Osteoarthritis and

Cardiovascular
co-morbidities

IN/CAL/0030a/12(1)date of preparation: February 2015

For the use of Registered Medical Practitioners
 Overview

I. OA
- In the Elderly
- Co-morbidities
- CV risk factors in OA patients
- Economic & social impact of OA patients

II. OA management
- ACR recommendations for hand, knee & hip OA

III. Risks involved with NSAIDS

IV. Tramadol/Paracetamol combination in OA

- Benefits
- Clinical evidence

V. Summary
Osteoarthritis (OA)
 OA in the Elderly

Osteoarthritis (OA) is the most common form of arthritis

World Health Organization (WHO) estimates - globally 25% of

adults aged over 65 year suffer from pain and disability associated

with this disease

Almost every age group is affected by OA, but prevalence

increases dramatically after age 50 year in men and 40 year in

women

Breedveld FC. Osteoarthritisthe impact of a serious disease. Rheumatology 2004;43(Suppl. 1):i4i8

 Comorbidities associated with OA

Impact of OA may be worsened by the presence of other diseases

or conditions

Large proportion of patients with OA suffer from comorbidities, like

-Hypertension
-Cardiovascular disease (CVD)
-Peripheral vascular disease (PVD)
-Congestive heart failure (CHD)
-Renal function impairment
-Diabetes
-Respiratory disease

Breedveld FC. Osteoarthritisthe impact of a serious disease. Rheumatology 2004;43(Suppl. 1):i4i8

 Comorbidities associated with OA (contd..)

Fig: Comorbid diagnoses in patients with end-stage hip osteoarthritis

Breedveld FC. Osteoarthritisthe impact of a serious disease. Rheumatology 2004;43(Suppl. 1):i4i8

 Cardiovascular risk factors in OA patients

Studies have shown that

patients with OA often have risk
factors for CVD , including

Hypertension

High cholesterol levels

Low high-density lipoprotein

cholesterol (HDL) levels
Fig: Prevalence of cardiovascular risk
Renal impairment factors in American osteoarthritis
patients
Diabetes

Breedveld FC. Osteoarthritisthe impact of a serious disease. Rheumatology 2004;43(Suppl. 1):i4i8

 Economic & social impact of OA

The social and economic impact of OA is substantial

Breedveld FC. Osteoarthritisthe impact of a serious disease. Rheumatology 2004;43(Suppl. 1):i4i8

Osteoarthritis Management
 OA Management

NICE Guidelines (2008). The care and management of osteoarthritis in adults. Available at:
http://www.nice.org.uk/nicemedia/pdf/CG59NICEguideline.pdf. Accessed on 6th June 2012.
 OA Management (contd..)

OA management algorithm
suggested by NICE in 2008
recommends starting treatment at the
center addressing core issues first
radiating outwards
Core treatments should be
considered for every person with
osteoarthritis given in the central
circle. Some of these may not be
relevant, depending on the person
Where further treatment is required,
consideration should be given to the
second ring, which contains relatively
safe pharmaceutical options. These
should be considered in light of the
persons individual needs and
preferences

NICE Guidelines (2008). The care and management of osteoarthritis in adults. Available at:
http://www.nice.org.uk/nicemedia/pdf/CG59NICEguideline.pdf. Accessed on 6th June 2012.
 OA Management (contd..)

Third outer circle gives adjunctive treatments

All these treatments meet at least one of the following

criteria
Less well-proven efficacy
Less symptom relief OR
Increased risk to the patient

Outer circle is further divided into four groups

Pharmaceutical options
Self-management techniques
Surgery
Non-pharmaceutical treatments.

NICE Guidelines (2008). The care and management of osteoarthritis in adults. Available
at: http://www.nice.org.uk/nicemedia/pdf/CG59NICEguideline.pdf. Accessed on 6 th June
 American College of Rheumatology (ACR) 2012
Recommendations on pharmacological management of
Hand OA

Health professionals should use one or more of the following1:

Topical capsaicin: Should be considered as an adjunct to core treatment2
Topical NSAIDs: Achieve similar efficacy with low systemic exposure; offer a lower potential
for adverse effects3
Oral NSAIDs, including COX-2 selective inhibitors: Given at the lowest effective dose & for
the shortest time in patients not responding to paracetamol3
Tramadol: Specifically recommended in musculoskeletal pain guidelines and neuropathic
pain guidelines, because of its efficacy, safety, and tolerability4

