Ligofragmin

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Overdose

The anticoagulant effect (i.e. prolongation of the APTT) induced by Ligofragmin is inhibited by protamine. Since protamine itself has an inhibiting effect on primary haemostasis it should be used only in an emergency. The prolongation of the clotting time induced by Ligofragmin may be fully neutralised by protamine, but the anti-Factor Xa activity is only neutralised to about 25-50%. 1 mg of protamine inhibits the effect of 100 IU (anti-Factor Xa) of Ligofragmin. Protamine should be given by intravenous injection over approximately 10 minutes.

Contraindications

Known hypersensitivity to Ligofragmin or other low molecular weight heparins and/or heparins e.g. history of confirmed or suspected immunologically mediated heparin induced thrombocytopenia (type II); acute gastroduodenal ulcer; cerebral haemorrhage; known haemorrhagic diathesis or other active haemorrhage; serious coagulation disorders; acute or sub-acute septic endocarditis; haemorrhagic pericardial effusion and haemorrhagic pleural effusion; injuries to and operations on the central nervous system, eyes and ears.

In patients receiving Ligofragmin for treatment rather than prophylaxis, local and/or regional anaesthesia in elective surgical procedures is contra-indicated with high doses of dalteparin (such as those needed to treat acute deep-vein thrombosis, pulmonary embolism, and unstable coronary artery disease).

In cancer patients with body weight < 40kg at time of venous thromboembolic event, Ligofragmin should not be used for extended treatment of symptomatic VTE and prevention of its recurrences due to lack of data.

Dalteparin should not be used in patients who have suffered a recent (within 3 months) stroke Unless due to systemic emboli.

Incompatibilities

Not applicable.

Undesirable effects

About 3% of the patients having had prophylactic treatment reported side-effects.

The reported adverse reactions, which may possibly be associated to dalteparin sodium, are listed in the following table by system organ class and frequency group: common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10 000).

System Organ Class

Frequency

Adverse reactions

Blood and lymphatic system disorders

Common

Mild thrombocytopenia (type I), which usually is reversible during the treatment

Not Known*

Immunologically-mediated heparin-induced thrombocytopenia (type II, with or without associated thrombotic complications)

Immune system disorders

Uncommon

Hypersensitivity

Not Known*

Anaphylactic reactions

Nervous system disorders

Not Known*

Intracranial bleeds have been reported and some have been fatal

Cardiac disorders

Not Known*

Prosthetic cardiac valve thrombosis

Vascular disorders

Common

Haemorrhage

Gastrointestinal disorders

Not Known*

Retroperitoneal bleeds have been reported and some have been fatal

Hepatic and biliary disorders

Common

Transient elevation of transaminases

Skin and subcutaneous tissue disorders

Uncommon

Urticaria, pruritus

Rare

Skin necrosis, transient alopecia

Not Known*

Rash

General disorders and administration site conditions

Common

Subcutaneous haematoma at the injection site

Pain at the injection site

Injury, Poisoning and Procedural Complications

Not Known*

Spinal or epidural hematoma

*(cannot be established from available data)

The risk of bleeding is depending on dose. Most bleedings are mild. Severe bleedings have been reported, some cases with fatal outcome.

Heparin products can cause hypoaldosteronism which may result in an increase in plasma potassium. Rarely, clinically significant hyperkalaemia may occur particularly in patients with chronic renal failure and diabetes mellitus.

Long term treatment with heparin has been associated with a risk of osteoporosis. Although this has not been observed with dalteparin, the risk of osteoporosis cannot be excluded.

Paediatric population

Frequency, type and severity of adverse reactions in children are expected to be the same as in adults. The safety of long term dalteparin administration has not been established.

Reporting of suspected adverse reactions

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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

Preclinical safety data

The acute toxicity of dalteparin sodium is considerably lower than that of heparin. The only significant finding, which occurred consistently throughout the toxicity studies after subcutaneous administration of the higher dose levels was local haemorrhage at the injection sites, dose-related in incidence and severity. There was no cumulative effect on injection site haemorrhages.

The haemorrhagic reaction was reflected in dose related changes in the anticoagulant effects as measured by APTT and anti-Factor Xa activities.

