For the use only of Registered Medical Practitioners or a Hospital or a Laboratory

CALPOL T

WARNING: 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)

1. GENERIC NAME

Tramadol Hydrochloride and Acetaminophen Tablets USP

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film coated tablet contains:

Tramadol Hydrochloride IP 37.5 mg
Paracetamol IP (Acetaminophen) 325 mg

Colours: Titanium Dioxide IP and Ferric Oxide USPNF (Yellow)

3. DOSAGE FORM AND STRENGTH

Film coated tablets

4. CLINICAL PARTICULARS

4.1 Therapeutic Indications

CALPOL T is indicated in adults for severe acute pain, for which alternative treatments are
inadequate, only for a period not exceeding 5 days.

Limitations of Use

CALPOL T is indicated for short-term use of five days or less.

Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses
(see 4.4 Special Warnings and Precautions for Use), reserve CALPOL T for use in patients for
whom alternative treatment options [e.g., non-opioid analgesics]:

• Have not been tolerated, or are not expected to be tolerated,

• Have not provided adequate analgesia, or are not expected to provide adequate analgesia.
4.2 Posology and Method of Administration

Important Dosage and Administration Instructions

• CALPOL T is not approved for use for more than 5 days.
• Do not exceed the recommended dose of CALPOL T. Do not co-administer CALPOL T with
other tramadol or acetaminophen containing products (see 4.4 Special Warnings and
Precautions for Use).
• Use the lowest effective dosage for the shortest duration consistent with individual patient
treatment goals (see 4.4 Special Warnings and Precautions for Use).
• Initiate the dosing regimen for each patient individually; taking into account the patient's
severity of pain, patient response, prior analgesic treatment experience, and risk factors for
addiction, abuse, and misuse (see 4.4 Special Warnings and Precautions for Use).
• Monitor patients closely for respiratory depression, especially within the first 24-72 hours of
initiating therapy and following dosage increases with CALPOL T and adjust the dosage
accordingly (see 4.4 Special Warnings and Precautions for Use).

Initial Dosage
The initial dose of CALPOL T is 2 tablets every 4 to 6 hours as needed for pain relief up to a
maximum of 8 tablets per day.

Dosage Modification in Patients with Renal Impairment

In patients with creatinine clearances of less than 30 mL/min, do not exceed 2 tablets every 12
hours.

Safe Reduction or Discontinuation of CALPOL T

Do not abruptly discontinue CALPOL T in patients who may be physically dependent on opioids.
Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids
has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid
discontinuation has also been associated with attempts to find other sources of opioid analgesics,
which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain
or withdrawal symptoms with illicit opioids, such as heroin, and other substances.
When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent
patient taking CALPOL T, there are a variety of factors that should be considered, including the
dose of CALPOL T the patient has been taking, the duration of treatment, the type of pain being
treated, and the physical and psychological attributes of the patient. It is important to ensure
ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so
that patient and provider goals and expectations are clear and realistic. When opioid analgesics are
being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or
refer for evaluation and treatment of the substance use disorder. Treatment should include
evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex
patients with comorbid pain and substance use disorders may benefit from referral to a specialist.
There are no standard opioid tapering schedules that are suitable for all patients. Good clinical
practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on
opioids who are physically opioid-dependent, initiate the taper by a small enough increment (e.g.,
no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and use a
gradual downward taper. Patients who have been taking opioids for briefer periods of time may
tolerate a more rapid taper.
It may be necessary to provide the patient with lower dosage strengths to accomplish a successful
taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they
emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning,
perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop,
including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia,
nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If
withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the
dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition,
monitor patients for any changes in mood, emergence of suicidal thoughts, or use of other
substances.
When managing patients taking opioid analgesics, particularly those who have been treated for a
long duration and/or with high doses for chronic pain, ensure that a multimodal approach to pain
management, including mental health support (if needed), is in place prior to initiating an opioid
analgesic taper. A multimodal approach to pain management may optimize the treatment of
chronic pain, as well as assist with the successful tapering of the opioid analgesic (see 4.4 Special
Warnings and Precautions for Use, 4.10 Drug Abuse and Dependence).

4.3 Contraindications

CALPOL T is contraindicated for:

• All children younger than 12 years of age (see 4.4 Special Warnings and Precautions for Use)
• Post-operative management in children younger than 18 years of age following tonsillectomy
and/or adenoidectomy (see 4.4 Special Warnings and Precautions for Use).

CALPOL T is also contraindicated in patients with:

• Significant respiratory depression (see 4.4 Special Warnings and Precautions for Use).
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative
equipment (see 4.4 Special Warnings and Precautions for Use).
• Patients with known or suspected gastrointestinal obstruction, including paralytic ileus (see 4.4
Special Warnings and Precautions for Use).
• Previous hypersensitivity to tramadol, acetaminophen, any other component of this product, or
opoids (see 4.4 Special Warnings and Precautions for Use).
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days (see
4.5 Drug Interactions).

4.4 Special Warnings and Precautions for Use

Addiction, Abuse and Misuse

CALPOL T contains tramadol. As an opioid, CALPOL T exposes users to the risks of addiction,
abuse, and misuse. (see 4.10 Drug Abuse and Dependence).
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately
prescribed CALPOL T. Addiction can occur at recommended dosages and if the drug is misused
or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing CALPOL T,
and monitor all patients receiving CALPOL T for the development of these behaviors and
conditions. Risks are increased in patients with a personal or family history of substance abuse
(including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The
potential for these risks should not, however, prevent the proper management of pain in any given
patient. Patients at increased risk may be prescribed opioids such as CALPOL T, but use in such
patients necessitates intensive counseling about the risks and proper use of CALPOL T along with
intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for
the emergency treatment of opioid overdose (4.3 special warning and precaution for use).

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal
diversion. Consider these risks when prescribing or dispensing CALPOL T. Strategies to reduce
these risks include prescribing the drug in the smallest appropriate quantity and advising the patient
on the proper disposal of unused drug.

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids,
even when used as recommended. Respiratory depression, if not immediately recognized and
treated, may lead to respiratory arrest and death. Management of respiratory depression may
include close observation, supportive measures, and use of opioid antagonists, depending on the
patient’s clinical status (see 4.9 Overdose). Carbon dioxide (CO2) retention from opioid-induced
respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use
of CALPOL T, the risk is greatest during the initiation of therapy or following a dosage increase.
Monitor patients closely for respiratory depression, especially within the first 24-72 hours of
initiating therapy with and following dosage increases of CALPOL T.

To reduce the risk of respiratory depression, proper dosing and titration of CALPOL T are essential
(see 4.2 Posology and Method of Administration). Overestimating the CALPOL T dosage when
converting patients from another opioid product can result in a fatal overdose with the first dose.

Accidental ingestion of even one dose of CALPOL T, especially by children, can result in
respiratory depression and death due to an overdose of tramadol.

Educate patients and caregivers on how to recognize respiratory depression and getting emergency
medical help right away in the event of a known or suspected overdose.

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-
related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients
who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper
(see 4.2 Posology and Method of Administration).

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the
patient and caregiver and assess the potential need for access to naloxone, both when initiating and
renewing treatment with CALPOL T. Educate patients and caregivers on how to recognize
respiratory depression and getting emergency medical help, even if naloxone is administered.

Consider prescribing naloxone, based on the patient’s risk factor for overdose, such as concomitant
use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. However, the
presence of risk factors for overdose should not prevent the proper management of pain in any
given patient. Also consider prescribing naloxone if the patient has household members (including
children) or other close contacts at risk for accidental exposure or overdose. If naloxone is
prescribed, educate patients and caregivers on how to treat with naloxone. (see 4.3 special warning
and precaution for use).

Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory
Depression in Children
Life-threatening respiratory depression and death have occurred in children who received
tramadol. Tramadol and codeine are subject to variability in metabolism based upon CYP2D6
genotype (described below), which can lead to increased exposure to an active metabolite. Based
upon postmarketing reports with tramadol or with codeine, children younger than 12 years of age
may be more susceptible to the respiratory depressant effects of tramadol. Furthermore, children
with obstructive sleep apnea who are treated with opioids for post-tonsillectomy and/or
adenoidectomy pain may be particularly sensitive to their respiratory depressant effect. Because
of the risk of life-threatening respiratory depression and death:

• CALPOL T is contraindicated for all children younger than 12 years of age (see 4.3
Contraindications).
• CALPOL T is contraindicated for post-operative management in pediatric patients younger
than 18 years of age following tonsillectomy and/or adenoidectomy (see 4.3
Contraindications).
• Avoid the use of CALPOL T in adolescents 12 to 18 years of age who have other risk factors
that may increase their sensitivity to the respiratory depressant effects of tramadol unless the
benefits outweigh the risks. Risk factors include conditions associated with hypoventilation
such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease,
neuromuscular disease, and concomitant use of other medications that cause respiratory
depression.
• As with adults, when prescribing opioids for adolescents, healthcare providers should choose
the lowest effective dose for the shortest period of time and inform patients and caregivers
about these risks and the signs of opioid overdose (see 4.6 Use in Special Populations, 4.9
Overdose).
Nursing Mothers

Tramadol is subject to the same polymorphic metabolism as codeine, with ultra-rapid metabolizers
of CYP2D6 substrates being potentially exposed to life-threatening levels of O-desmethyltramadol
(M1). At least one death was reported in a nursing infant who was exposed to high levels of
morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. A baby
nursing from an ultra-rapid metabolizer mother taking CALPOL T could potentially be exposed to
high levels of M1, and experience life-threatening respiratory depression. For this reason,
breastfeeding is not recommended during treatment with CALPOL T (see 4.6 Use in Special
Populations).

