe types (if applicable)?

What is the stability data for compounded octreotide syringes and continuous infusions? What data is available on concentrations, diluents, storage, stability and syringe types (if applicable)?

Comment by InpharmD Researcher

Several stability studies investigating the stability of compounded octreotide in polypropylene syringes have been published (Tables 1 to 3). Results generally indicate improved stability of octreotide with lower temperature and protection from light, with two studies finding an adequate percentage of initial octreotide concentration retained as long as 29 and 60 days depending on storage conditions. Limited applicable data were identified assessing the stability of octreotide in a continuous infusion application. A compounding formula for octreotide injection, including diluents and beyond-use dates, is presented in Table 5.

Background

Although evidence demonstrating the stability of octreotide in a continuous infusion application is limited, a 2014 study provides some insight into octreotide’s stability in a mixed infusion containing sodium bisulfite (SBS), particularly time-dependent stability in amino acid infusions under presence of different pH values, temperatures, and ingredients. Octreotide was mixed with SBS, with high-performance liquid chromatography (HPLC) used to assess concentration at 0, 1, 2, 3, and 4 hours after. Assessment of pH profile indicated that octreotide degradation occurred at pH 4 to 7. The impact of SBS on degradation was further evaluated; HPLC was used to determine degradation of octreotide (initial concentration 0.6 mcg/mL) plus SBS at 25°C and pH 4 to 7. Complex kinetic experiments were conducted, finding the stability of octreotide in a mixed infusion was influenced by pH and SBS concentration. Concrete data or recommendations to help guide clinical decision making when utilizing octreotide for direct patient care were not provided. [1]

Additionally, a 2009 study evaluated the stability of octreotide acetate in aqueous solutions at various pH values. Octreotide acetate was dissolved in various buffer solutions at a concentration of 100 µg/mL; the solutions were evaluated at a pH of 2.5-9. Reverse-phase high-performance liquid chromatographic method was developed to assess stability. The study found that pH affected the octreotide degradation rate which seemed to follow first-order kinetics. White the optimum pH for stability was not established, octreotide seemed to be most stable in acetate buffer at pH 4. At 55°C the half-life for degradation was 27.1 days, 60.3 days, 4.6 days, and 1.2 days at pH 2.5, 4, 7.4, and 9, respectively. Unfortunately, stability data specific to compounded octreotide syringes or continuous infusion was not included in this study. [2]

Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

What is the stability data for compounded octreotide syringes and continuous infusions? What data is available on concentrations, diluents, storage, stability and syringe types (if applicable)?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-5 for your response.

Stability of octreotide acetate in polypropylene syringes
Design	Stability study
Objective	To evaluate the stability of octreotide acetate in 3-mL polypropylene syringes at room temperature (23 °C) and refrigeration temperature (3 °C), typical conditions of the home care environment
Methods	Sixty, 3-mL polypropylene syringes were filled with 1 mL undiluted octreotide acetate solution (0.2 mg/mL) from multiple-dose glass vials (with preservative) aseptically in a laminar-airflow hood. Three syringes were placed in each storage condition (3 °C, 23 °C, daylight exposed, and daylight protected) and sampling time (baseline and 8, 15, 22, and 29 days). Syringes were capped after filling, and placed in appropriate conditions, along with an unopened 5-mL glass vial of octreotide to serve as a control. Stability was assessed by high-performance liquid chromatography (HPLC). Stable solutions were determined to contain ≥ 90% initial octreotide concentration per HPLC testing.
Duration	Up to 29 days
Outcome Measures	Stability (retaining ≥ 90% baseline concentration)
Results	Endpoint	Light protected	Light exposed
	% Initial concentration remaining at 3 °C 0 days 8 days 15 days 22 days 29 days	100.0 ± 3.3 97.0 ± 2.8 93.3 ± 3.1 100.9 ± 4.3 100.9 ± 3.4	100.0 ± 3.3 99.0 ± 3.4 93.4 ± 2.1 91.7 ± 2.9 95.7 ± 3.1
	% Initial concentration remaining at 23 °C 0 days 8 days 15 days 22 days 29 days	100.0 ± 3.3 94.5 ± 2.5 90.7 ± 3.4 93.1 ± 0.7 90.7 ± 2.3	100.0 ± 3.3 95.5 ± 1.7 95.1 ± 2.6 90.3 ± 1.7 90.5 ± 1.2
	At 22 days, even when protected from light, concentration of octreotide stored at 3 °C in polypropylene syringes decreased below 90% threshold after accounting for standard deviation. At 23 °C, octreotide in polypropylene syringes was stable for up to 15 days with protection from light and up to 22 days with light exposure when accounting for standard deviation.
Study Author Conclusions	Octreotide acetate in polypropylene syringes was stable for up to 29 days when stored at 3 °C and protected from light and for up to 22 days when stored at 23 °C and exposed to light. Storage at room temperature for more than one week is not recommended.

