Medical Preview: LORNOXICAM

Integrace

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Available Oxicams
Sudoxicam Piroxicam Tenoxicam Isoxicam Chlortenoxicam (Lornoxicam) Meloxicam

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Pharmacokinetic differences

Lornoxicam has a relatively short elimination half-life (35 hrs Vs approx 60 hrs for piroxicam & tenoxicam). This distinguishing feature of lornoxicam has been proposed as a possible advantage in terms of less risk of potential drug Sales Training Pain Reviews 1999; 6: 262278 accumulation and improved tolerability

Lornoxicam
Launched in 1997 Remarkable analgesic & anti-inflammatory potency in all animal models Highly potent {potency reflected by its usually low clinical dosing (8-16mg)}
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c-FOS Protein?
There is considerable evidence that expression of the nuclear protein c-fos encoded by the immediate early gene c-fos reflects the longer term intracellular changes associated with sustained nociceptive processing at the spinal cord level. At the level of the spinal cord, especially in the dorsal horn, c-fos protein expression provides an indirect marker of neuron involved in spinal nociceptive transmission

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Pain Reviews 1999; 6: 262278

Lornoxicam also inhibits PDGF

In addition to inhibiting COX activity potently, has also been demonstrated to inhibit dramatically the release of PDGF from human platelets in vitro

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Pain Reviews 1999; 6: 262278

What is PDGF?
IL-1

Conventional NSAIDs
Lornoxicam

PGE2

Whether lornoxicam has any special attributes in the management of RA is an issue that will become apparent only with accumulating clinical experience

Proliferation of
Inhibits Stimulates

PDGF

Synoviocytes

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PDGF: Platelet Derived Growth Factor

Pharmacokinetics (1)
After administration of lornoxicam 4 mg tablets to healthy volunteers, Cmax 280g/L within 2.5 hours Lornoxicam is rapidly absorbed from the gastrointestinal tract

The absolute bioavailability of lornoxicam is 90100%

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Pharmacokinetics (2)
Simultaneous intake of lornoxicam with meals
Reduces Cmax by approx 30% Tmax was increased from 1.5 to 2.3 hrs The absorption can be reduced by up to 20% SHOULD BE TAKEN BEFORE MEALS

Bioavailability following IM administration is 87%

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Pharmacokinetics (3)
Distribution: Plasma protein binding: 99.7 % Volume of distribution: 0.1-0.2 L/kg In synovial fluid,
Lornoxicam readily penetrates into perivascular spaces In pts with RA, synovial fluid : plasma AUC ratios is approx 0.5 after administration of 4 mg twice daily for 5 days

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Pharmacokinetics (4)
Metabolism: Extensively metabolized in liver, to inactive metabolite 5-hydroxy-lornoxicam Metabolized by cytochrome P450 2C9 Slow and rapid metabolisers exist for this drug

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Pharmacokinetics (5)
Excretion: Feces - 51% Renal - 42% Mean elimination half-life is 3 to 4 hours

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Drug drug interactions

Drug interactions of lornoxicam can be extrapolated from drug interactions of many other NSAIDs like ACE inhibitors, Lithium, Methotrexate, Sulphonylureas, diuretics, cimetidine , digoxin Lornoxicam has interactions with known inducers and inhibitors of CYP2C9 e.g. phenytoin, amiodarone, miconazole

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Contraindications/Precautions
Allergic to lornoxicam, or any of its excipients History of hypersensitivity reactions (bronchospasm, rhinitis, angioedema or urticaria) to other non-steroidal anti-inflammatory medicines, including, acetylicsalicylic acid History of gastro-intestinal bleeding, cerebrovascular bleeding Patients with bleeding and coagulation disorders Patients with active peptic ulceration or with a history of recurrent peptic ulceration Patients with severe liver or renal impairment Patient with thrombocytopenia Patients with severe or uncontrolled cardiac failure Pregnant or lactating

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Indications
Lornoxicam tablet is indicated for symptomatic treatment of pain and inflammation in osteoarthritis, rheumatoid arthritis, and other musculoskeletal inflammatory conditions like low back pain, ankylosing spondylitis, gouty arthritis Lornoxicam injection is indicated for the relief of postoperative pain or acute painful conditions requiring parenteral analgesic
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Dosage & Administration

For all patients the appropriate dosing regimen should be based upon individual response to treatment

For mild to moderate pain: The recommended dose of 8 mg to 16 mg per day given in 2 to 3 divided doses. The total daily dose should not exceed 16 mg
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Special populations
Pediatric Use Lornoxicam is not recommended for use in children under 18 years Pregnancy & Lactation No clinical data on exposed pregnancy & lactation are available for lornoxicam Geriatric Use No special dosage modification is required for elderly patients, unless renal or hepatic function is impaired Hepatic & renal Insufficiency For patients with hepatic/renal impairment the maximal recommended daily dose is reduced to 12 mg
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Adverse Reactions
Lornoxicam has a tolerability profile characteristics of NSAIDs, with gastro-intestinal disturbances i.e. abdominal pain, dyspepsia, nausea, vomiting being the most common events in clinical trials

