Linplant Clinical Pack - Product Instructions
(For Human Therapy)

The following sections contain helpful information on the proper uses of the sustained release insulin implant. As the severity of diabetes mellitus, health status, response to insulin, diet, etc. vary amongst individuals, it is IMPERATIVE that the subject should be closely monitored during the initial phase of the implant therapy, until routines have become familiar.

A) Contents:

20 sterile implants in small vials.
1 pair of sterile 12G hypodermic needle with stylet.
1 16G needle for piercing.
1 pair of sterile gloves.
3 packages of alcohol wipes.
1 first-aid adhesive bandage tape.

B) Recommended Implantation Sites:

The sustained release insulin implants should be inserted subcutaneously at any convenient sites, e.g. under abdominal skin, upper portion of lower arm, inner thigh region, etc.

C) Anesthesia:

Use local or topical anesthetics for dermal analgesia, if the subject appears apprehensive at the approaching insertion procedure.

D) Implantation:

1) Open an alcohol wipe provided and use the wipe to prepare the skin surface where implant insertion is intended. The additional packages are spares, in case of need.
2) Peel open the glove package from the top edges carefully. Then unfold completely the inner wrapper containing the sterile gloves and spread the paper on a sturdy table. DO NOT touch the sterile inside surface of the wrapping paper.
3) Unscrew and discard the tube cap. Empty the sterile implant inserter, the sterile 16G disposable hypodermic needle, and the small vials containing the sterile insulin implants carefully onto the sterile surface of the wrapping paper for the gloves already spread on the table.
4) Put gloves on ASEPTICALLY.
5) Open the STERILE small vial and empty all 20 of the insulin implants onto the center groove of the sterile glove wrapping paper.
6) Count the number of implants required (as calculated below) and put the implants not required back into the sterile small vial where they were taken from.
IMPORTANT!
* Check the accuracy of the dose calculation blow again, with respect to the weighing units used - kg or lbs
**Check the number of implants required and balance the count with the number of implants returned to the small vial. The total count should be 20.
7) Pinch and lift the skin with the thumb and index fingers, then use the sterile 16G disposable needle to puncture the skin at a ~30 degree angle to the flat skin surface, and then withdraw the needle.
8) Pull out the stylet by the end with the coloured plastic ball from the implant inserter and put it on the sterile inside surface of the glove package laid flat on the table. Carefully, advance the inserter subcutaneously through the skin orifice just created to a distance of at least 4 cm. (1.5 inches).
9) Load 5 implants into the open end of the inserter, and push the implants completely to the end of the subcutaneous tunnel gently and slowly by using the stylet.
10) Pull the inserter back about 0.5 cm (0.24 inch), then load and insert the next 5 implants as just described above.
11) Check the number of remaining implants as required once again, before completing the implantation. Pull the inserter back a further 0.5 cm before loading and inserting the implants as before.
12) Gently press on the skin over the tip of the inserter before withdrawing the stem of the inserter slowly. A rapid withdrawal, especially with the stylet still in the lumen of the inserter, is likely to create a vacuum which may lead to the extrusion of the last few of the inserted implants.

E) Dosages:

1) Weigh the subject with a minimum of light clothing on, and record the body weight with the unit shown on the scale. Select the starting dose as recommended in the following steps.
2) IMPORTANT! If the total body weight is taken in KILOGRAMS, then, for insulin-dependent (Type I) subjects:
Number of Implants Required = Body Wt. (kg) × 1 implant/4 kg
(If the total body weight is recorded in lbs, the number of implants required should be calculated by using the factor of 1 implant/8.8 lbs with the total body weight.)
3) If the recommended daily dose of insulin derived from the sustained release implants (i.e., number of implants × 2 U/24 hr/implant) is substantially lower than the regular total daily injection dose for an insulin-dependent subject, then insert a number of implants which will provide a total daily release equivalent to 50% of the daily injection dose. If required, insert 2 additional implants close to the other implants every 3 days until morning preprandial blood glucose test shows a level of around 4 mmol/L. DO NOT attempt the implant if the total daily injection dose is >80 U for any individual.
4) For an insulin dependent subject taking 3 regular meals with snacks in-between and moderate physical activity, the optimal implant dose (i.e. basal dose) should give a preprandial blood glucose level of ~4 mmol/L and postprandial blood glucose level of <14 mmol/L for <3 hr. Fluctuations in the blood glucose level, especially in the first few days, will vary with different individuals and should be expected.