References:

Stiles ML, Allen LV Jr, Resztak KE, Prince SJ. Stability of octreotide acetate in polypropylene syringes. Am J Hosp Pharm. 1993;50(11):2356-2358.

Stability of octreotide acetate in polypropylene syringes at 5 and -20 degrees C
Design	Stability study
Objective	To determine the chemical stability of octreotide withdrawn from multidose vials and stored in polypropylene syringes under refrigerated (5 °C) and frozen (-20 °C) conditions over 60 days
Methods	To prepare syringes, 1 mL of octreotide 200 mcg/mL was aseptically aspirated into 3 mL polypropylene syringes. A total of 27 syringes were prepared and capped, 6 for each time interval (7, 14, 28, and 60 days) as well as 3 controls for baseline (time 0) concentration. For each time interval, 3 samples were refrigerated at 2 to 8 °C and 3 were frozen at -17 to -23 °C. Samples were assessed using a high-performance liquid chromatographic (HPLC) assay.
Duration	Up to 60 days
Outcome Measures	Stability (≥ 90% of initial concentration and < 2.0% of des-Thr-ol [degradation product]).
Results	Endpoint	5 °C	-20 °C
	% Initial concentration remaining 7 days 14 days 28 days 60 days	100.7 ± 4.9 98.8 ± 2.1 96.8 ± 4.0 94.3 ± 2.1	101.0 ± 0.6 101.4 ± 4.6 93.7 ± 3.6 94.4 ± 0.7
	Percentage of octreotide remaining was ≥ 90% under both refrigerated and frozen conditions at all time intervals. Additionally, the percentage of des-Thr-ol remained < 2% throughout the study under both conditions. The pH values of the samples ranged from 4.1 to 4.3.
Study Author Conclusions	Octreotide 200 mcg/mL (as the acetate salt) withdrawn from multidose vials and stored in polypropylene syringes was stable at 5 °C or -20 °C for up to 60 days.

References:

Ripley RG, Ritchie DJ, Holstad SG. Stability of octreotide acetate in polypropylene syringes at 5 and -20 degrees C. Am J Health Syst Pharm. 1995;52(17):1910-1911. doi:10.1093/ajhp/52.17.1910

The compatibility and stability of octreotide acetate in the presence of diamorphine hydrochloride in polypropylene syringes

Design

Stability study

Objective

To investigate chemical compatibility and stability of combinations of octreotide acetate and diamorphine hydrochloride over a 48-hour period

Methods

Octreotide acetate injection and diamorphine hydrochloride injection were reconstituted with 8 mL water for injection BP and instilled into 10 mL polypropylene syringes. Diamorphine hydrochloride is administered concomitantly to aid with pain relief. Various combinations were prepared, with different proportions of octreotide acetate and diamorphine hydrochloride, per table below.

Amount of diamorphine HCL in 8 mL volume, mg	Amount of octreotide acetate in 8 mL volume, mcg
50	300
50	600
50	900
100	300
100	600
100	900
200	600

Three samples of each combination were prepared. Samples were stored in a controlled temperature of 37 °C for 48 hours with protection from light, and were analyzed by high-performance liquid chromatography (HPLC).

Duration

Up to 48 hours

Outcome Measures

Stability (≥ 95% initial concentration)

Results

Endpoint

300 mcg/8 mL

600 mcg/8 mL

900 mcg/8 mL

% Octreotide remaining in diamorphine hydrochloride 50 mg/8 mL solution

2 hours

4 hours

6 hours

8 hours

24 hours

102.5 ± 3.2

98.4 ± 4.2

101.3 ± 1.2

100.2 ± 1.1

99.4 ± 1.5

100.7 ±0.4

100.7 ± 1.3

100.2 ± 1.4

100.5 ± 2.8

100.3 ± 1.3

100.9 ± 1.2

101.3 ± 0.5

102.6 ± 2.9

100.2 ± 1.1

98.7 ± 2.4

% Octreotide remaining in diamorphine hydrochloride 100 mg/8 mL solution

2 hours

4 hours

6 hours

8 hours

24 hours

30 hours

48 hours

104.5 ± 4.4

103.8 ± 0.2

99.5 ± 4.9

104.5 ± 5.0

95.8 ± 3.8

96.8 ± 11.0

95.6 ± 2.1

99.3 ± 2.2

95.0 ± 2.6

96.3 ± 3.3

95.7 ± 2.1

98.4 ± 3.4

98.0 ± 3.8

94.0 ± 3.4

99.3 ± 2.6

99.9 ± 2.6

99.9 ± 1.9

102.3 ± 0.5

99.4 ± 2.5

99.8 ± 1.9

95.1 ± 4.2

% Octreotide remaining in diamorphine hydrochloride 200 mg/8 mL solution

2 hours

4 hours

6 hours

8 hours

24 hours

30 hours

48 hours

Not tested

98.8 ± 4.9

97.3 ± 7.3

98.3 ± 7.5

98.0 ± 1.9

100.0 ± 1.7

96.4 ± 5.6

94.2 ± 2.6

Not tested

All samples were stored at 37 °C.