It was concluded that dalteparin sodium may have an osteopenic effect at very high concentrations, and that this effect is less than that of unfractionated heparin at equivalent doses.

The results revealed no organ toxicity irrespective of the route of administration, doses or duration of treatment. No mutagenic effect was found. No embryotoxic or teratogenic effects and no effect on fertility reproductive capacity or peri- and postnatal development was shown.

Therapeutic indications

Treatment of venous thromboembolism (VTE) presenting clinically as deep vein thrombosis (DVT), pulmonary embolism (PE) or both.

Patients with solid tumours: Extended treatment of symptomatic venous thromboembolism (VTE) and prevention of its recurrence.

Pharmacodynamic properties

ATC Code BO1 AB 04: Antithrombotics

Dalteparin sodium is a low molecular weight heparin fraction (weight average molecular weight of 6000 Daltons (range between 5,600 and 6,400 Daltons)) produced from porcine-derived heparin sodium.

Mechanism of action

Dalteparin sodium is an antithrombotic agent, which acts mainly through its ability to potentiate the inhibition of Factor Xa and thrombin by antithrombin. It has a relatively higher ability to potentiate Factor Xa inhibition than to prolong plasma clotting time (APTT).

Pharmacodynamic effects

Compared with standard, unfractionated heparin, dalteparin sodium has a reduced adverse effect on platelet function and platelet adhesion, and thus has only a minimal effect on primary haemostasis. Still some of the antithrombotic properties of dalteparin sodium are thought to be mediated through the effects on vessel walls or the fibrinolytic system.

Clinical efficacy and safety

The randomized, open-label, controlled, multicenter CLOT study (Randomized Comparison of Low-Molecular Weight Heparin Versus Oral Anticoagulant Therapy for Long Term Anticoagulation in Cancer patients with Venous Thomboembolism) compared dalteparin to standard oral anticoagulant (OAC) therapy in the long term treatment of venous thromboembolism (VTE) in 676 patients with active malignancy who had experienced an acute symptomatic VTE (deep venous thrombosis (DVT) and/or a pulmonary embolism (PE)).

Patients were randomized to one of two groups:

- dalteparin arm prescribed at 200 IU/kg/day administered by subcutaneous (SC) injections (maximum 18,000 IU/day) during 1 month, then approximately 150 IU/kg/day from 2nd - 6th month, or

- VKA arm prescribed during 6 months (target INR 2-3), preceded by SC dalteparin 200 IU/kg/day OD (maximum 18,000 IU/day) during 5 to 7 days.

The most frequent diagnoses were: tumors of the gastrointestinal tract and pancreas (23.7%), genitourinary tumors (prostate, testicle, cervix, uterus, ovary and bladder) (21.5%), breast (16.0%), lung (13.3%). 10.4% of patients had haematological malignancies ; 75.1% of patients had metastatic disease.

The index VTE event was DVT alone in nearly 70% and PE with or without DVT in 30% of patients.

The primary endpoint was the time to first recurrence of symptomatic VTE (DVT and/or PE) during 6 months.

A total of 27 patients of 338 (8.0%) in the dalteparin arm and 53 patients of 338 (15.7%) in the VKA arm experienced at least one of the events of the composite primary endpoint. A significant 52% risk reduction in VTE recurrence at 6 months was seen with dalteparin (RR= 0.48, 95% CI [0.30-0.77], p=0.0016).

In the dalteparin arm, 19 patients (5.6%) experienced at least one episode of major bleeding compared to 12 patients (3.6%) in the VKA arm. The cumulative probability of experiencing a major bleeding at 6 months was respectively 6.5% and 4.9%, respectively. Any bleeding occurred with a higher frequency in the VKA arm (18.5% VKA vs 13.6% dalteparin). The comparison of the cumulative probability of first bleeding episode for the 2 treatments was of statistical significance in favour of dalteparin treatment (p=0.0487).

There was no significant difference in mortality between the two groups in deaths at 6 and 12 months (131 vs. 137 and 190 vs. 194 in the dalteparin and VKA arms, respectively).

There was no significant difference in the assessment of Quality of Life between the two groups of treatment.