CYP2D6 Genetic Variability: Ultra-rapid metabolizer

Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene
duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies
widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for
Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be
greater than 10% in certain racial/ethnic groups (i.e., Oceanian, Northern African, Middle Eastern,
Ashkenazi Jews, Puerto Rican). These individuals convert tramadol into its active metabolite, O-
desmethyltramadol (M1), more rapidly and completely than other people. This rapid conversion
results in higher than expected serum M1 levels. Even at labeled dosage regimens, individuals who
are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience
signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) (see 4.9 Overdose).
Therefore, individuals who are ultra-rapid metabolizers should not use CALPOL T.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of CALPOL T during pregnancy can result in withdrawal in the neonate. Neonatal
opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-
threatening if not recognized and treated, and requires management according to protocols
developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal
syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period
of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be
available (see 4.6 Use in Special Populations).

Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes

The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4
inhibitors, or 2D6 inhibitors on levels of tramadol and M1 from CALPOL T are complex. Use of
cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with CALPOL T requires careful
consideration of the effects on the parent drug, tramadol, which is a weak serotonin and
norepinephrine reuptake inhibitor and μ-opioid agonist, and the active metabolite, M1, which is
more potent than tramadol in μ-opioid receptor binding (see 4.5 Drug Interactions).
Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors

The concomitant use of CALPOL T with all cytochrome P450 2D6 inhibitors (e.g., amiodarone,
quinidine) may result in an increase in tramadol plasma levels and a decrease in the levels of the
active metabolite, M1. A decrease in M1 exposure in patients who have developed physical
dependence to tramadol, may result in signs and symptoms of opioid withdrawal and reduced
efficacy. The effect of increased tramadol levels may be an increased risk for serious adverse
events including seizures and serotonin syndrome.

Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease
in tramadol plasma levels and an increase in active metabolite M1 levels, which could increase or
prolong adverse reactions related to opioid toxicity and may cause potentially fatal respiratory
depression.

Follow patients receiving CALPOL T and any CYP2D6 inhibitor for the risk of serious adverse
events including seizures and serotonin syndrome, signs and symptoms that may reflect opioid
toxicity, and opioid withdrawal when CALPOL T is used in conjunction with inhibitors of CYP2D6
(see 4.5 Drug Interactions).

Cytochrome P450 3A4 Interaction

The concomitant use of CALPOL T with cytochrome P450 3A4 inhibitors, such as macrolide
antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease
inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin,
carbamazepine, and phenytoin, may result in an increase in tramadol plasma concentrations, which
could increase or prolong adverse reactions, increase the risk for serious adverse events including
seizures and serotonin syndrome, and may cause potentially fatal respiratory depression.

The concomitant use of CALPOL T with all cytochrome P450 3A4 inducers or discontinuation of
a cytochrome P450 3A4 inhibitor may result in lower tramadol levels. This may be associated with
a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid
withdrawal.

Follow patients receiving CALPOL T and any CYP3A4 inhibitor or inducer for the risk for serious
adverse events including seizures and serotonin syndrome, signs and symptoms that may reflect
opioid toxicity and opioid withdrawal when CALPOL T is used in conjunction with inhibitors and
inducers of CYP3A4 (see 4.5 Drug Interactions).

Hepatotoxicity

CALPOL T contains tramadol hydrochloride and acetaminophen. Acetaminophen 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 acetaminophen at doses that exceed 4,000
milligrams per day, and often involve more than one acetaminophen -containing product. The
excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as
patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing
products.

The risk of acute liver failure is higher in individuals with underlying liver disease and in
individuals who ingest alcohol while taking acetaminophen.

Instruct patients to look for acetaminophen on package labels and not to use more than one product
that contains acetaminophen. Instruct patients to seek medical attention immediately upon
ingestion of more than 4,000 milligrams of acetaminophen per day, even if they feel well.

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use
of CALPOL T with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine
sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics,
antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of
these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and
benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics
alone. Because of similar Pharmacological Properties, it is reasonable to expect similar risk with
the concomitant use of other CNS depressant drugs with opioid analgesics (see 4.5 Drug
Interactions).

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with
an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant
use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the
benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate
based on clinical response. If an opioid analgesic is initiated in a patient already taking a
benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic,
and titrate based on clinical response. Follow patients closely for signs and symptoms of
respiratory depression and sedation.

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of
opioid overdose (see 4.4 Special Warning and Precaution for use).

Advise both patients and caregivers about the risks of respiratory depression and sedation when
CALPOL T is used with benzodiazepines or other CNS depressants (including alcohol and illicit
drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant
use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk
of substance use disorders, including opioid abuse and misuse, and warn them of the risk for
overdose and death associated with the use of additional CNS depressants including alcohol and
illicit drugs (see 4.5 Drug Interactions).
Serotonin Syndrome Risk

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported with the
use of tramadol, including CALPOL T, during concomitant use with serotonergic drugs.

Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and
norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3
receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine,
trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors,
both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous
methylene blue) (see 4.5 Drug Interactions). This may occur within the recommended dosage
range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations,
coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia),
neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal
symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within
several hours to a few days of concomitant use, but may occur later than that. Discontinue
CALPOL T if serotonin syndrome is suspected.

Increased Risk of Seizures

Seizures have been reported in patients receiving tramadol within the recommended dosage range.
Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol
above the recommended range.

Concomitant use of tramadol increases the seizure risk in patients taking: (see 4.5 Drug
Interactions)

• Selective serotonin re-uptake inhibitors (SSRIs) and Serotonin-norepinephrine re-uptake

inhibitors (SNRIs) antidepressants or anorectics,
• Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine,
promethazine, etc.),
• Other opioids,
• MAO inhibitors (see 4.4 Special Warnings and Precautions for Use and 4.5 Drug Interaction),
• Neuroleptics, or
• Other drugs that reduce the seizure threshold.

Risk of seizures may also increase in patients with epilepsy, those with a history of seizures, or in
patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and
drug withdrawal, CNS infections).

In tramadol overdose, naloxone administration may increase the risk of seizure.

Suicide Risk

• Do not prescribe CALPOL T for patients who are suicidal or addiction-prone. Consideration
should be given to the use of non-narcotic analgesics in patients who are suicidal or depressed
(see 4.10 Drug Abuse and Dependence).
• Prescribe CALPOL T with caution for patients with a history of misuse and/or are currently
taking CNS-active drugs including tranquilizers, or antidepressant drugs, or alcohol in excess,
and patients who suffer from emotional disturbance or depression (see 4.5 Drug Interactions).
• Inform patients not to exceed the recommended dose and to limit their intake of alcohol (see
4.2 Posology and Method of Administration and 4.4 Special Warnings and Precautions for
Use).

Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater
than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms
and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood
pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as
soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses
of corticosteroids. Wean the patient off the opioid to allow adrenal function to recover and continue
corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases
reported use of a different opioid without recurrence of adrenal insufficiency. The information
available does not identify any particular opioids as being more likely to be associated with adrenal
insufficiency.

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in

Elderly, Cachectic, or Debilitated Patients

The use of CALPOL T in patients with acute or severe bronchial asthma in an unmonitored setting
or in the absence of resuscitative equipment is contraindicated (see 4.3 Contraindications).

Patients with Chronic Pulmonary Disease: CALPOL T treated patients with significant chronic
obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased
respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased
risk of decreased respiratory drive including apnea, even at recommended dosages of CALPOL T
(see 4.4 Special Warnings and Precautions for Use).

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely

to occur in elderly, cachectic, or debilitated patients because they may have altered
pharmacokinetics, or altered clearance, compared to younger, healthier patients (see 4.4 Special
Warnings and Precautions for Use).

Monitor such patients closely, particularly when initiating and titrating CALPOL T and when
CALPOL T is given concomitantly with other drugs that depress respiration (see 4.4 Special
Warnings and Precautions for Use and 4.5 Drug Interactions). Alternatively, consider the use of
non-opioid analgesics in these patients.
Severe Hypotension

CALPOL T may cause severe hypotension including orthostatic hypotension and syncope in
ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure
has already been compromised by a reduced blood volume or concurrent administration of certain
CNS depressant drugs (e.g., phenothiazines or general anesthetics) (see 4.5 Drug Interactions).
Monitor these patients for signs of hypotension after initiating or titrating the dosage of CALPOL
T. In patients with circulatory shock, CALPOL T may cause vasodilation that can further reduce
cardiac output and blood pressure. Avoid the use of CALPOL T in patients with circulatory shock.

