1. PMA Pharmaceuticals, Inc.
PHEN 601 ASSIGNMENT
DHRUV JAIN
Email Id:dj85@njit.edu
EXALGO
GENERAL INFORMATION:
a. Device Generic Name: hydromorphone
b. Device Trade Name :EXALGO
c. Company Name/Current Manufacturer: Mallinckrodt(the pharmaceutical business of Covidien)
d. Treatment for: Pain
DOSAGE FORM:
EXALGO (hydromorphone HCI) extended-release tablets (CII) is indicated for the management of pain in
opioid-tolerant patients severe enough to require daily, around-the clock, long-term opioid treatment
and for which alternative treatment options are inadequate. They come under different drug
concentrations like 8mg/day, 16mg/day and 32 mg/day
INDICATIONS FOR USAGE:
Patients considered opioid tolerant are those who are receiving, for one week or longer, at least 60 mg
oral morphine per day, 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral
hydromorphone/day, 25 mg oral oxymorphone/day or an equianalgesic dose of another opioid.
Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and
because of the greater risks of overdose and death with extended-release opioid formulations, we
reserve EXALGO for use in patients for whom alternative treatment options are ineffective, not
tolerated, or would be otherwise inadequate to provide sufficient management of pain.

2. CONTRADICTIONS
Exalgo is contraindicated in opioid non-tolerant patients, in management of mild pain or pain not
expected to persist, in patients with compromised respiratory function or in patients with narrowed or
obstructed gastrointestinal tract or with known hypersensitivity to any components including
hydromorphone hydrochloride and sulfites. Concurrent use of Exalgo with CNS depressants, including
alcohol, increases risk of respiratory depression, hypotension, and profound sedation, potentially
resulting in coma or death. It is also contraindicated in patients with acute or severe bronchial asthma.
SIDE EFFECTS
 blurred vision, double vision
 flushing (warmth, redness, or tingly feeling)
 nausea, vomiting, constipation, diarrhea, stomach pain
 dizziness, drowsiness
 dry mouth
 sweating
METHOD OF ACTION:
Hydromorphone, a semi-synthetic morphine derivative, is a hydrogenated ketone of morphine.
Hydromorphone is principally an agonist of mu-receptors, showing a weak affinity for κ-receptors.
Comparing relative binding affinity for mu-and κ-opioid receptors, hydromorphone binds more
specifically to mu-receptors than structurally related morphine. As an opioid agonist, the principle
therapeutic action of hydromorphone is analgesia. The precise mechanism of action of opioid analgesics
is not known but the effects are thought to be mediated through opioid-specific receptors located
predominantly in the central nervous system (CNS). Interaction with the mu-opioid receptor subtype is
believed to be responsible for most of hydromorphone's clinical effects. There is no intrinsic limit to the
analgesic effect of hydromorphone. Clinically, however, dosage limitations are imposed by the adverse
effects, primarily respiratory depression, sedation, nausea, and vomiting, which can result from high
doses.
DATE RELEASED ONTO THE MARKET:
Aug 27 2012
FDA approved Mallinckrodt's Exalgo (hydromorphone HCl) Extended-Release
Tablets 32 mg (CII) for Opioid-Tolerant Patients with Moderate-to-Severe chronic
pain
Mar 2 2010
FDA approved Exaglo (hydromorphone HCl) Extended-Release Tablets.(8 ,12,16 mg tablets)

3. CLINICAL DATA SUMMARY:
EXALGO was administered to a total of 2,524 patients in 15 controlled and uncontrolled clinical studies.
Of these, 423 patients were exposed to EXALGO for greater than 6 months and 141 exposed for greater
than one year.
A 12-week double-blind, placebo-controlled, randomized withdrawal study was conducted in opioid
tolerant patients with moderate to severe low back pain. A total of 447 patients were enrolled into the
open-label titration phase with 268 patients randomized into the double-blind treatment phase. The
adverse reactions that were reported in at least 2% of the patients are contained in Table 1.
Table 1: Number (%) of Patients with Adverse Reactions Reported in ≥ 2% of Patients with
Moderate to Severe Low Back Pain during the Open-Label Titration Phase or Double-Blind
Treatment Phase by Preferred Term
PREFERRED
TERM
OPEN-LABEL
TITRATION
PHASE
EXALGO
(N=447)
DOUBLE-BLIND
TREATMENT PHASE
EXALGO
(N=134)
PLACEBO
(N=134)
Constipation 69 (15) 10 (7) 5 (4)
Nausea 53 (12) 12 (9) 10 (7)
Somnolence 39 (9) 1 (1) 0 (0)
Headache 35 (8) 7 (5) 10 (7)
Vomiting 29 (6) 8 (6) 6 (4)
Pruritus 21 (5) 1 (1) 0 (0)
Dizziness 17 (4) 3 (2) 2 (1)
Insomnia 13 (3) 7 (5) 5 (4)
Dry Mouth 13 (3) 2 (1) 0 (0)
Edema Peripheral 13 (3) 3 (2) 1 (1)
Hyperhidrosis 13 (3) 2 (1) 2 (1)
Anorexia/Decreased
Appetite 10 (2) 2 (1) 0 (0)
Arthralgia 9 (2) 8 (6) 3 (2)
Abdominal Pain 9 (2) 4 (3) 3 (2)
Muscle Spasms 5 (1) 3 (2) 1 (1)
Weight Decreased 3 (1) 4 (3) 3 (2)