Paediatric population

There is limited safety and efficacy information on the use of dalteparin in paediatric patients. If dalteparin is used in these patients, anti-Xa levels should be monitored.

The largest prospective study investigated the efficacy, safety and relation of dose to plasma anti-Xa activity of dalteparin in prophylaxis and therapy of arterial and venous thrombosis in 48 paediatric patients (Nohe et al, 1999).

Nohe et al (1999) Study Demographics and Trial Design

Trial design

Patients

Diagnosis

Indication, Ligofragmin Dose, Target anti-Xa, Duration

Single-center, open label trial;

Age:

31 week preterm to 18 years

Arterial or venous thrombosis; PVOD; PPH

Prophylaxis:

Primary Therapy:

Secondary Therapy:

(n = 48)

(n = 10)

(n = 25)

(n = 13)

Gender:

32 males, 16 females

95 ± 52 anti-Xa IU/kg sc qd;

129 ± 43 anti-Xa IU/kg sc qd;

129 ± 43 anti-Xa IU/kg sc qd;

0.2 to 0.4 IU/mL

0.4 to 1.0 IU/mL

0.4 to 1.0 IU/mL

3-6 months

3-6 months

3-6 months

In this study, no thromboembolic events occurred in the 10 patients receiving dalteparin for thromboprophylaxis. In the 23 patients given dalteparin for primary antithrombotic therapy of arterial or venous thrombosis, complete recanalization was seen in 7/23 (30%), partial recanalization in 7/23 (30%) and no recanalization in 9/23 (40%). In the 8 patients administered dalteparin for secondary antithrombotic therapy following successful thrombolysis, recanalisation was maintained or improved. In the 5 patients receiving dalteparin for secondary therapy following failed thrombolysis, no recanalization was seen. Minor bleeding, reported in 2/48 children (4%), resolved after dose reduction. Patient platelet counts ranged from 37,000/μl to 574,000/μl. The authors attributed platelet counts below normal (150,000/μl) to immunosuppressive therapy. A reduction in platelet count > 50% of the initial value, a sign of heparin-induced thrombocytopenia type 2 (HIT 2), was not observed in any patient. For both prophylaxis and therapy groups, the dalteparin doses (anti-Xa IU/kg) required to achieve target anti-Xa activities (IU/ml) were inversely related to age (r2 = 0.64, P = 0.017; r2 = 0.13, P = 0.013). The predictability of the anticoagulant effect with weight-adjusted doses appears to be reduced in children compared to adults, presumably due to altered plasma binding.

Pharmacokinetic properties

Elimination

The half life following i.v. and s.c. administration is 2 hours and 3.5-4 hours respectively, twice that of unfractionated heparin.

Bioavailability

The bioavailability following s.c. injection is approximately 87 per cent and the pharmacokinetics are not dose dependent. The half life is prolonged in uraemic patients as dalteparin sodium is eliminated primarily through the kidneys.

Special Populations

Haemodialysis:

In patients with chronic renal insufficiency requiring haemodialysis, the mean terminal hal-life of anti-Factor Xa activity following a single intravenous dose of 5000 IU dalteparin was 5.7 ± 2.0 hours, i.e. considerably longer than values observed in healthy volunteers, therefore, greater accumulation can be expected in these patients.

Paediatric Population:

Infants less than approximately 2 to 3 months of age or < 5 kg have increased LMWH requirements per kg likely due to their larger volume of distribution. Alternative explanations for the increased requirement of LMWH per body weight in young children include altered heparin pharmacokinetics and/or a decreased expression of anticoagulant activity of heparin in children due to decreased plasma concentrations of antithrombin.

Name of the medicinal product

Ligofragmin

Qualitative and quantitative composition

Dalteparin Sodium

Special warnings and precautions for use

Do not administer by the intramuscular route. Due to the risk of haematoma, intramuscular injection of other medical preparations should be avoided when the twenty-four hour dose of dalteparin exceeds 5,000 IU.