Risk of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or
Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with
evidence of increased intracranial pressure or brain tumors), CALPOL T may reduce respiratory
drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such
patients for signs of sedation and respiratory depression, particularly when initiating therapy with
CALPOL T.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of
CALPOL T in patients with impaired consciousness or coma.

Serious Skin Reactions

Rarely, acetaminophen 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.

Risk of Use in Patients with Gastrointestinal Conditions

CALPOL T is contraindicated in patients with known or suspected gastrointestinal obstruction,

including paralytic ileus (see 4.3 Contraindications).

The tramadol in CALPOL T may cause spasm of the sphincter of Oddi. Opioids may cause
increases in serum amylase. Monitor patients with biliary tract disease, including acute
pancreatitis, for worsening symptoms.

Anaphylaxis and Other Hypersensitivity Reactions

Serious and rarely fatal anaphylactic reactions have been reported in patients receiving therapy
with tramadol. When these events do occur it is often following the first dose. Other reported
allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis,
and Stevens-Johnson syndrome. Patients with a history of anaphylactoid reactions to tramadol and
other opioids may be at increased risk and therefore should not receive CALPOL T. If anaphylaxis
or other hypersensitivity occurs, stop administration of CALPOL T immediately, discontinue
CALPOL T permanently, and do not rechallenge with any formulation of tramadol. Advise patients
to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction
(see 4.3 Contraindications).

There have been postmarketing reports of hypersensitivity and anaphylaxis associated with the use
of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory
distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening
anaphylaxis requiring emergency medical attention. Instruct patients to discontinue CALPOL T
immediately and seek medical care if they experience these symptoms. Do not prescribe CALPOL
T for patients with acetaminophen allergy.

Increased Risk of Hepatotoxicity with Concomitant Use of Other Acetaminophen-containing

Products

Due to the potential for acetaminophen hepatotoxicity at doses higher than the recommended dose,
CALPOL T should not be used concomitantly with other acetaminophen containing products.

Withdrawal

Do not abruptly discontinue CALPOL T in a patient physically dependent on opioids. When

discontinuing CALPOL T in a physically dependent patient, gradually taper the dosage. Rapid
tapering of tramadol and acetaminophen in a patient physically dependent on opioids may lead to
a withdrawal syndrome and return of pain (see 4.2 Posology and Method of Administration, 4.10
Drug Abuse and Dependence).

Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and
butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full
opioid agonist analgesic, including CALPOL T. In these patients, mixed agonist/antagonist and
partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal
symptoms (see 4.5 Drug Interactions).

Hyponatremia

Hyponatremia (Serum sodium <135 mmol/L) has been reported with the use of tramadol, and
many cases are severe (sodium level <120 mmol/L). Most cases of hyponatremia occurred in
females over the age of 65 and within the first week of therapy. In some reports, hyponatremia
resulted from the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Monitor for
signs and symptoms of hyponatremia (e.g., confusion, disorientation), during treatment with
CALPOL T, especially during initiation of therapy. If signs and symptoms of hyponatremia are
present, initiate appropriate treatments (e.g., fluid restriction) and discontinue CALPOL T (see 4.2
Posology and Method of Administration).
Hypoglycemia

Cases of tramadol-associated hypoglycemia have been reported, some resulting in hospitalization.

In most cases, patients had predisposing risk factors (e.g. diabetes). If hypoglycemia is suspected
monitor blood glucose levels and consider drug discontinuation as appropriate (see 4.2 Posology
and Method of Administration).

4.5 Drug Interactions

Clinically Significant Drug Interactions with CALPOL T

Inhibitors of CYP2D6
Clinical Impact: The concomitant use of CALPOL T and CYP2D6 inhibitors may result in
an increase in the plasma concentration of tramadol and a decrease in the
plasma concentration of M1, particularly when an inhibitor is added after a
stable dose of CALPOL T is achieved. Since M1 is a more potent μ-opioid
agonist, decreased M1 exposure could result in decreased therapeutic
effects, and may result in signs and symptoms of opioid withdrawal in
patients who had developed physical dependence to tramadol. Increased
tramadol exposure can result in increased or prolonged therapeutic effects
and increased risk for serious adverse events including seizures and
serotonin syndrome.

After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline,

the tramadol plasma concentration will decrease and the M1 plasma
concentration will increase which could increase or prolong therapeutic
effects but also increase adverse reactions related to opioid toxicity, and
may cause potentially fatal respiratory depression (see 5. Pharmacological
Properties).
Intervention: If concomitant use of a CYP2D6 inhibitor is necessary, follow patients
closely for adverse reactions including opioid withdrawal, seizures and
serotonin syndrome.

If a CYP2D6 inhibitor is discontinued, consider lowering CALPOL T

dosage until stable drug effects are achieved. Follow patients closely for
adverse events including respiratory depression and sedation.
Examples Quinidine, fluoxetine, paroxetine and bupropion.

Inhibitors of CYP3A4
Clinical Impact: The concomitant use of CALPOL T and CYP3A4 inhibitors can increase
plasma concentration of tramadol and may result in a greater amount of
metabolism via CYP2D6 and greater levels of M1. Follow patients closely
for increased risk of serious adverse events including seizures and serotonin
syndrome, and adverse reactions related to opioid toxicity including
potentially fatal respiratory depression, particularly when an inhibitor is
added after a stable dose of CALPOL T is achieved.
 After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline,
the tramadol plasma concentration will decrease (see 5. Pharmacological
Properties), resulting in decreased opioid efficacy and possibly signs and
symptoms of opioid withdrawal in patients who had developed physical
dependence to tramadol.
Intervention: If concomitant use is necessary, consider dosage reduction of CALPOL T
until stable drug effects are achieved. Follow patients closely for seizures
and serotonin syndrome, and signs of respiratory depression and sedation
at frequent intervals.

If a CYP3A4 inhibitor is discontinued, consider increasing the CALPOL T

dosage until stable drug effects are achieved and follow patients for signs
and symptoms of opioid withdrawal.
Examples Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g.
ketoconazole), protease inhibitors (e.g., ritonavir).
CYP3A4 Inducers
Clinical Impact: The concomitant use of CALPOL T and CYP3A4 inducers can decrease the
plasma concentration of tramadol (see 5. Pharmacological Properties),
resulting in decreased efficacy or onset of a withdrawal syndrome in
patients who have developed physical dependence to tramadol.

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the
tramadol plasma concentration will increase (see 5. Pharmacological
Properties), which could increase or prolong both the therapeutic effects
and adverse reactions, and may cause serious respiratory depression,
seizures and serotonin syndrome.
Intervention: If concomitant use is necessary, consider increasing the CALPOL T dosage
until stable drug effects are achieved. Follow patients for signs of opioid
withdrawal.

If a CYP3A4 inducer is discontinued, consider CALPOL T dosage

reduction and monitor for seizures and serotonin syndrome, and signs of
sedation and respiratory depression.

Patients taking carbamazepine, a CYP3A4 inducer, may have a

significantly reduced analgesic effect of tramadol. Because carbamazepine
increases tramadol metabolism and because of the seizure risk associated
with tramadol, concomitant administration of CALPOL T and
carbamazepine is not recommended.
Examples: Rifampin, carbamazepine, phenytoin.
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact: Due to additive pharmacologic effect, the concomitant use of
benzodiazepines or other CNS depressants, including alcohol, can increase
the risk of hypotension, respiratory depression, profound sedation, coma,
and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for
whom alternative treatment options are inadequate. Limit dosages and
durations to the minimum required. Follow patients closely for signs of
respiratory depression and sedation (see 4.4 Special Warnings and
Precautions for Use).
If concomitant use is warranted, consider prescribing naloxone for the
emergency treatment of opioid overdose (see 4.4 Special Warnings and
Precautions for Use)
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers,
muscle relaxants, general anesthetics, antipsychotics, other opioids,
alcohol.
Serotonergic Drugs
Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic
neurotransmitter system has resulted in serotonin syndrome.
Intervention: If concomitant use is warranted, carefully observe the patient, particularly
during treatment initiation and dose adjustment. Discontinue CALPOL T
if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and
norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants
(TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the
serotonin neurotransmitter system (e.g., mirtazapine, trazodone,
tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat
psychiatric disorders and also others, such as linezolid and intravenous
methylene blue).

Monoamine Oxidase Inhibitors (MAOIs)

Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome (see
4.4 Special Warnings and Precautions for Use) or opioid toxicity (e.g.,
respiratory depression, coma) (see 4.4 Special Warnings and Precautions
for Use).
Intervention: Do not use CALPOL T in patients taking MAOIs or within 14 days of
stopping such treatment.
Examples: phenelzine, tranylcypromine, linezolid.
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact: May reduce the analgesic effect of CALPOL T and/or precipitate
withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine.