Persons age 75 years should use topical rather than oral NSAIDs1

1. Hochberg MC. et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of
the hand, hip, and knee. Arthritis Care Res (Hoboken). Apr 2012 ;64(4):455-74.
2. NICE Guidelines (2008). The care and management of osteoarthritis in adults. Available at: http://www.nice.org.uk/nicemedia/pdf/CG59NICEguideline.pdf. Accessed on
6th July 2012.
3. Leeb B. Structure Modification in Osteoarthritis Time to Update the Guidelines. European Congress of Rheumatology, European League Against Rheumatism
(EULAR). Touch briefings 2009.Available at:http://www.touchbriefings.com/pdf/3339/EULAR.pdf. Accessed on 15 th July 2012
4. Schug SA. The role of tramadol in current treatment strategies for musculoskeletal pain. Therapeutics and Clinical Risk Management 2007;3:71723
 American College of Rheumatology (ACR) 2012
Recommendations on pharmacological
management of Knee OA

*Conditional recommendations use1 -

Acetaminophen: Dose of up to 4 g/day can be an effective initial oral analgesic for treatment of
mild to moderate pain2
Oral NSAIDs: Should be used at the lowest effective dose; long-term use should be avoided2
Topical NSAIDs: Used as an adjunct/alternative to oral analgesic/anti-inflammatory agents2
Tramadol: Specifically recommended in musculoskeletal pain guidelines and neuropathic pain
guidelines, because of its efficacy, safety, and tolerability3
Intraarticular corticosteroid injections: Should be considered in patients with moderate to
severe pain not responding satisfactorily to oral analgesic/ anti inflammatory agents2

*Conditional recommendations mean that the majority of informed patients would choose the recommended management but many
would not, so clinicians must ensure that patients care is in keeping with their values and preferences

1. Hochberg MC et al. American College of Rheumatology 2012 Recommendations for the Use of Nonpharmacologic and Pharmacologic Therapies in Osteoarthritis of the Hand, Hip, and
Knee. Arthritis Care & Research 2012:64:465 74
2. Zhang W. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis and Cartilage
2008; 16, 137- 162.
3. Schug SA. The role of tramadol in current treatment strategies for musculoskeletal pain. Therapeutics and Clinical Risk Management 2007;3:71723
 American College of Rheumatology (ACR) 2012
Recommendations on pharmacological
management of Knee OA

Conditional recommendations Not to use1

Chondroitin sulfate
Glucosamine

Topical capsaicin: Should be considered as an adjunct to core

treatment2

No recommendations available on1

Intraarticular hyaluronates
Duloxetine
Opioid analgesics

1. Hochberg MC et al. American College of Rheumatology 2012 Recommendations for the Use of Nonpharmacologic and Pharmacologic Therapies in Osteoarthritis of
the Hand, Hip, and Knee. Arthritis Care & Research 2012:64:465 74
2. NICE Guidelines (2008). The care and management of osteoarthritis in adults. Available at: http://www.nice.org.uk/nicemedia/pdf/CG59NICEguideline.pdf. Accessed
on 6th July 2012.
 American College of Rheumatology (ACR) 2012
Recommendations on pharmacological management of
Hip OA

Conditional recommendations use

- Acetaminophen
- Oral NSAIDs
- Tramadol
- Intraarticular corticosteroid injections

Conditional recommendations not to use

- Chondroitin sulfate
- Glucosamine

No recommendations
- Topical NSAIDs
- Intraarticular hyaluronate injections
- Duloxetine
- Opioid analgesics
Hochberg MC et al. American College of Rheumatology 2012 Recommendations for the Use of Nonpharmacologic and Pharmacologic Therapies in
Osteoarthritis of the Hand, Hip, and Knee. Arthritis Care & Research 2012:64:465 74
 OA Management

Treatments aim to relieve pain, decrease joint stiffness and swelling, maintain joint
function, prevent loss of cartilage, and preserve the patients quality of life.

First-line pharmacological therapy for pain relief may be simple non-opioid analgesics,
such as acetaminophen.