4. Table 2: Number (%) of Patients with Adverse Reactions Reported in ≥ 2% of Patients with Chronic
Pain Receiving EXALGO in 14 Clinical Studies by Preferred Term
PREFERRED TERM
ALL PATIENTS
(N=2,474)
Constipation 765 (31)
Nausea 684 (28)
Vomiting 337 (14)
Somnolence 367 (15)
Headache 308 (12)
Asthenia/Fatigue 272 (11)
Dizziness 262 (11)
Diarrhea 201 (8)
Pruritus 193 (8)
Insomnia 161 (7)
Hyperhidrosis 143 (6)
Edema Peripheral 135 (5)
Anorexia/Decreased Appetite 139 (6)
Dry Mouth 121 (5)
Abdominal Pain 115 (5)
Anxiety 95 (4)
Back Pain 95 (4)
Dyspepsia* 88 (4)
Depression 81 (3)
Dyspnea 76 (3)
Muscle Spasms 74 (3)
Arthralgia 72 (3)
Rash 64 (3)
Pain in Extremity 63 (3)
Pain 58 (2)
Drug Withdrawal Syndrome 55 (2)
Pyrexia 52 (2)
Fall 51 (2)
Chest pain 51 (2)

5. SALES SUMMARY:
When Exalgo was first launched in April 2010, Covidien's CEO believed the drug had peak sales in the
$200 million range. He confirmed this only last year. Covidien dedicated 275 sales reps to the product.
However, paramount to achieving that level of sales is the introduction of the 32mg dose. The 32mg
dose puts Exalgo in a better competitive position to effective take market share from hydromorphone
immediate release formulations and Opana-ER, an extended release oxymorphone product.Zalicus Inc.
(Nasdaq Capital Market: ZLCS) is a biopharmaceutical company that discovers and develops novel
treatments for patients suffering from pain. Zalicus recognized $6.7 million in royalty revenue from
Mallinckrodt based on Exalgo net sales for the year ended December 31, 2013 and Zalicus has
recognized a total of $16.0 million in royalty revenue from Exalgo through December 31, 2013 since its
commercial launch in April 2010. Zalicus sold all rights to future royalties on sales of Exalgo to
Mallinckrodt in January 2014.
ORIGINAL BUSINESS CASE TO GET DRUG ON TO THE MARKET:
Hydromorphone is a well-characterized potent opioid analgesic that has been used in the United States
for over 80 years. Immediate release formulations of hydromorphone are approved and available for
treatment of both acute and chronic pain conditions. However, the short duration of action of these
formulations necessitate taking these products at least every 4 to 6 hours. For patients with chronic
pain, availability of a long acting formulation will improve convenience and perhaps compliance. In
comparison to other potent opioids, hydromorphone has the additional advantages of having a low
likelihood of pharmacokinetic drug-drug interactions. EXALGO would provide healthcare professionals
with another extended release formulation option for the treatment of chronic pain; many of the
existing extended release formulations are only approved for twice daily administration. Once daily
administration would reduce the total number of tablets needed for therapeutic effect, thereby
improving patient convenience and, perhaps, patient compliance. Given the large number of patients
who have an inadequate response to a given opioid, availability of another treatment option for chronic
treatment is important for both patients and their healthcare providers. Furthermore, given the
common practice of opioid rotation, EXALGO provides an important once daily option for patients
suffering from chronic pain.
POST NDA SAFETY DATA SUMMARY:
Reviews-“The pain management Dr prescribed morphine sulfate (due to cost) rather than OxyContin. It
was horrible. I felt loopy and sick with pain in my side. So a different Dr switched me to Exalgo SR.What
a relief! I am finally thinking clearer. I think it is much better than OxyContin. I am so glad I am getting
pain relief without feel sick and doped up. I think Exalgo is a perfect match for me”
CONCLUSION:
EXALGO was indicated for the management of pain in opioid-tolerant patients and has proven its
efficacy. The product was well received by the participating physicians.
Looking at the sales figure to further extrapolate, we believe the drug looks really promising. It holds a
good future and we strongly encourage marketing the drug.

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