Muscle Relaxants
Clinical Impact: Tramadol may enhance the neuromuscular blocking action of skeletal
muscle relaxants and produce an increased degree of respiratory
depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than
otherwise expected and decrease the dosage of CALPOL T and/or the
muscle relaxant as necessary. Due to the risk of respiratory depression with
 concomitant use of skeletal muscle relaxants and opioids, consider
prescribing naloxone for the emergency treatment of opioid overdose (see
4.4 Special Warnings and Precautions for Use).
Diuretics
Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of
antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood
pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary
retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility
when CALPOL T is used concomitantly with anticholinergic drugs.
Digoxin
Clinical Impact: Post-marketing surveillance of tramadol has revealed rare reports of
digoxin toxicity.
Intervention: Follow patients for signs of digoxin toxicity and adjust dosage of digoxin
as needed.
Warfarin
Clinical Impact: Post-marketing surveillance of tramadol has revealed rare reports of
alteration of warfarin effect, including elevation of prothrombin times.
Intervention: Monitor the prothrombin time of patients on warfarin for signs of an
interaction and adjust the dosage of warfarin as needed.

4.6 Use in Special Populations

Pregnancy

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal
syndrome (see 4.4 Special Warnings and Precautions for Use). Available data with CALPOL T in
pregnant women are insufficient to inform a drug-associated risk for major birth defects and
miscarriage.

In animal reproduction studies, the combination of tramadol and acetaminophen decreased fetal
weights and increased supernumerary ribs at 1.6 times the maximum recommended human daily
dosage (MRHD). In separate animal reproduction studies, tramadol administration alone during
organogenesis decreased fetal weights and reduced ossification in mice, rats, and rabbits at 1.4,
0.6, and 3.6 times the maximum recommended human daily dosage (MRHD). Tramadol decreased
pup body weight and increased pup mortality at 1.2 and 1.9 times the MRHD.

Reproductive and developmental studies in rats and mice from the published literature identified
adverse events at clinically relevant doses with acetaminophen. Treatment of pregnant rats with
doses of acetaminophen approximately 1.3 times the maximum human daily dose (MRHD)
showed evidence of fetotoxicity and increases in bone variations in the fetuses. In another study,
necrosis was observed in the liver and kidney of both pregnant rats and fetuses at doses
approximately 1.9 times the MHDD. In mice treated with acetaminophen at doses within the
clinical dosing range, cumulative adverse effects on reproduction were seen in a continuous
breeding study. A reduction in number of litters of the parental mating pair was observed as well
as retarded growth and abnormal sperm in their offspring and reduced birth weight in the next
generation (see ‘Data’ below). Based on animal data, advise pregnant women of the potential risk
to a fetus.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can
result in respiratory depression and physical dependence in the neonate and neonatal opioid
withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep
pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration,
and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used,
duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the
newborn. Observe newborns for symptoms and signs of neonatal opioid withdrawal syndrome and
manage accordingly (see 4.4 Special Warnings and Precautions for Use).

Neonatal seizures, neonatal withdrawal syndrome, fetal death and stillbirth have been reported
with tramadol hydrochloride during postmarketing.

Labor or Delivery

CALPOL T is not recommended for use in pregnant women during or immediately prior to labor,
when other analgesic techniques are more appropriate. Opioids cross the placenta and may produce
respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as
naloxone, must be available for reversal of opioid induced respiratory depression in the neonate.
CALPOL T is not recommended for use in pregnant women during or immediately prior to labor,
when other analgesic techniques are more appropriate. Opioid analgesics, including CALPOL T,
can prolong labor through actions which temporarily reduce the strength, duration, and frequency
of uterine contractions. However, this effect is not consistent and may be offset by an increased
rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid
analgesics during labor for signs of excess sedation and respiratory depression.

Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical
veins compared to maternal veins was 0.83 for 40 women given tramadol during labor.

The effect of CALPOL T, if any, on the later growth, development, and functional maturation of
the child is unknown.
Data

Animal Data

No drug-related teratogenic effects were observed in the progeny of rats treated orally with
tramadol and acetaminophen. The tramadol/acetaminophen combination product was shown to be
embryotoxic and fetotoxic in rats at a maternally toxic dose, 50/434 mg/kg
tramadol/acetaminophen (1.6 times the maximum daily human tramadol/acetaminophen dosage),
but was not teratogenic at this dose level. Embryo and fetal toxicity consisted of decreased fetal
weights and increased supernumerary ribs. Tramadol has been shown to be embryotoxic and
fetotoxic in mice, (120 mg/kg), rats (25 mg/kg) and rabbits (75 mg/kg) at maternally toxic dosages,
but was not teratogenic at these dose levels. These doses on a mg/m2 basis are 1.9, 0.8, and 4.9
times the maximum recommended human daily dosage (MRHD) for mouse, rat and rabbit,
respectively.

No drug-related teratogenic effects were observed in progeny of mice (up to 140 mg/kg), rats (up
to 80 mg/kg) or rabbits (up to 300 mg/kg) treated with tramadol by various routes. Embryo and
fetal toxicity consisted primarily of decreased fetal weights, skeletal ossification and increased
supernumerary ribs at maternally toxic dose levels. Transient delays in developmental or
behavioral parameters were also seen in pups from rat dams allowed to deliver. Embryo and fetal
lethality were reported only in one rabbit study at 300 mg/kg, a dose that would cause extreme
maternal toxicity in the rabbit. The dosages listed for mouse, rat and rabbit are 2.3, 2.6, and 19
times the MRHD, respectively.

Tramadol alone was evaluated in peri- and post-natal studies in rats. Progeny of dams receiving
oral (gavage) dose levels of 50 mg/kg (300 mg/m2 or 1.6 times the maximum daily human
tramadol dosage) or greater had decreased weights, and pup survival was decreased early in
lactation at 80 mg/kg (480 mg/m2 or 2.6 times the maximum daily human tramadol dosage).

Studies in pregnant rats that received oral acetaminophen during organogenesis at doses up to 1.3
times the maximum human daily dose (MHDD = 2.6 grams/day, based on a body surface area
comparison) showed evidence of fetotoxicity (reduced fetal weight and length) and a dose-related
increase in bone variations (reduced ossification and rudimentary rib changes). Offspring had no
evidence of external, visceral, or skeletal malformations.

When pregnant rats received oral acetaminophen throughout gestation at doses of 1.9-times the
MHDD (based on a body surface area comparison), areas of necrosis occurred in both the liver
and kidney of pregnant rats and fetuses. These effects did not occur in animals that received oral
acetaminophen at doses 0.5-times the MHDD, based on a body surface area comparison.

In a continuous breeding study, pregnant mice received 0.25, 0.5, or 1.0% acetaminophen via the
diet (357, 715, or 1430 mg/kg/day). These doses are approximately 0.7, 1.3, and 2.7 times the
MHDD, respectively, based on a body surface area comparison. A dose-related reduction in body
weights of fourth and fifth litter offspring of the treated mating pair occurred during lactation and
post-weaning at all doses. Animals in the high dose group had a reduced number of litters per
mating pair, male offspring with an increased percentage of abnormal sperm, and reduced birth
weights in the next generation pups.

Lactation

Risk Summary

CALPOL T is not recommended for obstetrical preoperative medication or for post-delivery

analgesia in nursing mothers because its safety in infants and newborns has not been studied.

Tramadol and its metabolite, O-desmethyltramadol (M1), are present in human milk. There is no
information on the effects of the drug on the breastfed infant or the effects of the drug on milk
production. The M1 metabolite is more potent than tramadol in mu opioid receptor binding.
Published studies have reported tramadol and M1 in colostrum with administration of tramadol to
nursing mothers in the early post-partum period. Women who are ultra-rapid metabolizers of
tramadol may have higher than expected serum levels of M1, potentially leading to higher levels
of M1 in breast milk that can be dangerous in their breastfed infants. In women with normal
tramadol metabolism, the amount of tramadol secreted into human milk is low and dose-
dependent. Because of the potential for serious adverse reactions, including excess sedation and
respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended
during treatment with CALPOL T.

Clinical Considerations

If infants are exposed to CALPOL T through breast milk they should be monitored for excess
sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when
maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Data

Following a single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16
hours post-dose was 100 μg of tramadol (0.1% of the maternal dose) and 27 μg of M1.

Females and Males of Reproductive Potential

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential.
It is not known whether these effects on fertility are reversible (see 4.8 Undesirable Effects, 5
Pharmacological Properties and 6 Non-Clinical Properties).

Pediatric Use

The safety and effectiveness of CALPOL T in pediatric patients have not been established.
Life-threatening respiratory depression and death have occurred in children who received tramadol
(see 4.4 Special Warnings and Precautions for Use). In some of the reported cases, these events
followed tonsillectomy and/or adenoidectomy, and one of the children had evidence of being an
ultra-rapid metabolizer of tramadol (i.e., multiple copies of the gene for cytochrome P450
isoenzyme 2D6). Children with sleep apnea may be particularly sensitive to the respiratory
depressant effects of tramadol.