F) Aftercare:

1) The tiny skin defect after the insertion will soon contract and requires no suturing or clips for closure. However, the placement of a first aid adhesive bandage over the skin defect will help prevent topical infection.
2) Since the implant releases a basal dose continuously over the 24-hr. day, it is advisable to avoid extremes in food intakes and physical activities, unless under qualified supervision.
3) The sustained release may potentiate the insulin action, especially in new recipients of implant therapy. Therefore, until the routines are established, it is advisable to monitor the subject closely or to encourage frequent self-monitoring during the first 3 days after implantation.
4) If hyperglycemia seems to persist due to less than optimal dose given, thus, it may be desirable to test whether the implants are releasing insulin. Delay the breakfast for a few hours and then test the glucose. The preprandial blood glucose should be <10 mmol/L.

G) Precautions:

1) Segments broken from an implant which are longer than 1 mm in length will not result in drastic changes in insulin release rate because the shortest distance to the center of the implant remains >1 mm. However, the implants should not be broken intentionally. Discard any broken implants.
2) Each tiny implant can withstand >2 kg of compressive stress applied vertically. Therefore, it is unlikely that when imbedded subcutaneously in the soft tissue, an implant will fracture upon moderate, blunt impact. However, the implant should not be placed at or near stress or weight bearing locations on the body.
3) In some subjects, minor subcutaneous hemorrhage may result in a small, unsightly bruise over the implant site after a few days. Although the implant release rate is not affected, the appearance of the bruise may be objectionable to some. If the bruise also results at another site after the next implantation, do not attempt further implant therapy.
4) Do not compress and rub the skin over the implant site continuously because this action will enhance the implant release rate abruptly. However, do not attempt to use this feature to obtain a bolus, as the rate of abrupt enhanced release may not be predictable.
5) Unless there are no other recourses, the retrieval of the tiny subcutaneous implants should NOT be contemplated.

H) Next Implantation:

1) At the specified release rate of ~2 U/24 hr/implant, there is enough insulin in each implant to last for 60 days. However, between day 50 and 55, the usual symptoms of postprandial hyperglycemia may begin to intensify gradually, and preparations for the next implantation should be considered. if it is impractical to see the implant recipient on a regular basis, then schedule a visit for the morning of day 56 and advise the individual to refrain from any food intakes during that morning.
Only when the morning preprandial blood glucose test shows a level of >12 mmol/L is the insertion of new implants recommended. Without insulin from the implant, the morning preprandial blood glucose level of an insulin-dependent subject exceeds 18 mmol/L.
2) The selection of another site is strongly advised for the next implantation, as prolonged sustained release of insulin at a particular location may lead to lipohypertrophy.
3) The removal of the implants after the depletion of insulin is not necessary, as the remnants will be absorbed in a few weeks.

I) Complications:

1) Inadvertent trace contamination, by whatever causes, may result in the development of an abscess at the implantation site in 1 to 2 weeks. The insulin release may then appear to cease suddenly. Unless under qualified medical supervision, the draining of the palpable, soft and nodular abscess should not be attempted. When undisturbed, the abscess will eventually recede, however, if there is any implant remnants still present by then, the bits may gradually self-extrude through the skin in a few weeks.
2) Moderate over-dose as manifested by sustained periods of CONTINUOUS mild hypoglycemia may lead to and/or aggravate hypertension.

J) Warnings:

1) The implant therapy for subjects with insulin-dependent diabetes should be considered only under the supervision of an experienced medical practitioner familiar with the treatment of Type I diabetes mellitus.
2) Injections of preprandial supplemental insulin doses in conjunction with implant therapy should be undertaken strictly at the recommendation of a practitioner.
3) The implant therapy is NOT recommended:
(a) for pre-pubertal, adolescent, or geriatric subjects,
(b) during pregnancy or lactation,
(c) when there are frequent gastrointestinal disturbances due to whatever causes,
(d) with concurrent anti-coagulant therapy or existing clotting disorders, and
(e) whenever insulin therapy is contra-indicated.
4) Hypoglycemia may occur even with the recommended doses if the usual frequency and amount of food intake are greatly reduced due to whatever other causes, e.g., dieting, supplemental medications, travel, other ailments, mental disorder, etc.

K) Storage:

Keep at room temperature. No Refrigeration Required.

L) Product Information:

Composition: Human insulin (recombinant DNA origin) in micro-recrystallized palmitic acid.
Weight: 26 ± 2 mg/implant.
Dimension: 2 mm in diameter, 7 mm in length (insertable by 12 gauge hypodermic needle).
Release Rate (basal dose only): ~2 U/24 hr/implant for ~56 days subcutaneously (erodible in vivo).
Dosage: 1 implant/4 kg (or per 8.8 lbs) of body weight.
Indication: Replacement therapy in treatment of diabetes mellitus.

Caution: Do not immerse in alcohol.

MADE IN CANADA
CANADIAN PATENT 1 257 199
U.S. PATENT 5 110 595 and others