Perfalgan Va

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In Post OperativePain Management

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1. Benhamou D, Berti M, Brodner G et al. Postoperative Analgesic Therapy Observational Survey (PATHOS) : A practice pattern study in 7 central/southern European countries. Pain 2008,

136:134-141. 2. Stephens J, Laskin B, Pashos C et al. The burden of acute postoperative pain and the potential role of the COX-2-specific inhibitors. Rheumatol 2003;42(suppl 3): iii40-

iii52. 3. Apfelbaum L.J et al., Postoperative Pain Experience: Results from a National Survey Suggest Postoperative Pain Continues to Be Undermanaged. Anesth Analg 2003; 97:534-40

4. Commission on the provision of surgical services. Report of the working party on pain after surgery. London: The royal college of surgeons of England, The college of Anaesthetists,

1990. 5.Lorenz M Fischer et al, Discontinuation of Nonsteroidal Anti-inflammatory Drug Therapy and Risk of Acute Myocardial Infarction. Anch Intern Med. 2004: 164:2472-2476 6. Andrew

Moore R et al, Nonsteroidal anti-inflammatory drugs ( NSAIDs), Cyclooxygenase-2 selective inhibitors(coxibs) and gastrointestinal harm: review of clinical trials and clinical practice. BMC

Musculoskeletal Disorders 2006, 7:79 7. Giannoudis P.V et al, Nonunion of the femoral diaphysis. J Bone Joint Surg 2000; 82-B: 655-8. 8. http ;//arthritis-symptom.com/arthritis

drugs/opioid.htm(1 to 8) 9. Timothy D Warner et al, Cyclooxygenase-3 (COX-3): Filling in the gaps toward a COX continuum? PNAS October 15,2002. Vol 99, No.21: 13371-13373

10. Chandrashekaran .N.V et al, COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression. PNAS. Oct

15,2002, Vol 99, No.21, 13926-13931 11. Olivier Malaise et al, Intravenous paracetamol: a review of efficacy and safety in therapeutic use. Future Neurol 2007. 2(6), 673-688. 12. I Power,

Recent advances in postoperative pain therapy. BJA 2005, 95 (1): 43-51 13. Duggan S.t et al, Intravenous Paracetamol, Drugs 2009, 69(1) :101-113. 14. V. Piguet et al, Lack of

acetaminophen ceiling effect on R-III nociceptive flexion reflex. Eur J Clin Pharmacol 1998, 53:321-324. 15. M Depre et al, Tolerence and pharmacokineticsof propacetamol, a paracetamol

formulation for intravenous use. Fundam Clin Pharmacol 1992, 6: 259 – 262. 16. Bannwarth .B.et al, Plasma and cerebrospinal fluid concentration of paracetamol after a single intravenous

dose of propacetamol. Eur J Clin Pharmacol 1992, 34: 79-81. 17. Perfalgan Product Monograph, India 2009. 18. India Product Insert, 2009. 19. Oscier C.D et al, Peri-operative use of

paracetamol. Anaesthesia, 2009, 64:65-72. 20. James C. Crews, Multimodal Pain Management Strategies for Office-Based and ambulatory procedures. JAMA, Aug 2002,Vol288. No.5

21. Acute Pain Management: Scientific Evidence, Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine. Second edition 2005. 22. Henrich W.L et al,

Anal;gesics and Kidney, AJKD, 1996, Vol 27, No.1, 162-165 23. Tian J Zhou et al, Propacetamol versus ketorolac for the treatment of acute postoperative pain after total hip or knee

replacement. Anaesth Analg 2001, 92 1569-75 24. Hynes D et al, Analgesic efficacy of parentral paracetamol(propacetamol) and diclofenac in post-operative orthopedic pain. Acta

Anaesthesiol Scand 2006: 50: 374-381. 25. Hugo Van Aken et al, Assessing Analgesia in single and repeated administrations of propacetamol for postoperative pain: Comparison with

Morphine after Dental Surgery. Anesth Analg 2004: 98:159-65. 26. Alhashemi J.A et al, Intravenous acetaminophen Vs oral ibuprofen in combination with morphine PCIA after Cesarean

delivery. Can J Anesth 2006, 53:12: 1200-1206. 27. Lolter Cattabriga et al, Intravenous paracetamol as adjunctive treatment for postoperative pain after cardiac surgery: a double bling

randomized controlled trial. Eur J of Cardio-thoracic surgery 2007, 32:527-531. 28. Kehlet H et al, Multimodal strategies to improve surgical outcome. The American Journal of Surgery

2002, 183:630-641. 29. Peduto V.A et al, Efficacy of propacetamol in the treatment of postoperative pain. Acta Anaesthesiol Scand 1998: 42: 293-298. 30. Sinatra R.s et al, Efficacy and

safety of single and repeated administration of 1 gram Intravenous Acewtaminophen Injection for pain management after Major Orthopedic Surgery.Anaesthesiology 2005: 102:822-31.