Because of the risk of life-threatening respiratory depression and death:

• CALPOL T is contraindicated for all children younger than age 12 years of age (see 4.3
Contraindications).
• CALPOL T is contraindicated for post-operative management in pediatric patients younger
than 18 years of age following tonsillectomy and/or adenoidectomy (see 4.3
Contraindications).
• Avoid the use of CALPOL T in adolescents 12 to 18 years of age who have other risk factors
that may increase their sensitivity to the respiratory depressant effects of tramadol unless the
benefits outweigh the risks. Risk factors include conditions associated with hypoventilation
such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease,
neuromuscular disease, and concomitant use of other medications that cause respiratory
depression.

Geriatric Use

Elderly patients (65 years of age or older) may have increased sensitivity to tramadol. In general,
use caution when selecting a dosage for an elderly patient, usually starting at the low end of the
dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and
of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred
after large initial doses were administered to patients who were not opioid-tolerant or when opioids
were co-administered with other agents that depress respiration. Titrate the dosage of CALPOL T
slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory
depression (see 4.4 Special Warnings and Precautions for Use).

Tramadol and acetaminophen are known to be substantially excreted by the kidney, and the risk
of adverse reactions to this drug may be greater in patients with impaired renal function. Because
elderly patients are more likely to have decreased renal function, care should be taken in dose
selection, and it may be useful to monitor renal function.

Hepatic Impairment

The pharmacokinetics and tolerability of CALPOL T in patients with impaired hepatic function
have not been studied. Based on information using tramadol immediate-release tablets in subjects
with advanced cirrhosis of the liver, tramadol exposure was higher and half-lives of tramadol and
active metabolite M1 were longer than in subjects with normal hepatic function (see 5
Pharmacological Properties).
As tramadol and acetaminophen are both extensively metabolized by the liver, the use of CALPOL
T in patients with hepatic impairment is not recommended (see 4.4 Special Warnings and
Precautions for Use).

Renal Impairment

The pharmacokinetics and tolerability of CALPOL T in patients with renal impairment has not
been studied. Based on studies using tramadol extended-release tablets, the excretion of tramadol
and metabolite M1 is reduced in patients with creatinine clearance of less than 30 mL/min. In
patients with creatinine clearances of less than 30 mL/min, it is recommended that the dosage of
CALPOL T not exceed 2 tablets every 12 hours. (see 4.2 Posology and Method of Administration).
The total amount of tramadol and M1 removed during a 4 hour dialysis period is less than 7% of
the administered dose based on studies using tramadol alone. Monitor closely for signs of
respiratory depression, sedation, and hypotension.

Sex

Tramadol clearance was 20% higher in female subjects compared to males in four Phase 1 studies
of CALPOL T in 50 male and 34 female healthy subjects. The clinical significance of this
difference is unknown.

4.7 Effects on Ability to Drive and Use Machines

CALPOL T may impair the mental or physical abilities needed to perform potentially hazardous
activities such as driving a car or operating machinery. Warn patients not to drive or operate
dangerous machinery unless they are tolerant to the effects of CALPOL T and know how they will
react to the medication.

4.8 Undesirable Effects

The following serious adverse reactions are discussed, or described in greater detail, in section 4.4
Special Warnings and Precautions for Use:

• Addiction, Abuse, and Misuse

• Life-Threatening Respiratory Depression
• Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory
Depression in Children
• Neonatal Opioid Withdrawal Syndrome
• Hepatotoxicity
• Interactions with Benzodiazepines or other CNS Depressants
• Serotonin Syndrome
• Seizures
• Suicide
• Adrenal Insufficiency
• Severe Hypotension
• Gastrointestinal Adverse Reactions
• Hypersensitivity Reactions
• Withdrawal

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in practice.

The most common incidence of treatment-emergent adverse events (≥3.0%) in subjects from
clinical trials was constipation, diarrhea, nausea, somnolence, anorexia, dizziness, and sweating
increased.

Table 1 shows the incidence rate of treatment-emergent adverse events reported in ≥2.0% of
subjects over five days of Tramadol/acetaminophen combination use in clinical trials (subjects
took an average of at least 6 tablets per day).

Table 1: Incidence of Treatment-Emergent Adverse Events (≥2.0%)

Body System Tramadol/acetaminophen

combination (N=142)
Preferred Term (%)
Gastrointestinal System Disorders
Constipation 6
Diarrhea 3
Nausea 3
Dry Mouth 2
Psychiatric Disorders
Somnolence 6
Anorexia 3
Insomnia 2
Central & Peripheral Nervous System
Dizziness 3
Skin and Appendages
Sweating Increased 4
Pruritus 2
Reproductive Disorders, Male*
Prostatic Disorder 2
*Number of males = 62

Incidence at least 1%, causal relationship at least possible or greater:

The following lists adverse reactions that occurred with an incidence of at least 1% in single-dose
or repeated-dose clinical trials of tramadol/acetaminophen combination.
Body as a Whole – Asthenia, fatigue, hot flushes
Central and Peripheral Nervous System – Dizziness, headache, tremor
Gastrointestinal System – Abdominal pain, constipation, diarrhea, dyspepsia, flatulence, dry
mouth, nausea, vomiting
Psychiatric Disorders – Anorexia, anxiety, confusion, euphoria, insomnia, nervousness,
somnolence
Skin and Appendages – Pruritus, rash, increased sweating

Selected Adverse events occurring at less than 1%:

The following lists clinically relevant adverse reactions that occurred with an incidence of less
than 1% in tramadol/acetaminophen combination clinical trials.

Body as a Whole – Chest pain, rigors, syncope, withdrawal syndrome

Cardiovascular Disorders – Hypertension, aggravated hypertension, hypotension
Central and Peripheral Nervous System – Ataxia, convulsions, hypertonia, migraine, aggravated
migraine, involuntary muscle contractions, paresthesias, stupor, vertigo
Gastrointestinal System – Dysphagia, melena, tongue edema
Hearing and Vestibular Disorders – Tinnitus
Heart Rate and Rhythm Disorders – Arrhythmia, palpitation, tachycardia
Liver and Biliary System – Hepatic function abnormal
Metabolic and Nutritional Disorders – Weight decrease
Psychiatric Disorders – Amnesia, depersonalization, depression, drug abuse, emotional liability,
hallucination, impotence, paroniria, abnormal thinking
Red Blood Cell Disorders – Anemia
Respiratory System – Dyspnea
Urinary System – Albuminuria, micturition disorder, oliguria, urinary retention
Vision Disorders – Abnormal vision

Postmarketing Experience

The following adverse reactions have been identified during post approval use of tramadol-
containing products. Because these reactions are reported voluntarily from a population of
uncertain size, it is not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have

been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more
often following greater than one month of use.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in CALPOL T.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids (see
5 Pharmacological Properties).
QT prolongation/torsade de pointes: Cases of QT prolongation and/or torsade de pointes have been
reported with tramadol use. Many of these cases were reported in patients taking another drug
labeled for QT prolongation, in patients with a risk factor for QT prolongation (e.g., hypokalemia),
or in the overdose setting.

Eye disorders – miosis, mydriasis

Metabolism and nutrition disorders – Cases of hypoglycemia have been reported very rarely in
patients taking tramadol. Most reports were in patients with predisposing risk factors, including
diabetes or renal insufficiency, or in elderly patients.

Nervous system disorders – movement disorder, speech disorder

Psychiatric disorders – delirium

Other clinically significant adverse experiences previously reported with tramadol hydrochloride:

Other events which have been reported with the use of tramadol products and for which a causal
association has not been determined include: vasodilation, orthostatic hypotension, myocardial
ischemia, pulmonary edema, allergic reactions (including anaphylaxis and urticaria, Stevens-
Johnson syndrome/TENS), cognitive dysfunction, difficulty concentrating, depression, suicidal
tendency, hepatitis, liver failure, and gastrointestinal bleeding. Reported laboratory abnormalities
included elevated creatinine and liver function tests. Serotonin syndrome (whose symptoms may
include mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis,
seizures, and coma) has been reported with tramadol when used concomitantly with other
serotonergic agents such as SSRIs and MAOIs.

4.9 Overdose

Clinical Presentation

CALPOL T is a combination product. The clinical presentation of overdose may include the signs
and symptoms of tramadol toxicity, acetaminophen toxicity or both. The initial symptoms of
tramadol overdosage may include respiratory depression and/or seizures. The initial symptoms
seen within the first 24 hours following an acetaminophen overdose are: anorexia, nausea,
vomiting, malaise, pallor and diaphoresis.

Tramadol

Acute overdosage with tramadol can be manifested by respiratory depression, somnolence

progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils,
and, in some cases, pulmonary edema, bradycardia, QT prolongation, hypotension, partial or
complete airway obstruction, atypical snoring, seizures, and death. Marked mydriasis rather than
miosis may be seen with hypoxia in overdose situations.
Deaths due to overdose have been reported with abuse and misuse of tramadol (see 4.4 Special
Warnings and Precautions for Use: Misuse, Abuse, and Diversion). Review of case reports has
indicated that the risk of fatal overdose is further increased when tramadol is abused concurrently
with alcohol or other CNS depressants, including other opioids.