Opioid analgesics, such as codeine may be useful for the short-term treatment of
acute pain"

NSAIDs, such as ibuprofen, are also often used to control the pain and inammation
of mild-to-moderate OA

However, the long-term use of these drugs may be limited by gastrointestinal (GI) or
renal toxicity, and the former may prove fatal

Breedveld FC. Osteoarthritisthe impact of a serious disease. Rheumatology (Oxford). Feb 2004;43 (Suppl. 1):i4i8
Risks involved with NSAIDs
 Risks involved with NSAIDs
2

Non-selective NSAIDs confer a dose-related

risk for GI adverse events, including ulcers and
bleeding1

Estimated incidence of GI bleeding or

perforation due to NSAID use is 0.69%, 2

compared with 0.002% in patients not taking

these agents1

1. Breedveld FC. Osteoarthritisthe impact of a serious disease. Rheumatology 2004;43(Suppl. 1):i4i8.

2. Lo V et al. When should COX-2 selective NSAIDs be used for osteoarthritis and rheumatoid arthritis? The Journal of Family Practice
2006;55:260-2.
 Risks involved with NSAIDs (contd..)
Renal toxicity

Even with the advent of selective COX-2 inhibitors, nephrotoxicity still

remains a concern

Adverse effects of NSAIDs are mediated via inhibition of prostaglandin

synthesis from arachidonic acid by non-specific blocking of the enzyme
cyclooxygenase leading to vasoconstriction and reversible mild renal
impairment in volume contracted states

When unopposed, this may lead to acute tubular necrosis and acute renal
failure

Ejaz P et al. NSAIDs and Kidney. JAPI 2004:52:632-40.

 CV risk of NSAIDs

The selective COX-2 inhibitors first became the centre of attention

after the publication of the VIGOR (Vioxx GI Outcomes Research)
study in 2000, which was the first to show an increased risk of
cardiovascular adverse events (MI) associated with the selective
COX-2 inhibitor rofecoxib compared with naproxen1

Several RCTs have yielded data on the CV effects of NSAIDs

MI myocardial infarction
COX-2 - cyclooxygenase-2
RCT Randomized control trial

1. Fosbol EL et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs among healthy individuals. Expert Opin. Drug Saf. 2010;9(6):1-11.
 Comparison of effects of selective COX 2 inhibitors versus traditional
NSAIDs on vascular events, myocardial infarction

Overall, compared with naproxen, allocation

to a selective COX 2 inhibitor was
associated with a highly significant increase
in the incidence of a vascular event (rate
ratio 1.57, 1.21 to 2.03; P = 0.0006) and a
twofold increased risk of a myocardial
infarction (2.04, 1.41 to 2.96; P = 0.0002)

There was no significant difference in the

incidence of stroke (rate ratio 1.10, 0.73 to
1.65; P = 0.7) or of vascular death (1.47,
0.90 to 2.40; P = 0.1)

Kearney PM. et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of
atherothrombosis? Meta-analysis of randomised trials. BMJ. Jun 2006;332(7553):1302-8.
 Risk of CV risk with NSAIDs even
among healthy individuals

NSAID use and cardiovascular risk has not been investigated previously in
healthy individuals in a study

A recent cohort study among one million healthy people showed that the
selective COX-2 inhibitors as well as diclofenac are associated with an
increased risk of death or myocardial infarction

This was further underlined by a dose-response relationship

Fosbl EL. et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs among healthy individuals. Expert Opin Drug Saf. Nov 2010;9(6):893-903.
 Risk of death with Diclofenac & Ibuprofen

Incidence rates of death per 1000 person-years during treatment with individual nonsteroidal anti-inflammatory drugs
(NSAIDs). Treatment periods were split into 1-week intervals. The horizontal line indicates the overall incidence rate for
the entire study population. CI indicates confidence interval.

Overall NSAID treatment was associated with statistically significantly increased risk of death at the beginning of the
treatment, and the increased risk persisted throughout the course of treatment.
The traditional NSAID diclofenac was associated with increased risk from the beginning of treatment, and the risk
persisted throughout the course of treatment. Ibuprofen showed an increased risk when used for 1 week

Schjerning Olsen AM. et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior
myocardial infarction: a nationwide cohort study. Circulation. May 2011;123(20):2226-35.
 Risk of death/Recurrent myocardial infarction (Re-MI)
with NSAIDs in patients with previous MI

Denmark nationwide registry study of

patients with prior MI demonstrated that
short-term treatment with most NSAIDs is
associated with increased cardiovascular
risk

Incidence rates of death/recurrent myocardial infarction

(Re-MI) per 1000 person-years during treatment with all
nonsteroidal antiinflammatory drugs (NSAIDs) grouped
together.
Treatment periods were split into 1-week intervals. The
horizontal line indicates the overall incidence rate for the
entire study population. CI indicates confidence intervals.