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Clinical Studies
Lornoxicam has been evaluated in relief of acute pain arising from surgical procedures, low back pain, arthritis (OA & RA), sciatica, migraine
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Lornoxicam in OA
A double blind, multicentre, placebo controlled trial of lornoxicam in patients with osteoarthritis of the hip and knee

Oral lornoxicam 12 milligrams daily for 4 weeks has demonstrated efficacy superior to placebo in the treatment of patients with osteoarthritis of the hip or knee, as evidenced by significant decreases in pain relief and improvements in functional index scores
Annals of the Rheumatic Diseases 1992; 51: 238-242
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Lornoxicam in OA
Treatment withdrawal due to inadequate symptom relief:
30% - Placebo 15% - Lornoxicam 8mg 10% - Lornoxicam 12mg

Annals of the Rheumatic Diseases 1992; 51: 238-242

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Another study in OA
Lornoxicam 8 mg twice daily improved pain & functional disability in a long term (12-month) noncomparative study in 104 elderly (age >65 years) patients with OA of knee or hip Significant improvement was evident at 1 month & continued to improve throughout the study with Lequesne index & pain intensity scores (VAS) being reduced by 45% & 55% respectively
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Drugs 1996; 51(4): 639-57

Results

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Lornoxicam in RA
To evaluate the therapeutic action and safety of lornoxicam, a new non steroidal antiinflammatory drug, in 2 oral daily dose regimens of 8 and 16 mg in comparison with oral diclofenac 150 mg/day in patients with RA for 10 days
Reumatismo. 2002 Jul-Sep;54(3):238-42
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Results & Conclusions

Lornoxicam 8 and 16 mg/day showed a good therapeutic activity, comparable with diclofenac 150 mg/day. Two patients complained adverse events with diclofenac Lornoxicam 16 mg/day was associated with a more sharp action and a better tolerability than diclofenac in rheumatoid arthritis
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Lornoxicam-long term use in RA

Open trial was carried out on different dosage schedules of lornoxicam (4 or 8 mg bid and 4 mg tid) administered for 6-12 mths in 34 pts CONCLUSIONS: Lornoxicam presented a worth-while therapeutic action and a good tolerability in rheumatoid arthritis long term treatment
Sales Training Minerva Med. 2002 Aug;93(4):315-20

Lornoxicam in acute pain

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Lornoxicam GI safety
Gastrointestinal effects are common adverse effects associated with NSAIDs Study-1 Eighteen healthy male volunteers received lornoxicam 8 mg b.d. or naproxen 500 mg b.d. administered orally over two 7-day dosing periods Lornoxicam 8 mg b.d. caused significantly less mucosal injury than naproxen 500 mg b.d. in the stomach/duodenal bulb, as well as in the mid/distal duodenum

Sales Training Aliment Pharmacol Ther. 1996 Apr;10(2):151-6

Comparison with available molecules

Parameter MOA Lornoxicam Inhibitor of COX Well absorbed Absolute bioavailability upto 100% 50% (Ratio SF:PL AUC = 0.5) Diclofenac Inhibitor of COX Piroxicam 50 times lesser COX inhibition Well absorbed Meloxicam Selective COX II than other oxicams Bioavailability 89%

PK

Bioavailability 50% First pass metabolism 70%

synovial fluid Dosage

40-50%

40%

8-16 mg 50 mg TDS/ 100 mg 20 mg OD divided doses OD (BD/single dose injection)

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7.5mg OD

Parameter Lornoxicam T1/2 3-4 hrs

Diclofenac 1-2 hrs

Piroxicam 60 hrs

Meloxicam 20 hrs

In comparison with established oxicams, lornoxicam has a relatively short elimination half-life This distinguishing feature of lornoxicam has been proposed as a possible advantage in terms of less risk of potential drug accumulation and improved tolerability
Clinical Efficacy Comparable to diclofenac, tramadol and morphine. Better than naproxen Well tolerated than diclo, tramadol and piroxicam GI safety comparable to coxibs Comparable to lornoxicam, Better analgesia than piroxicam, meloxicam More ADR than lornoxicam, meloxicam. Comparable to Piroxicam
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Lesser than diclofenac

Comparable to piroxicam, naproxen Lesser analgesic than diclofenac,

Adverse event profile

Comparable to Well tolerated than diclofenac diclo, piroxicam

USP
More potent inhibitor of COX as compared to tenoxicam and piroxicam Proved clinical equivalency to Morphine, diclofenac, tramadol and naproxen Lesser adverse effects as compared to morphine, diclofenac, tramadol and naproxen Available as Parenteral preparation GI tolerance comparable to rofecoxib

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