OFIRMEV (acetaminophen IV)
• 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.
• 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.