Olsen AMS et al. Duration of Treatment With Nonsteroidal Anti-Inflammatory Drugs and Impact on Risk of Death and Recurrent Myocardial Infarction in Patients With Prior
Myocardial Infarction. Circulation. 2011;123:2226-35
 Clinical implications
Short-term treatment with most NSAIDs is associated with increased CV
risk
Commonly used diclofenac, which in some countries is available over the
counter without any expert advice on potential side effects, is associated
with increased risk treatment onset, and the risk continued to persist
during the course of treatment
Further, diclofenac was associated with higher cardiovascular risk
than the selective COX-2 inhibitor rofecoxib, which was withdrawn
from the market in 2004 owing to its unfavourable CV risk profile
There is no apparent safe therapeutic window for NSAIDs in patients
with prior MI & this study challenges the current recommendations of low-
dose and short-term use of NSAIDs as being safe

Olsen AMS et al. Duration of Treatment With Nonsteroidal Anti-Inflammatory Drugs and Impact on Risk of Death and Recurrent Myocardial Infarction in Patients With
Prior Myocardial Infarction. Circulation. 2011;123:2226-35
 CV risk of OA patients on NSAIDs

Lanas, et al reported a study with 60,868 patients, 17,105 with diagnosis of

OA
-32% had a history of CV events
-57.6% were treated with anti-hypertensive therapy
-22.6% had uncontrolled hypertension
Patients with a positive CV history received non selective NSAIDs in 41.3%
Patients with a positive CV history received COX-2-selective NSAIDs in
31.7% cases
Results showed
-Over 90% of patients with OA are at increased GI and/or CV risk
-In over half of these patients, the prescription of NSAIDs was not in
accordance with current
guidelines or recommendations made by regulatory agencies

Lanas A et al. Prescription patterns and appropriateness of NSAID therapy according to gastrointestinal risk and cardiovascular history in patients with diagnoses of
osteoarthritis. BMC Medicine 2011, 9:38-45
Tramadol/Paracetamol
combination in OA
 Tramadol in OA

Tramadol is specifically recommended in musculoskeletal pain

guidelines and neuropathic pain guidelines, because of its efficacy,
safety, and tolerability
OA patients without particular risk factors should receive background
analgesia with up to 4 g/day of paracetamol
For a short-term flare, NSAIDs or the immediate release paracetamol
tramadol fixed combination tablet should be administered
If this does not adequately control the pain then, immediate release
tramadol can be administered

Schug SA. The role of tramadol in current treatment strategies for musculoskeletal pain. Therapeutics and Clinical Risk Management 2007;3:71723
 Moderate to Severe OA Pain: Systemic Analgesia Patients
without Particular Risk Factors

Schug SA. The role of tramadol in current treatment strategies for musculoskeletal pain. Therapeutics and Clinical Risk Management 2007;3:71723
 Benefits of Tramadol over traditional opioids

Schug SA. The role of tramadol in current treatment strategies for musculoskeletal pain. Therapeutics and Clinical Risk Management 2007;3:71723
 Efficacy of Tramadol + Acetaminophen in
elderly with OA flare

113 patients aged 65 and older with an OA flare up were included

The primary efficacy outcomes of average daily pain intensity (P=.034) &
average daily pain relief (P=.010) on Days 1 through 5 improved
significantly in elderly patients taking tramadol/APAP plus NSAIDs
compared with patients receiving placebo plus NSAIDs

Rosenthal NR. Tramadol/acetaminophen combination tablets for the treatment of pain associated with osteoarthritis flare in an elderly patient population. J Am Geriatr
Soc. 2004 Mar;52(3):374-80.
 Tramadol + Acetaminophen in elderly with OA flare

Average daily pain intensity scores in the tramadol/APAP group

decreased from 2.30 at baseline to 1.38 on Days 1 through 5,
compared with a decrease from 2.40 to 1.64 in the placebo group

Average daily pain intensity scores in the tramadol/acetaminophen (APAP) group versus the placebo group is shown at baseline and
for Days 1 through 5 for all patients, for patients younger than 65, and for patients aged 65 and older. P-value based on analysis of
covariance model including treatment as main effect and baseline pain intensity value as covariate. *P < .001; P = .002; P = .034.
Tr = Tramadol.