31. Flouvant B et al, Bioequivalence study comparing a new paracetamol solution for injection and propacetamol after single intravenous infusion in healthy subjects Int J Clin Pharmacol

Therapeutics. 2004;42(1):50-7

References:

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2009

Evidence suggests that post-operative pain is sub-optimally 1 2managed and is not limited to the immediate recovery period

CONSEQUENCES OF INADEQUATE PAIN CONTROL FOLLOWING SURGERY ARE4

SIGNIFICANT AND CAN RESULT IN IMMEDIATE AND LONG-TERM COMPLICATIONS

• Hypoxaemia/atelectasis/pneumonitis

• Deep venous thrombosis/pulmonary embolus

• Delayed recovery of bowel function

• Myocardial Ischemia and infarction

• Urinary retention

• Residual psychological trauma

3Approximately 80% surgical patients have inadequate pain relief

*Post operative pain management

In POPM*

Yourst 1 Step

Matters

Limitations of Current Analgesics Agents in POPM*

Limitations of NSAID’s5

Inhibition of Platelet aggregation

Increased incidence of Gastrointestinal6ulcers

7Impairment of Bone healing

6Increased Cardiovascular risk

In POPM*

Yourst

1 StepMatters


4,8Limitations of Opioids

Restlessness or Nervousness

Respiratory depression Hypotension

Constipation

Urinary retention

Severe weakness

Nausea and Vomiting

Stomach Pain or Cramps

1g IVUnleash the True Power & Potential of Unique I.V. Para Infusioncetamol

NSAIDs

Inhibition ofperipheral and

centralCox-1/Cox-2

(inhibition10,12

of PG synthesis)Interaction withserotoninergic

descending11inhibitory pathway

Inhibition of9central Cox-2 ,

10 Cox-3 (Inhibition of PG synthesis)

Opioids

Mode of Action of Analgesics

Activationof Opioid

12receptors

IV 13 ACTS AT BOTH, CENTRAL & PERIPHERAL COMPONENTS OF PAIN PATHWAY

1g IVUnleash the True Power & Potential of Unique I.V. Para Infusioncetamol

15IMPROVED PHARMACOKINETICS VS ORAL PROPACETAMOL

*p<0.0001

Bioavailability

T max

C max

AUC0-

IV propacetamol

100%

15 min*

12.72 µg/ml*

25.53 µg/ml.h*

Oral propacetamol

82.2%

1 h 28 min*

5.49 µg/ml*

21.04µg/ml.h*

Higher peak plasma paracetamol14concentrations

Higher paracetamol concentrations14cross the blood-brain barrier

14Heightened antinociceptive effects

Plasma and CSF paracetamol concentrations following a single IV dose of16paracetamol (2g) in patients with nerve root compression pain

CSF concentrations

Plasma concentrations

Para

ceta

mol

(µ

g/m

l)

0

2

4

6

8

10

12

14

16

0 2 4 6 8 10 12

Time (hrs)

3(adapted from Bannawarth B et al)

The Analgesic effect of Paracetamol is probablydependent on the Rate & Amount of active drug

14 reaching the CNS

lacks the Ceiling effect observed with oral propacetamol & exerts a Dose-

14dependent central Antinociceptive effect

IV

31Paracetamol 1g IV given as propacetamol 2g IV : bio-equivalent formulations therapeutically equivalent

1g IV

17Oxygen-Free Manufacturing Process

Preservative Free Solution pH Adjustment(5.5 for Max. Shelf-life)

Oxygen Free Manufacturing(Nitrogen & Argon gas + Cysteine

Hydrochloride Monohydrate)

Solubilization(Mannitol+Di sodium Phosphate)

(Terminal Sterilsation)