Caution should be exercised in patients in whom there is an increased risk of bleeding complications, e.g. following surgery or trauma, haemorrhagic stroke, severe liver or renal failure, thrombocytopenia or defective platelet function, uncontrolled hypertension, hypertensive or diabetic retinopathy, patients receiving concurrent anticoagulant/antiplatelet agents (see Interactions Section). Caution shall also be observed at high-dose treatment with dalteparin (such as those needed to treat acute deep-vein thrombosis, pulmonary embolism, and unstable coronary artery disease).

Limited data are available regarding the safety and efficacy of antithrombotic therapy in patients with primary or metastatic tumours of the brain who develop concurrent thromboembolic events. There is a risk of fatal intracranial bleeding with use of anticoagulation in this category of patients. Therefore, if the treatment with Ligofragmin was considered, it should be monitored closely with regular re-assessment of the status of tumour involvement of the brain and other individual risks.

Thrombocytopenia, should it occur, usually appears within three weeks following the beginning of therapy. Therefore, it is recommended that the platelet counts are measured before starting treatment with Ligofragmin and monitored closely in first three weeks and regularly thereafter during the treatment. Special caution is necessary in rapidly developing thrombocytopenia and severe thrombocytopenia (<100,000/µl) associated with positive or unknown results of in-vitro tests for anti-platelet antibody in the presence of Ligofragmin or other low molecular weight (mass) heparins and/or heparin.

Ligofragmin induces only a moderate prolongation of the APTT and thrombin time. Accordingly, dosage increments based upon prolongation of the APTT may cause overdosage and bleeding. Therefore, prolongation of the APTT should only be used as a test of overdosage.

Monitoring Anti-Xa Levels

Monitoring of Anti-Xa Levels in patients using Ligofragmin is not usually required but should be considered for specific patient populations such as paediatrics, those with renal failure, those who are very thin or morbidly obese, pregnant or at increased risk for bleeding or rethrombosis.

Where monitoring is necessary, laboratory assays using a chromogenic substrate are considered the method of choice for measuring anti-Xa levels. Activated partial thromboplastin time (APTT) or thrombin time should not be used because these tests are relatively insensitive to the activity of dalteparin. Increasing the dose of dalteparin in an attempt to prolong APTT may result in bleeding.

Patients under chronic haemodialysis with dalteparin need as a rule fewer dosage adjustments and as a result fewer controls of anti-Xa levels. Patients undergoing acute haemodialysis may be more unstable and should have a more comprehensive monitoring of anti-Xa levels.

Patients with severely disturbed hepatic function, significant renal failure or chemotherapy induced thrombocytopenia may need a reduction in dosage and should be monitored accordingly.

If a transmural myocardial infarction occurs in patients where thrombolytic treatment might be appropriate, this does not necessitate discontinuation of treatment with Ligofragmin but might increase the risk of bleeding.

As individual low molecular weight (mass) heparins have differing characteristics, switching to an alternative low molecular weight heparin should be avoided. The directions for use relating to each specific product must be observed as different dosages may be required.

Interchangeability with other anticoagulants

Dalteparin cannot be used interchangeably (unit for unit) with unfractionated heparin, other low molecular weight heparins, or synthetic polysaccharides. Each of these medicines differ in their starting raw materials, manufacturing process, physico-chemical, biological, and clinical properties, leading to differences in biochemical identity, dosing and possibly clinical efficacy and safety. Each of these medicines is unique and has its own instructions for use.

Heparin can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium or taking potassium sparing drugs. The risk of hyperkalaemia appears to increase with duration of therapy but is usually reversible. Plasma potassium should be measured in patients at risk before starting heparin therapy and monitored regularly thereafter particularly if treatment is prolonged beyond about 7 days.

When neuraxial anaesthesia (epidural/spinal anaesthesia) or spinal puncture is employed, patients are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis. The risk of these events is increased by the use of indwelling epidural catheters or by the concomitant use of drugs affecting hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture. Patients should be monitored frequently for signs and symptoms of neurological impairment when anticoagulation is given in connection with epidural/spinal anaesthesia.

Insertion or removal of the epidural or spinal catheter should be postponed to 10-12 hours after dalteparin doses administered for thrombosis prophylaxis, while in those receiving higher therapeutic dalteparin doses (such as 100 IU/kg -120 IU/kg every 12 hours or 200 IU/kg once daily), the interval should be a minimum of 24 hours.