Rosenthal NR. Tramadol/acetaminophen combination tablets for the treatment of pain associated with osteoarthritis flare in an elderly patient population. J Am Geriatr
Soc. 2004 Mar;52(3):374-80.
 Tramadol + Paracetamol in elderly with OA flare

Statistically significant improvement with tramadol/PCM versus placebo

was seen on the WOMAC overall score (P=.011) as well as on the pain
(P=.005) and physical function (P=.027) subscores in elderly patients
Mean WOMAC Score* P-value
Tramadol/ Tramadol/
Acetaminophen Acetamino
(n=69) Placebo (n=44) phen
vs
Category Baseline Final Baseline Final Placebo
Pain 5.58 3.19 5.89 4.22 .005

Joint 6.28 4.17 6.38 4.77 .167

stiffness
Physical 5.72 3.61 5.81 4.30 .027
function
Overall|| 5.76 3.55 5.91 4.38 .011

Scores on the Western Ontario and McMaster

Universities (WOMAC) Osteoarthritis Index
Questionnaire

Tramadol/PCM add-on therapy effectively managed painful OA flare in elderly and was generally well
tolerated.
Rosenthal NR. et al. Tramadol/acetaminophen combination tablets for the treatment of pain associated with osteoarthritis flare in an elderly patient
population. J Am Geriatr Soc. Mar 2004;52(3):374-80.
 Tramadol + Acetaminophen in OA Meta analysis

The meta analysis included 11 RCTs with a total of 1019 participants who
received tramadol or tramadol/APAP and 920 participants who received
placebo or active control

Participants who received tramadol reported

Less pain

12% relative decrease in pain intensity

Higher degree of global improvement: one of every 6 individuals taking tramadol or

tramadol/paracetamol exhibited at least moderate global improvement (95% CI 4 to 9)

Improvement in stiffness and function, an 8.5% relative improvement in Western

Ontario and McMaster University Osteoarthritis Index score

Cepeda MS. Tramadol for osteoarthritis: a systematic review and metaanalysis.. J Rheumatol. 2007 Mar;34(3):543-55.
Summary
 Summary

Osteoarthritis affects a significant elderly population

It causes serious disability & is a social & economic burden
Cardiovascular comorbidity is common in patients with OA
OA management is based on use of Paracetamol, Oral non selective of
COX 2 selective NSAIDs & Tramadol
Oral NSAIDs are associated with several adverse effects
Meta analysis and large cohort studies reveal that NSAIDs like Diclofenac
carry a higher risk of Cardiovascular side effects like MI, Vascular events,
Stroke & death compared to Rofecoxib that has been removed from the
market due to CV side effects
Tramadol & Paracetamol combination forms an effective alternative in
management of moderate to severe osteoarthritis pain especially in the
elderly
 Safety Information
Contraindications

CALPOL T should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, paracetamol,

any other component of this product or opioids. CALPOL T is contraindicated in any situation where opioids are contraindicated,

including acute intoxication with any of the following: alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or

psychotropic drugs. CALPOL T may worsen central nervous system and respiratory depression in these patients.

Special Warnings and Special Precautions for Use

Warnings - Hepatotoxicity

CALPOL T contains tramadol HCl and paracetamol. Paracetamol has been associated with cases of acute liver failure, at times

resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of paracetamol at doses that

exceed 4,000 milligrams per day, and often involve more than one paracetamol-containing product. The excessive intake of

paracetamol may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly

take other paracetamol-containing products. The risk of acute liver failure is higher in individuals with underlying liver disease and

in individuals who ingest alcohol while taking paracetamol. Instruct patients to look for paracetamol on package labels and not to

use more than one product that contains paracetamol. Instruct patients to seek medical attention immediately upon ingestion of

more than 4,000 milligrams of paracetamol per day, even if they feel well.

Serious Skin Reactions

Rarely, paracetamol may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-

Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs

of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of

hypersensitivity.
Precautions

General

The recommended dose of CALPOL T should not be exceeded.

Do not co-administer CALPOL T with other tramadol or paracetamol-containing products.

Pediatric Use

The safety and effectiveness of CALPOL T has not been studied in the pediatric population.

Geriatric Use

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of
decreased hepatic, renal, or cardiac function; of concomitant disease and multiple drug therapy.