Acetaminophen

Acetaminophen overdose may be injurious to liver.

In acute acetaminophen overdosage, dose-dependent, potentially fatal hepatic necrosis is the most
serious adverse effect. Renal tubular necrosis, hypoglycemic coma, and thrombocytopenia also
occur. Plasma acetaminophen levels > 300 mcg/mL at 4 hours after oral ingestion were associated
with hepatic damage in 90% of patients; minimal hepatic damage is anticipated if plasma levels at
4 hours are < 150 mcg/mL or < 37.5 mcg/mL at 12 hours after ingestion. Early symptoms following
a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis, and general
malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72
hours post-ingestion.

Treatment of Overdose

A single or multiple drug overdose with tramadol and acetaminophen is a potentially lethal
polydrug overdose, and consultation with a regional poison control center is recommended.
Immediate treatment includes support of cardiorespiratory function and measures to reduce drug
absorption. Oxygen, intravenous fluids, vasopressors, assisted ventilation, and other supportive
measures should be employed as indicated.

Tramadol

In case of overdose, priorities are the re-establishment of a patent and protected airway and
institution of assisted or controlled ventilation, if needed. Employ other supportive measures
(including oxygen and vasopressors) in the management of circulatory shock and pulmonary
edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques.

Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting
from opioid overdose.

For clinically significant respiratory or circulatory depression secondary to tramadol overdose,

administer an opioid antagonist.
While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the
risk of seizures is also increased with naloxone administration. In animals, convulsions following
the administration of toxic doses of Tramadol/acetaminophen combination could be suppressed
with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration
did not change the lethality of an overdose in mice. Hemodialysis is not expected to be helpful in
an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period.
Because the duration of opioid reversal is expected to be less than the duration of action of
tramadol in CALPOL T, carefully monitor the patient until spontaneous respiration is reliably re-
established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer
additional antagonist as directed by the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage

of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal
symptoms experienced will depend on the degree of physical dependence and the dose of the
antagonist administered. If a decision is made to treat serious respiratory depression in the
physically dependent patient, administration of the antagonist should be begun with care and by
titration with smaller than usual doses of the antagonist.

Acetaminophen

If an acetaminophen overdose is suspected, obtain a serum acetaminophen assay as soon as

possible, but no sooner than 4 hours following oral ingestion. Obtain liver function studies initially
and repeat at 24-hour intervals. Administer the antidote N-acetylcysteine (NAC) as early as
possible. As a guide to treatment of acute ingestion, the acetaminophen level can be plotted against
time since oral ingestion on a nomogram Rumack-Matthew). The lower toxic line on the
nomogram is equivalent to 150 mcg/mL at 4 hours and 37.5 mcg/mL at 12 hours. If serum level is
above the lower line, administer the entire course of NAC treatment. Withhold NAC therapy if the
acetaminophen level is below the lower line.

Gastric decontamination with activated charcoal should be administered just prior to N-

acetylcysteine (NAC) to decrease systemic absorption if acetaminophen ingestion is known or
suspected to have occurred within a few hours of presentation. Serum acetaminophen levels should
be obtained immediately if the patient presents 4 hours or more after ingestion to assess potential
risk of hepatotoxicity; acetaminophen levels drawn less than 4 hours post-ingestion may be
misleading. To obtain the best possible outcome, NAC should be administered as soon as possible
where impending or evolving liver injury is suspected. Intravenous NAC may be administered
when circumstances preclude oral administration.

Vigorous supportive therapy is required in severe intoxication. Procedures to limit the continuing
absorption of the drug must be readily performed since the hepatic injury is dose-dependent and
occurs early in the course of intoxication.

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the
patient and caregiver and assess the potential need for access to naloxone, both when initiating
and renewing treatment with CALPOL T (see 4.4 Special Warnings and Precautions for Use).

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as
concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose.
However, the presence of risk factors for overdose should not prevent the proper management of
pain in any given patient (see 4.4 Special Warnings and Precautions for Use).
Consider prescribing naloxone if the patient has household members (including children) or other
close contacts at risk for accidental exposure or overdose.

4.10 Drug Abuse and Dependence

Abuse

ULTRACET contains tramadol, a substance with a high potential for abuse similar to other opioids
and can be abused and is subject to misuse, addiction, and criminal diversion (see 4.4 Special
Warnings and Precautions for Use).

All patients treated with opioids require careful monitoring for signs of abuse and addiction, since
use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once,
for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop
after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling
its use, persisting in its use despite harmful, or potentially harmful, consequences, a higher priority
given to drug use than to other activities and obligations, increased tolerance, and sometimes a
physical withdrawal.

“Drug seeking” behavior is very common in persons with substance use disorders. Drug seeking
tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate
examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions, and
reluctance to provide prior medical records or contact information for other treating physician(s).
“Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common
among drug abusers and people suffering from untreated addiction. Preoccupation with achieving
adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care
providers should be aware that addiction may not be accompanied by concurrent tolerance and
symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the
absence of true addiction.

CALPOL T, like other opioids, can be diverted for non-medical use into illicit channels of
distribution.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy,
and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of CALPOL T

CALPOL T is for oral use only. Abuse of CALPOL T poses a risk of overdose and death. The risk
is increased with concurrent abuse of CALPOL T with alcohol and other central nervous system
depressants.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as
hepatitis and HIV.

Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is
the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the
absence of disease progression or other external factors). Tolerance may occur to both the desired
and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence is a physiological state in which the body adapts to the drug after a period of
regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant
dosage reduction of a drug. Withdrawal also may be precipitated through the administration of
drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist
analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine).
Physical dependence may not occur to a clinically significant degree until after several days to
weeks of continued opioid usage.

Do not abruptly discontinue CALPOL T in a patient physically dependent on opioids. Rapid

tapering of CALPOL T in a patient physically dependent on opioids may lead to serious
withdrawal symptoms, uncontrolled pain and suicide.

Rapid discontinuation has also been associated with attempts to find other sources of opioid
analgesics, which may be confused with drug-seeking for abuse.

When discontinuing opioids, gradually taper the dosage using a patient-specific plan that considers
the following: the dose of the opioid the patient has been taking, the duration of treatment, and the
physical and psychological attributes of the patient. To improve the likelihood of a successful taper
and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed
upon by the patient. In patients taking opioids for a long duration at high doses, ensure that a
multimodal approach to pain management, including mental health support (if needed), is in place
prior to initiating an opioid analgesic taper (see 4.2 Posology and Method of Administration and
4.4 Special Warnings and Precautions of use).

Infants born to mothers physically dependent on opioids will also be physically dependent and
may exhibit respiratory difficulties and withdrawal signs (see 4.6 Use in Specific Populations)
5. PHARMACOLOGICAL PROPERTIES

The following information is based on studies of tramadol alone or acetaminophen alone, except
where otherwise noted:

5.1 Mechanism of Action

CALPOL T contains tramadol, an opioid agonist and inhibitor of norepinephrine and serotonin re-
uptake, and acetaminophen. Although the mode of action of tramadol is not completely
understood, the analgesic effect of tramadol is believed to be due to both binding to μ-opioid
receptors and weak inhibition of reuptake of norepinephrine and serotonin.

Opioid activity of tramadol is due to both low affinity binding of the parent compound and higher
affinity binding of the O-demethylated metabolite M1 to μ-opioid receptors. In animal models, M1
is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-
opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist
naloxone in several animal tests. The relative contribution of both tramadol and M1 to human
analgesia is dependent upon the plasma concentrations of each compound.

Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have
some other opioid analgesics. These mechanisms may contribute independently to the overall
analgesic profile of tramadol.

Acetaminophen is a non-opioid, non-salicylate analgesic. The site and mechanism for the analgesic
effect of acetaminophen has not been determined but is thought to primarily involve central
actions.

5.2 Pharmacodynamic Properties

Effects on the Central Nervous System

Tramadol produces respiratory depression by direct action on brain stem respiratory centers. The
respiratory depression involves a reduction in the responsiveness of the brain stem respiratory
centers to both increases in carbon dioxide tension and electrical stimulation.

Tramadol causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but
are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce
similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose
situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Tramadol causes a reduction in motility associated with an increase in smooth muscle tone in the
antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and
propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased,
while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced
effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi,
and transient elevations in serum amylase.

Effects on the Cardiovascular System

Tramadol produces peripheral vasodilation which may result in orthostatic hypotension or

syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus,
flushing, red eyes, sweating, and/or orthostatic hypotension.