Should a physician, as a clinical judgement, decide to administer anticoagulation in the context of epidural or spinal anaesthesia, extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurologic impairment such as back pain, sensory or motor deficits (numbness and weakness in lower limbs) and bowel or bladder dysfunction. Nurses should be trained to detect such signs and symptoms. Patients should be instructed to inform immediately a nurse or a clinician if they experience any of these.

If signs or symptoms of epidural or spinal haematoma are suspected, urgent diagnosis and treatment may include spinal cord decompression.There have been no adequate studies to assess the safe and effective use of Ligofragmin in preventing valve thrombosis in patients with prosthetic heart valves. Prophylactic doses of Ligofragmin are not sufficient to prevent valve thrombosis in patients with prosthetic heart valves. The use of Ligofragmin cannot be recommended for this purpose.

At long-term treatment of unstable coronary artery disease, such as e.g., before revascularisation, dose reduction should be considered at reduced kidney function (S-creatinine > 150 μmol/l).

Paediatric population:

Clinical experience of treatment of children is limited. If dalteparin is used in children the anti-Xa levels should be monitored.

The administration of medications containing benzyl alcohol as a preservative to premature neonates has been associated with a fatal “Gasping Syndrome”.

Elderly patients (especially patients aged eighty years and above) may be at an increased risk for bleeding complications within the therapeutic dosage ranges. Careful clinical monitoring is advised.

Effects on ability to drive and use machines

Ligofragmin does not affect the ability to drive or operate machinery.

Dosage (Posology) and method of administration

Treatment of venous thromboembolism (VTE) presenting clinically as deep vein thrombosis (DVT), pulmonary embolism (PE) or both:

Adults

A single dose of Ligofragmin is administered subcutaneously, once daily according to the following weight ranges. Monitoring of the anticoagulant effect is not usually necessary.

Weight (kg)

Dose

< 46

7,500 IU

46-56

10,000 IU

57-68

12,500 IU

69-82

15,000 IU

83 and over

18,000 IU

Abbreviations: IU = International Unit

The single daily dose should not exceed 18,000 IU.

Simultaneous anti-coagulation with vitamin K antagonists can be started immediately. Treatment with Ligofragmin is continued until the prothrombin complex levels (Factor II, VII, IX and X) have decreased to a therapeutic level. At least five days of combined treatment is normally required.

Patients with solid tumours: Extended treatment of symptomatic venous thromboembolism (VTE) and prevention of its recurrence.

Month 1

Administer Ligofragmin 200 IU/kg total body weight subcutaneously (SC) once daily for the first 30 days of treatment. The total daily dose should not exceed 18,000 IU daily.

Body Weight (kg)

Dose (IU)

<46

7 500

46-56

10 000

57-68

12 500

69-82

15 000

83 and over

18 000*

* Maximum dose of 18, 000 IU was used in patient weighing up to 132 kg in the CLOT study.

In the case of chemotherapy-induced thrombocytopenia, Ligofragmin dose should be adopted as follows:

- In patients receiving Ligofragmin who experience platelet counts between 50,000 and 100,000/mm3, the daily dose of Ligofragmin should be reduced by 2,500 IU until the platelet count recovers to >100,000/mm3.

- In patients receiving Ligofragmin who experience platelet counts <50,000/mm3, Ligofragmin should be discontinued until the platelet count recovers above 50,000/mm3.

Months 2-6

Ligofragmin should be administered at a dose of approximately 150 IU/kg, subcutaneously, once daily using fixed dose syringes and the table shown below.

Body Weight (kg)

Dose (IU)

≤56

7 500

57 to 68

10 000

69 to 82

12 500

83 to 98

15 000

>99

18 000

Recommended duration of treatment is 6 months (first month of Ligofragmin treatment is included). Relevance of continuing treatment beyond this period will be evaluated according to individual risk/benefit ratio, taking into account particularly the progression of cancer. No data is available with dalteparin beyond 6 months of treatment in the CLOT study.