Acute Abdominal Conditions

The administration of CALPOL T may complicate the clinical assessment of patients with acute abdominal
conditions.

Use in Renal Disease

CALPOL T has not been studied in patients with impaired renal function. Experience with tramadol
suggests that impaired renal function results in a decreased rate and extent of excretion of tramadol and its
active metabolite, M1. In patients with creatinine clearances of less than 30 mL/min, it is recommended that
the dosing interval of CALPOL T be increased not to exceed 2 tablets every 12 hours.
 Adverse Reactions

Incidence 1%: Asthenia, fatigue, hot flushes, dizziness, headache, tremor, abdominal pain,
constipation, diarrhea, dyspepsia, flatulence, dry mouth, nausea, vomiting, anorexia, anxiety,
confusion, euphoria, insomnia, nervousness, somnolence, pruritus, rash, increased sweating.
Incidence <1%: Chest pain, rigors, syncope, withdrawal syndrome, hypertension, aggravated
hypertension, hypotension, ataxia, convulsions, hypertonia, migraine, aggravated migraine,
involuntary muscle contractions, paresthesias, stupor, vertigo, dysphagia, melena, tongue
edema, tinnitus, arrhythmia, palpitation, tachycardia, hepatic function abnormality, weight
decrease, amnesia, depersonalization, depression, drug abuse, emotional liability, hallucination,
impotence, paroniria, abnormal thinking, anemia, dyspnea, albuminuria, micturition disorder,
oliguria, urinary retention, abnormal vision. Other AEs with tramadol: vasodilation, orthostatic
hypotension, myocardial ischemia, pulmonary edema, allergic reactions (including anaphylaxis
and urticaria, Stevens-Johnson syndrome/TENS), cognitive dysfunction, difficulty concentrating,
suicidal tendency, hepatitis liver failure and gastrointestinal bleeding, elevated creatinine,
serotonin syndrome. Rare adverse events with Paracetamol: Allergic reactions/hypersensitivity.
 For the use of Registered Medical Practitioners only
Abbreviated Prescribing information of CALPOL T tablets

Taking more than daily dose may cause serious liver damage or allergic reactions
(e.g.
swelling of the face, mouth and throat, difficulty in breathing, itching or rash)

Active Ingredient: Each film coated tablet contains: Paracetamol IP 325 mg and Tramadol Hydrochloride BP 37.5 mg.
Indications: Severe acute pain only for period not exceeding 5 days. Dosage and Administration: 2 tablets every 4
to 6 hours as needed for pain relief up to a maximum of 8 tablets per day for maximum 5 days. If creatinine clearance is
< 30 mL/min, do not exceed 2 tablets every 12 hours. Dose selection for an elderly patient should be cautious. Do not
exceed recommended dose.
Contra-indications: Known hypersensitivity to any component of this product or opioids, any situation where opioids
are contraindicated including acute intoxication with alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or
psychotropic drugs.

Warnings & Precautions: Risk of acute liver failure is higher in individuals with underlying liver disease and in those
who ingest alcohol while taking paracetamol. Instruct patients to look for paracetamol on package labels and not to use
more than one product that contains paracetamol. Instruct patients to seek medical attention immediately upon
ingestion of >4,000 mg of paracetamol per day, even if they feel well. Rarely, paracetamol may cause serious skin
reactions which can be fatal. Inform patients about signs of serious skin reactions, and discontinue drug at first sign of
skin rash or hypersensitivity. Seizure risk is increased in patients taking doses of tramadol above recommended range,
in patients taking selective serotonin reuptake inhibitors (SSRIs), antidepressants or anorectics, tricyclic
antidepressants (TCAs), other tricyclic compounds, other opioids,
MAO inhibitors, neuroleptics or other drugs that reduce seizure threshold and in patients with epilepsy, history of
seizures or with recognized risk of seizures. Do not prescribe CALPOL T for patients who are suicidal or addiction-
prone and prescribe with caution for patients taking tranquilizers or antidepressant drugs and who use alcohol in excess
and who suffer from emotional disturbance or depression due to reports of tramadol-related deaths in such patients.
Potentially life threatening serotonin syndrome may occur with concomitant use of serotonergic drugs such as SSRIs,
SNRIs, TCAs, MAOIs, triptans and drugs which impair metabolism of serotonin or tramadol. Patients with history of
anaphylactoid reactions to codeine and other opioids or paracetamol allergy should not receive CALPOL T.
CALPOL T should be used cautiously in patients at risk for respiratory or CNS depression including those receiveing alcohol, opioids,

anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics and patients with increased intracranial pressure or

head injury. CALPOL T should not be used concomitantly with other paracetamol-containing products and in patients with liver disease.