Characteristics of an Ideal Analgesic Agent in POPM*

1g IVUnleash the True Power & Potential of a Unique I.V. Para Infusioncetamol

Fast Onset of Action

Usage Flexibility

Support Balanced Analgesia

Usage in Wide Patient Type

Tolerability

Dosage Convenience

Characteristics18 5-10 Minutes19 Peri-operative

11Yes, Reducing Opioid Usage upto 46%

Yes

Yes

Ready to use Infusion

IV

IV 20,21is an effective analgesic for acute pain


1g IVComparable postoperative analgesic efficacy

27undergoing cardiac surgery against placeboCardiac Surgery: provides significant pain reduction in patients1g IV

Diclofenac 75mg IM

24Total Hip Arthroplasty

1g IV

, 2 Dose 5 hours apart1g IV

26Cesarean Delivery

Perfalgan 1g IV is a reasonable alternative toIbuprofen 400mg Oral as an adjunct to morphine patient-

controlled analgesia after Cesarean delivery

Ibuprofen 400mg 6 hourly6 hourly1g IV

1g IV

25Dental Surgery

Morphine 10mg IMSingle Dose1g IV

Ketorolac 30mg IV

1g IV

23Total Hip or Knee Replacement

Single Dose1g IV

Balanced analgesia improves28postoperative pain relief through:

• synergisticAdditive or effects of multiple agents

• Reduction of side-effects (e.g. opioid sparing)

1g IVAn effective partner in balanced Analgesia

Sparing effect*29

43-46%

Morphine

1g Ø

: proven opioid-sparing effect

0

4

8

12

16

20 i.v. paracetamol (n=42)

placebo (n=47)

***p<0.001

PCAboluses

(no.)

PCAdose(mg)

24-hour morphine consumption in terms of total PCAin mg and total number of boluses

Hip Arthroplasty

-46%of morphineconsumption

9

17 ***

9.4

17.6 ***

4g paracetamol saved 8mg of morphine over 24 hours, which is equal to a sparing effect of 43-46%31

Ø Paracetamol 1g IV given as propacetamol 2g IV : bio-equivalent formulations therapeutically equivalent*


HAS THE RECOGNIZED SAFETY PROFILE OF PARACETAMOL

• Not associated with increased Incidence of nausea, vomiting and respiratory depression30 observed with opioids

• Not associated with deleterious gastrointestinal, haematological and renal effects associated30

with NSAID’s and COX-2 inhibitors30• Few drug interactions and contra-indications

• Recommended by the National Kidney Foundation (US) as the non-narcotic analgesic of choice22 in patients with underlying renal disease

29Renal and Hepatic tolerance at therapeutic doses similar to placebo

30Historically low incidence of adverse events and drug interactions


Safety and Tolerability18

The overall of adverse events in Perfalgan patients to placebo within the clinical trial set1can be observed in the tables bellow.

Adverse events in adults-greater than 100% (observed in the clinical trial set)

Perfalgan %n=99

Placebo%n=102

Neurological Dizziness Headache Dystonia

Gastrointestinal Vomiting Dry mouth Diarrhea Constipation Nausea Dyspepsia Enlarged abdomen Gastrointestinal disorder Haematological Anemia Post operative hemorrhage

Hepatobiliary Gamma GT - Increase SGPT - increase

2.71.3-

4.0-

1.36.710.01.32.02.0

2.72.0

1.31.3

2.94.9-

2.9--

11.88.8---

6.9-

--

Psychiatric Insomnia

Skin and Appendage Injection site pain Injection site reaction Post-Operative site reation Pruritus

- 1.96

Respiratory Alveolitis Coughing

Endocrine/Metabolic Hyperglycemia Hypokalaemia

General Fatigue Fever Oedema-peripheral Chest pain

Perfalgan %n=99

Placebo %n=102

2.02.672.673.3

---

4.9

1.32.0

2.94-

1.31.3

--

1.59--

1.33

-5.9--

_Severe renal impairment (creatinine clearance<30ml/min) : 6 hourly dosing schedule


• Administrated as a 15-minute IV infusion• Available in 100ml clear glass vials in packs of 12 vials• No need to reconstitute

• Store at room temperature, below 30° C• Shelf life of 2 years

is convenient and ready-to-use in patients with IV line1g

It is important to consider the contribution of all paracetamol containing medications, includingnon-prescription, oral or PR forms of drug to this total daily paracetamol dose prior to administering

18Dosage Profile

Dosing Interval

Adults (›50kg)

O Hrs

1g 1g

4-6 Hrs

1g

12 Hrs

1g

18 Hrs Maximum Daily dose

4g

Perfalgan Va

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