Study Author Conclusions

The results indicate that octreotide acetate remains stable in the presence of diamorphine hydrochloride at 37°C for 24 h. In addition, the solutions prepared maintained their clarity, with no signs of precipitation upon visual examination under normal light conditions.

The use of a continuous subcutaneous infusion of octreotide acetate is more practical than bolus injections. If combined with diamorphine hydrochloride in the concentrations analysed it is now confirmed that patients will receive the correct amount of octreotide acetate. This will negate the need to infuse octreotide acetate and diamorphine hydrochloride separately, avoiding the use of two syringe drivers.

References:

Fielding H, Kyaterekera N, Skellern GG, et al. The compatibility and stability of octreotide acetate in the presence of diamorphine hydrochloride in polypropylene syringes. Palliat Med. 2000;14(3):205-207. doi:10.1191/026921600666997498

Tolerability of Continuous Subcutaneous Octreotide Used in Combination with Other Drugs
Design	Prospective cohort study N= 44
Objective	To assess tolerability, compatibility, and efficacy of octreotide administered by continuous subcutaneous infusion alone or in combination with other drugs
Study Groups	All patients (N= 44)
Inclusion Criteria	Patients with advanced cancer administered octreotide alone or in combination with other drugs
Exclusion Criteria	N/A
Methods	Patients were administered octreotide in varying dosages and durations of time, as well as with different concurrent drugs (including morphine, haloperidol, prochlorperazine, buprenorphine, metoclopramide, ondansetron, and chlorpromazine). Octreotide was administered through a 10 or 20 mL syringe driver at 1 mm/hour. Concentrations were variable based on clinical need, ranging from 0.04 to 0.06 mg/mL. Preservative-free saline solution was added to the syringe to complete volume up to 10 mL. The continuous infusion system operated for 48 hours without need for refilling.
Duration	Up to 48 hours
Outcome Measures	Tolerability, compatibility
Baseline Characteristics		All patients (N= 44)
	Age, years	62
	Female	46%
	Duration of infusion, days	18.2
	Mean number of drugs mixed in same syringe	2.56
Results	Endpoint	All patients (N= 44)
	Mean number of drugs mixed in same syringe	2.56
	Injection site irritation	None observed
	Precipitation, per visual inspection after 48 hours at room temperature	None observed
Adverse Events	N/A
Study Author Conclusions	In conclusion, continuous subcutaneous infusion of octreotide in combination with the majority of the drugs delivered by this route of administration in palliative care offers a safe, simple, locally tolerable alternative technique when oral medications cannot be used, permitting the control of distressing symptoms such as pain and vomiting in the patient's final days.
InpharmD Researcher Critique	This dated study did not assess efficacy or stability of any administered drug using assays or formal testing. Results were merely based on visual observation of injection site reactions and formation of precipitate, hindering any conclusive data that may be extrapolated.

References:

Mercadante S. Tolerability of continuous subcutaneous octreotide used in combination with other drugs. J Palliat Care. 1995;11(4):14-16.

Octreotide 50 mcg/mL Injection Compounding Formula
Ingredients (for 100 mL final product)	Octreotide acetate (equivalent to 5 mg octreotide) 5.3 mg
	Lactic acid 340 mg
	Mannitol 4.5 g
	Sodium carbonate qs pH 3.9 to 4.7
	Sterile water for injection qs 100 mL
Method of Preparation	Calculate the required quantity of each ingredient for the total amount to be prepared Weigh and/or measure each ingredient Dissolve octreotide acetate, lactic acid, and mannitol in approximately 90 mL of sterile water for injection Add sufficient sodium carbonate to adjust pH to 3.9 to 4.7 Add sufficient sterile water for injection to final volume, mix well Sterile filter into appropriate sterile containers Package and label
Packaging	Tight, light-resistant container; store in refrigerator
Stability	If no sterility testing is conducted, a beyond-use date of 24 hours may be used if stored at room temperature, 3 days under refrigeration, or 45 days in solid frozen state (-25 to -10 ºC or colder). If sterility testing program is in place, a beyond-use-date of up to 14 days can be used when stored under refrigeration.

References:

Allen LV. Octreotide 50-mcg/mL. Int J Pharm Compd. 2013;17(1):72.