The effect of oral tramadol on the QTcF interval was evaluated in a double-blind, randomized,
four-way crossover, placebo-and positive-(moxifloxacin) controlled study in 68 adult male and
female healthy subjects. At a 600 mg/day dose (1.5-fold the maximum immediate-release daily
dose), the study demonstrated no significant effect on the QTcF interval.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing
hormone (LH) in humans (see 4.4 Special Warnings and Precautions for Use, 4.8 Undesirable
Effects). They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion
of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to

androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea,
or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown
because the various medical, physical, lifestyle, and psychological stressors that may influence
gonadal hormone levels have not been adequately controlled for in studies conducted to date (see
4.8 Undesirable Effects).

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in
vitro and animal models. The clinical significance of these findings is unknown. Overall, the
effects of opioids appear to be modestly immunosuppressive.

Concentration–Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially
among patients who have been previously treated with potent opioid agonists. The minimum
effective analgesic concentration of tramadol for any individual patient may increase over time
due to an increase in pain, the development of a new pain syndrome and/or the development of
analgesic tolerance (see 4.2 Posology and Method of Administration).

Concentration–Adverse Reaction Relationships

There is a relationship between increasing tramadol plasma concentration and increasing

frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and
respiratory depression. In opioid-tolerant patients, the situation may be altered by the development
of tolerance to opioid-related adverse reactions (see 4.2 Posology and Method of Administration).

5.3 Pharmacokinetic Properties

Tramadol is administered as a racemate and both the [-] and [+] forms of both tramadol and M1
are detected in the circulation.

Absorption

The absolute bioavailability of tramadol from tramadol/acetaminophen combination tablets has

not been determined. Tramadol has a mean absolute bioavailability of approximately 75%
following administration of a single 100 mg oral dose of tramadol/acetaminophen combination
tablets. The mean peak plasma concentration of racemic tramadol and M1 after administration of
two tramadol/acetaminophen combination tablets occurs at approximately two and three hours,
respectively, post-dose.

The pharmacokinetics of plasma tramadol and acetaminophen following oral administration of one
tablet of tramadol 37.5mg and acetaminophen 325mg combination are shown in Table 2.
Tramadol has a slower absorption and longer half-life when compared to acetaminophen.

Table 2: Summary of Mean (±SD) Pharmacokinetic Parameters of the (+)- and (-)
Enantiomers of Tramadol and M1 and Acetaminophen Following A Single Oral Dose Of
One Tramadol/Acetaminophen Combination Tablet (37.5 mg/325 mg) in Volunteers

Parametera (+)-Tramadol (-)-Tramadol (+) -M1 (-) -M1 Acetaminophen

Cmax (ng/mL) 64.3 (9.3) 55.5 (8.1) 10.9 (5.7) 12.8 (4.2) 4.2 (0.8)
tmax (h) 1.8 (0.6) 1.8 (0.7) 2.1 (0.7) 2.2 (0.7) 0.9 (0.7)
CL/F (mL/min) 588 (226) 736 (244) - - - - 365 (84)
t1/2 (h) 5.1 (1.4) 4.7 (1.2) 7.8 (3.0) 6.2 (1.6) 2.5 (0.6)
a
For acetaminophen, Cmax was measured as μg/mL.

A single dose pharmacokinetic study of tramadol/acetaminophen combination in volunteers

showed no drug interactions between tramadol and acetaminophen.

Upon multiple oral dosing to steady state, however, the bioavailability of tramadol and metabolite
M1 was lower for the combination tablets compared to tramadol administered alone. The decrease
in AUC was 14% for (+)-tramadol, 10.4% for (-)-tramadol, 11.9% for (+)-M1 and 24.2% for (-)-
M1. The cause of this reduced bioavailability is not clear.

Peak plasma concentrations of acetaminophen occur within one hour and are not affected by co-
administration with tramadol. Following single- or multiple-dose administration of
tramadol/acetaminophen combination, no significant change in acetaminophen pharmacokinetics
was observed when compared to acetaminophen given alone.
Food Effect

When tramadol/acetaminophen was administered with food, the time to peak plasma concentration
was delayed for approximately 35 minutes for tramadol and almost one hour for acetaminophen.
However, peak plasma concentrations, and the extents of absorption, of tramadol and
acetaminophen were not affected. The clinical significance of this difference is unknown.

Distribution

The volume of distribution of tramadol was 2.6 and 2.9 L/kg in male and female subjects,
respectively, following a 100 mg intravenous dose. The binding of tramadol to human plasma
proteins is approximately 20% and binding also appears to be independent of concentration up to
10μg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically
relevant range.

Acetaminophen appears to be widely distributed throughout most body tissues except fat. Its
apparent volume of distribution is about 0.9 L/kg. A relative small portion (~20%) of
acetaminophen is bound to plasma protein.

Elimination

Tramadol is eliminated primarily through metabolism by the liver and the metabolites are
eliminated primarily by the kidneys. The mean (SD) apparent total clearance of tramadol after a
single 37.5 mg dose is 588 (226) mL/min for the (+) isomer and 736 (244) mL/min for the (-)
isomer. The plasma elimination half-lives of racemic tramadol and M1 are approximately 5-6 and
7 hours, respectively, after administration of tramadol/acetaminophen combination. The apparent
plasma elimination half-life of racemic tramadol increased to 7-9 hours upon multiple dosing of
tramadol/acetaminophen combination.

The half-life of acetaminophen is about 2 to 3 hours in adults. It is somewhat shorter in children

and somewhat longer in neonates and in cirrhotic patients. Acetaminophen is eliminated from the
body primarily by formation of glucuronide and sulfate conjugates in a dose-dependent manner.

Metabolism

Following oral administration, tramadol is extensively metabolized by a number of pathways,

including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. The major
metabolic pathways appear to be N- and O-demethylation and glucuronidation or sulfation in the
liver. Metabolite M1 (O-desmethyltramadol) is pharmacologically active in animal models.
Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition, which may affect
the therapeutic response (see 4.5 Drug Interactions).

Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of

cytochrome P450. These individuals are “poor metabolizers” of debrisoquine, dextromethorphan,
tricyclic antidepressants, among other drugs. Based on a population PK analysis of Phase 1 studies
in healthy subjects, concentrations of tramadol were approximately 20% higher in “poor
metabolizers” versus “extensive metabolizers”, while M1 concentrations were 40% lower. In vitro
drug interaction studies in human liver microsomes indicate that inhibitors of CYP2D6 such as
fluoxetine and its metabolite norfluoxetine, amitriptyline and quinidine inhibit the metabolism of
tramadol to various degrees. The full pharmacological impact of these alterations in terms of either
efficacy or safety is unknown.

Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three
principal separate pathways:

a) conjugation with glucuronide;

b) conjugation with sulfate; and
c) oxidation via the cytochrome, P450-dependent, mixed-function oxidase enzyme pathway
to form a reactive intermediate metabolite, which conjugates with glutathione and is then
further metabolized to form cysteine and mercapturic acid conjugates. The principal
cytochrome P450 isoenzyme involved appears to be CYP2E1, with CYP1A2 and CYP3A4
as additional pathways.

In adults, the majority of acetaminophen is conjugated with glucuronic acid and, to a lesser extent,
with sulfate. These glucuronide-, sulfate-, and glutathione-derived metabolites lack biologic
activity. In premature infants, newborns, and young infants, the sulfate conjugate predominates.

Excretion
Approximately 30% of the tramadol dose is excreted in the urine as unchanged drug, whereas 60%
of the dose is excreted as metabolites.

Less than 9% of acetaminophen is excreted unchanged in the urine.

Special Populations

Hepatic Impairment

Pharmacokinetics of tramadol was studied in patients with mild or moderate hepatic impairment
after receiving multiple doses of tramadol extended-release 100 mg. The exposure of (+)-and (-)­
tramadol was similar in mild and moderate hepatic impairment patients in comparison to patients
with normal hepatic function. However, exposure of (+)- and (-)-M1 decreased ~50% with
increased severity of the hepatic impairment (from normal to mild and moderate). The
pharmacokinetics of tramadol after the administration of tramadol extended-release has not been
studied in patients with severe hepatic impairment. After the administration of tramadol
immediate-release tablets to patients with advanced cirrhosis of the liver, tramadol area under the
plasma concentration time curve was larger and the tramadol and M1 half-lives were longer than
subjects with normal hepatic function (see 4.6. Use In Special Populations).

Renal Impairment

Impaired renal function results in a decreased rate and extent of excretion of tramadol and
its active metabolite, M1. The pharmacokinetics of tramadol were studied in patients with mild or
moderate renal impairment after receiving multiple doses of tramadol extended-release 100 mg.
There is no consistent trend observed for tramadol exposure related to renal function in patients
with mild (CLcr: 50-80 mL/min) or moderate (CLcr: 30-50 mL/min) renal impairment in
comparison to patients with normal renal function. However, exposure of M1 increased 20-40%
with increased severity of the renal impairment (from normal to mild and moderate). tramadol
extended-release has not been studied in patients with severe renal impairment (CLcr
< 30 mL/min). The total amount of tramadol and M1 removed during a 4-hour dialysis period is
less than 7% of the administered dose (see 4.6 Use in Special Populations).