Consider possibility of illegal or illicit use when prescribing or dispensing

CALPOL T if there is an increased risk of misuse, abuse, or diversion. Withdrawal symptoms may occur if discontinued abruptly; can be

avoided by tapering dose.Tramadol overdose can cause central nervous system depression, respiratory depression and death.

Paracetamol overdose may cause hepatic (centrilobular) necrosis, leading to hepatic failure and death. Safety and effectiveness not

studied in patients below 16 years of age and in patients with impaired renal and hepatic function. Clinical assessment of acute

abdominal conditions can be complicated by its administration. Drug interactions: Concomitant administration of CYP2D6 inhibitors

(quinidine,fluoxetine, paroxetine and amitriptyline) and/or CYP3A4 inhibitors (ketoconazole and erythromycin) may reduce metabolic

clearance of tramadol. Caution is advised when coadministered with SSRIs, MAOIs, triptans, linezolid, lithium, or St. Johns Wort.

Concomitant administration with carbamazepine is not recommended. Rifampin may affect metabolism of tramadol. Digoxin toxicity

reported rarely with

tramadol. Periodic evaluation of prothrombin time when CALPOL T and warfarin-like compounds are administered concurrently since

elevation of prothrombin times seen rarely. Effects on ability to drive and use machinery: Tramadol may impair mental and or

physical abilities required for driving a car or operating machinery. Pregnancy and Lactation: Do not use in pregnant women prior to or

during labor unless potential benefits outweigh risks. Safe use in pregnancy not established. Tramadol crosses placenta. Chronic use

during pregnancy may lead to physical dependence and post-partum withdrawal

symptoms in newborn. Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported with tramadol.

Not recommended for obstetrical pre operative medication or for postdelivery analgesia in nursing mothers. contd...
Adverse Reactions: Incidence 1%: Asthenia, fatigue, hot

flushes, dizziness, headache, tremor, abdominal pain, constipation, diarrhea, dyspepsia, flatulence, dry mouth, nausea, vomiting,

anorexia, anxiety, confusion, euphoria, insomnia, nervousness, somnolence, pruritus, rash, increased sweating. Incidence <1%:

Chest pain, rigors, syncope, withdrawal syndrome, hypertension, aggravated hypertension, hypotension, ataxia, convulsions,

hypertonia, migraine, aggravated migraine, involuntary muscle contractions, paresthesias, stupor, vertigo, dysphagia, melena, tongue

edema, tinnitus, arrhythmia, palpitation, tachycardia, hepatic function abnormality, weight decrease, amnesia, depersonalization,

depression, drug abuse, emotional liability, hallucination, impotence, paroniria, abnormal thinking, anemia, dyspnea, albuminuria,

micturition disorder, oliguria, urinary retention, abnormal vision. Other AEs with tramadol: vasodilation, orthostatic

hypotension,myocardial ischemia, pulmonary edema, allergic reactions (including anaphylaxis and urticaria, Stevens-Johnson

syndrome/TENS), cognitive dysfunction, difficulty concentrating, suicidal tendency, hepatitis, liver failure and gastrointestinal

bleeding, elevated creatinine, serotonin syndrome. Rare adverse events with Paracetamol: Allergic reactions/hypersensitivity.

Overdose: Paracetamol overdose may be injurious to liver. Assisted or controlled ventilation should be instituted. Circulatory shock,

pulmonary edema, cardiac arrest or arrhythmias and convulsions should be managed with supportive measures. Naloxone will

reverse some symptoms but seizures risk is also increased. Fatal hepatic necrosis, renal tubular necrosis, hypoglycemic coma, and

coagulation defects may occur. Administer activated charcoal prior to N-acetylcysteine (NAC). Administer oral or intravenous NAC

immediately if impending or evolving liver injury is suspected. Vigorous supportive therapy is required in severe intoxication.

Refer to full prescribing information before use.

Full prescribing information available on request from:

GlaxoSmithKline Pharmaceuticals Limited, Dr Annie Besant Road, Worli, Mumbai-400030.

Version: CALT/API/IN/2014/01 v01 dated 20th March 2014

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any GSK product to the company at
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