In the case of chemotherapy-induced thrombocytopenia, Ligofragmin dose should be adopted as follows:

- With platelet counts <50,000/mm3, Ligofragmin dosing should be interrupted until the platelet count recovers above 50,000/mm3

- For platelet counts between 50,000 and 100,000/mm3, Ligofragmin should be reduced as illustrated in the table below depending on the patient's weight. Once the platelet count has recovered to >100,000/mm3, Ligofragmin should be re-instituted at full dose.

Body Weight (kg)

Scheduled Ligofragmin Dose (IU)

Reduced Ligofragmin Dose (IU)

≤56

7 500

5 000

57 to 68

10 000

7 500

69 to 82

12 500

10 000

83 to 98

15 000

12 500

>99

18 000

15 000

Renal failure:

In the case of significant renal failure, defined as a creatinine clearance <30 ml/min, the dose of Ligofragmin should be adjusted based on anti-Factor Xa activity. If the anti-Factor Xa level is below or above the desired range, the dose of Ligofragmin should be increased or reduced respectively, and the anti-Factor Xa measurement should be repeated after 3-4 new doses. This dose adjustment should be repeated until the desired anti-Factor Xa level is achieved.

As an indication, on the basis of the data available in CLOT, the observed mean levels (min, max) between 4 and 6 hours after administration in patients without severe renal insufficiency were 1.11 IU anti-Factor Xa/ml (0.6; 1.88) and 1.03 IU anti-Factor Xa/ml (0.54; 1.70), respectively, on week 1 and 4 of dalteparin 200 IU/kg OD. Anti-Factor Xa activity determinations were conducted by the chromogenic method.

For patients with an increased risk of bleeding, it is recommended that Ligofragmin be administered according to the twice daily regimen detailed in the Summary of Product Characteristics for Ligofragmin 10,000 IU/1ml ampoules or Ligofragmin Multidose Vial.

Paediatric population

The safety and efficacy of dalteparin sodium in children has not been established.2 but no recommendation on a posology can be made.

Monitoring Anti-Xa levels in children

Measurement of peak anti-Xa levels at about 4 hours post-dose should be considered for certain special populations receiving Ligofragmin, such as children. For therapeutic treatment with doses administered once daily, peak anti-Xa levels should generally be maintained between 0.5 and 1.0 IU/mL measured at 4 hours post-dose. In the case of low and changing physiologic renal function such as in neonates, close monitoring of anti-Xa levels is warranted. For prophylaxis treatment the anti- Xa levels should generally be maintained between 0.2-0.4 IU/mL.

As with all antithrombotic agents, there is a risk of systemic bleeding with Ligofragmin administration. Care should be taken with Ligofragmin use in high dose treatment of newly operated patients. After treatment is initiated patients should be carefully monitored for bleeding complications. This may be done by regular physical examination of the patients, close observation of the surgical drain and periodic measurements of hemoglobin, and anti-Xa determinations.

Elderly

Ligofragmin has been used safely in elderly patients without the need for dosage adjustment.

Method of administration

By subcutaneous injection, preferably into the abdominal subcutaneous tissue anterolaterally or posterolaterally, or into the lateral part of the thigh. Patients should be supine and the total length of the needle should be introduced vertically, not at an angle, into the thick part of a skin fold, produced by squeezing the skin between thumb and forefinger; the skin fold should be held throughout the injection.

Special precautions for disposal and other handling

The Needle-Trap consists of a plastic needle “catcher” which is firmly attached to the syringe label. Together, these two components comprise the Needle-Trap (safety) feature. The Needle-Trap is designed to specifically help prevent accidental needle sticks following the proper administration of injectable medications.

The Needle-Trap requires specific actions by the user to “activate” the Needle-Trap, which will render the needle harmless after the injection is administered:

- The user grasps the tip of the plastic needle catcher and bends it away from needle shield.

- The needle shield is removed from the syringe.

- The injection is administered normally.

- The needle is removed from the patient. The Needle-Trap is activated by placing the plastic catcher against a hard, stable surface and with one hand, pivoting the syringe barrel upward against the needle forcing the needle into the catcher where it locks in place (an audible 'click” is heard when the needle is locked in the catcher). The needle is bent until the syringe exceeds a 45 degree angle with the flat surface to render it permanently unusable.

- The syringe is properly disposed of normally.