OFIRMEV (acetaminophen IV)

Background: 1
•    Cadence Pharmaceuticals’ proprietary intravenous formulation of acetaminophen.
•    Same product was marketed in Europe since 2002 as Perfalgan (also under the name Acetavance) by Bristol-Meyers Squibb.
•    Cadence acquired the exclusive rights to OFIRMEV in the US and Canada in 2006.
•    NDA was filed in 2009

Paracetamol (Perfalgan) solution for infusion 2
1.    Therapeutic indication:  Short-term treatment of moderate pain, especially following surgery, and for short-term treatment of fever, when administration by intravenous route is clinically justified by an urgent need to treat pain or hyperthermia and/or when other routes of administration are not possible
2.    Dosage:  Adults: 1gm Q4H, max 4gm per day
Children: 15mg/kg up Q4H to 4 times a day, max dose: 60mg/kg/day
(3g/day children >=33kg or 2g/day for children with weight between 10 & 33kg)
Severe renal insufficiency (CrCL =30ml/min): Q6H
Hepatocellular insufficiency, chronic alcoholism, chronic malnutrition, dehydration: maximum 3g/day.
3.    Method of administration: IV infusion over 15 minutes.
Can be diluted with NS or D5W, but must be infused within 1 hour including the infusion time.
4.    Pharmacological properties:
    Pain relief: onset: 5-10 minutes after the start of infusion, peak is 1 hour, duration: 4-6 hours.
    Fever: onset: within 30 minutes, duration: 6 hours.
5.    Contraindications, DDI, S/E: similar to Tylenol.

Clinical Trial:
•    2 pivotal clinical trials for the treatment of acute pain in patients following orthopedic surgery
•    1 pivotal clinical trial for the treatment of fever
•    9 placebo-controlled clinical trials
•    4 active-controlled clinical trials
•    7 other safety or pharmacokinetic trials

1.  A Phase III, Multi-Center, Randomized, Double-blind, Placebo-Controlled 24 Hour Study of the Efficacy and Safety of Intravenous Acetaminophen in Abdominal Laparoscopic Surgery3
Trial number: NCT0064486
Duration: Nov 2007 – Nov 2008
Inclusion criteria: patients with pain intensity (PI) at least moderate on a 4-point categorical scale and >=40 and <=70mm on a 100mm visual analog scale.
Primary efficacy endpoint: weighted sum of PI differences over 24h comparing IV APAP 1g vs. the combined placebo group.

IV APAP (1g)     IV APAP (650mg)    Placebo
N (Total = 244)    92    42    110
Pain Intensity    Significantly reduced PI (p=0.0068)    Significantly reduced PI (p=0.0183)
Satisfactory rating to the treatment for their pain    More satisfactory than placebo

Time to meaningful pain relief     Shorter than placebo (p=0.0029)
Tolerability    Similar adverse event profile (including hepatic event) between IV APAP regimens and placebo

2.    A Randomized, Four-period, Crossover Pharmacokinetic trial 4
Trial number: NCT00564629
Subjects: 32 adult males
Treatment: IV Acetavance vs. oral acetaminophen
Result: IV Acetavance had comparable pharmacokinetics, pharmacodynamics and a similar side effect profile to oral acetaminophen

3.    A Randomized, Double-blind, Placebo Controlled, Single Dose, Phase III Trial 4
Trial number: NCT00493311
Subjects: healthy volunteers
Treatment: IV paracetamol or placebo following endotoxin-induced fever.
Result: fever significantly reduced over 6 hours in IV paracetamol group

Trouble in Getting Approval by FDA: 1
•    Deficiencies were observed during the FDA’s facility inspection of Cadence’s third party manufacturer.
•    No safety or efficacy issues were cited
•    No additional studies need to be conducted.
•    Cadence plans to request a meeting with the FDA to ensure the deficiencies have been addressed to meet the requirement for NDA approval.

Clinical Advantage of IV APAP:
•    Patients with N/V that can not tolerate PO formulation.
•    NPO patients
•    Neutropenic patients who cannot use suppository formulation.
•    Better side effects profile compared to IV NSAID or opioid.
•    An excellent anti-pyretic or mild analgesic agent for oncology patients.

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Posted on มกราคม 24, 2013, in บทความ. Bookmark the permalink. ใส่ความเห็น.


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