Geriatric Population

A population pharmacokinetic analysis of data obtained from a clinical trial in patients with
chronic pain treated with tramadol/acetaminophen combination which included 55 patients
between 65 and 75 years of age and 19 patients over 75 years of age, showed no significant changes
in the pharmacokinetics of tramadol and acetaminophen in elderly patients with normal renal and
hepatic function (see 4.6 Use in Special Populations).

Sex

Tramadol clearance was 20% higher in female subjects compared to males on four phase I studies
of tramadol/acetaminophen combination in 50 male and 34 female healthy subjects. The clinical
significance of this difference is unknown.

Poor / Extensive Metabolizers, CYP2D6

The formation of the active metabolite, M1, is mediated by CYP2D6. Approximately 7% of the
population has reduced activity of the CYP2D6 isoenzyme of cytochrome P-450. These
individuals are “poor metabolizers” of debrisoquine, dextromethorphan, and tricyclic
antidepressants, among other drugs. Based on a population PK analysis of Phase I studies with
immediate-release tablets in healthy subjects, concentrations of tramadol were approximately 20%
higher in “poor metabolizers” versus “extensive metabolizers,” while M1 concentrations were
40% lower.

Drug Interaction Studies

CYP2D6 Inhibitors

In vitro drug interaction studies in human liver microsomes indicate that inhibitors of CYP2D6
(fluoxetine, norfluoxetine, amitriptyline, and quinidine) inhibit the metabolism of tramadol to
various degrees, suggesting that concomitant administration of these compounds could result in
increases in tramadol concentrations and decreased concentrations of M1. The full
pharmacological impact of these alterations in terms of either efficacy or safety is unknown.
Quinidine

Tramadol is metabolized to M1 by CYP2D6. A study was conducted to examine the effect of

quinidine, a selective inhibitor of CYP2D6, on the pharmacokinetics of tramadol by administering
200 mg quinidine two hours before the administration of 100 mg tramadol extended release tablet.
The results demonstrated that the exposure of tramadol increased 50­ 60% and the exposure of M1
decreased 50-60%. In vitro drug interaction studies in human liver microsomes indicate that
tramadol has no effect on quinidine metabolism (see 4.4 Special Warnings and Precautions for
Use and 4.5 Drug Interactions).

Cimetidine

Concomitant administration of tramadol and cimetidine does not result in clinically significant
changes in tramadol pharmacokinetics. Therefore, no alteration of the CALPOL T dosage regimen
is recommended.

CYP3A4 Inhibitors and Inducers

Tramadol is metabolized by CYP3A4. Administration of CYP3A4 inhibitors, such as

ketoconazole and erythromycin, or CYP3A4 inducers, such as rifampin and St. John’s Wort, with
tramadol may affect the metabolism of tramadol leading to altered tramadol exposure (see 4.4
Special Warnings and Precautions for Use and 4.5 Drug Interactions).

Carbamazepine

Carbamazepine, a CYP3A4 inducer, increases tramadol metabolism. Patients taking

carbamazepine may have a significantly reduced analgesic effect of tramadol. Concomitant
administration of tramadol and carbamazepine is not recommended.

Potential for Tramadol to Affect Other Drugs

In vitro studies indicate that tramadol is unlikely to inhibit the CYP3A4-mediated metabolism of
other drugs when tramadol is administered concomitantly at therapeutic doses. Tramadol does not
appear to induce its own metabolism in humans, since observed maximal plasma concentrations
after multiple oral doses are higher than expected based on single dose data.

6. NONCLINICAL PROPERTIES

6.1 Animal Toxicology and Pharmacology

Carcinogenesis, Mutagenesis, Impairment of Fertility

There are no animal or laboratory studies on the combination product (tramadol and
acetaminophen) to evaluate carcinogenesis, mutagenesis, or impairment of fertility. Data on the
individual components are described below.
Carcinogenesis

A slight but statistically significant increase in two common murine tumors, pulmonary and
hepatic, was observed in an NMRI mouse carcinogenicity study, particularly in aged mice. Mice
were dosed orally up to 30 mg/kg in the drinking water (0.5 times the maximum recommended
daily human dosage or MRHD) for approximately two years, although the study was not done with
the Maximum Tolerated Dose. This finding is not believed to suggest risk in humans. No evidence
of carcinogenicity was noted in a rat 2- year carcinogenicity study testing oral doses of up to 30
mg/kg in the drinking water (1 times the MRHD).

Long-term studies in mice and rats have been completed by the National Toxicology Program to
evaluate the carcinogenic potential of acetaminophen. In 2-year feeding studies, F344/N rats and
B6C3F1 mice were fed a diet containing acetaminophen up to 6000 ppm. Female rats demonstrated
equivocal evidence of carcinogenic activity based on increased incidences of mononuclear cell
leukemia at 1.2 times the maximum human daily dose (MHDD) of 2.6 grams/day, based on a body
surface area comparison. In contrast, there was no evidence of carcinogenic activity in male rats
(1.1 times) or mice (1.9-2.2 times the MHDD, based on a body surface area comparison).

Mutagenesis

Tramadol was mutagenic in the presence of metabolic activation in the mouse lymphoma assay.
Tramadol was not mutagenic in the in vitro bacterial reverse mutation assay using Salmonella and
E. coli (Ames), the mouse lymphoma assay in the absence of metabolic activation, the in vitro
chromosomal aberration assay, or the in vivo micronucleus assay in bone marrow.

Acetaminophen was not mutagenic in the bacterial reverse mutation assay (Ames test). In contrast,
acetaminophen tested positive for induction of sister chromatid exchanges and chromosomal
aberrations in in vitro assays using Chinese hamster ovary cells. In the published literature,
acetaminophen has been reported to be clastogenic when administered a dose of 1500 mg/kg/day
to the rat model (3.6-times the MHDD, based on a body surface area comparison). In contrast, no
clastogenicity was noted at a dose of 750 mg/kg/day (2.8-times the MHDD, based on a body
surface area comparison), suggesting a threshold effect.

Impairment of Fertility

No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg in male rats
and 75 mg/kg in female rats. These dosages are 1.6 and 2.4 times the MRHD (see 4.6 Use in
Special Populations).

In studies of acetaminophen conducted by the National Toxicology Program, fertility assessments

have been completed in Swiss mice via a continuous breeding study. There were no effects on
fertility parameters in mice consuming up to 1.7 times the MHDD of acetaminophen, based on a
body surface area comparison. Although there was no effect on sperm motility or sperm density
in the epididymis, there was a significant increase in the percentage of abnormal sperm in mice
consuming 1.7 times the MHDD (based on a body surface area comparison) and there was a
reduction in the number of mating pairs producing a fifth litter at this dose, suggesting the potential
for cumulative toxicity with chronic administration of acetaminophen near the upper limit of daily
dosing.

Published studies in rodents report that oral acetaminophen treatment of male animals at doses that
are 1.2 times the MHDD and greater (based on a body surface area comparison) result in decreased
testicular weights, reduced spermatogenesis, reduced fertility, and reduced implantation sites in
females given the same doses. These effects appear to increase with the duration of treatment. The
clinical significance of these findings is not known.

7. DESCRIPTION

CALPOL T combines two analgesics, tramadol hydrochloride (an opioid agonist), and
acetaminophen (paracetamol).

The chemical name for tramadol hydrochloride is (±)cis-2-[(dimethylamino)methyl]-1-(3-

methoxyphenyl) cyclohexanol hydrochloride. Its structural formula is:

The molecular weight of tramadol hydrochloride is 299.84. Tramadol hydrochloride is a white,

bitter, crystalline, and odorless powder.

The chemical name for acetaminophen is N-acetyl-p-aminophenol. Its structural formula is:

The molecular weight of acetaminophen is 151.17. Acetaminophen is an analgesic and antipyretic

agent which occurs as a white, odorless, crystalline powder, possessing a slightly bitter taste.

CALPOL T tablets contains 37.5 mg of tramadol hydrochloride and 325 mg acetaminophen and
are light yellow in color.
8. PHARMACEUTICAL PARTICULARS

8.1 List of Excipients

Pregelatinised Starch, Maize Starch, Sodium Starch Glycolate, Microcrystalline Cellulose,
Magnesium Stearate, Opadry Yellow, Hypromellose 6, Titanium Dioxide, Triacetin, Iron Oxide
Yellow.

8.2 Incompatibilities

No incompatibilities have been identified.

8.3 Shelf Life

The expiry date is indicated on the label and packaging.

8.4 Packaging Information

Blister strips in a carton or CRSF (Child Resistant Senior Friendly) blister strips in a carton.

8.5 Storage and Handling Information

Store protected from light and moisture at temperature not exceeding 30°C.

Keep out of reach of children.

These tablets come in special packaging to prevent children removing them.

To take out a tablet gently push one end of the tablet through the foil layer.
For more information open the link below:

https://www.youtube-nocookie.com/embed/OYXJcPkJrVA

9. PATIENT COUNSELLING INFORMATION

Registered Medical Practitioners may counsel their patients (and/or patient’s caregiver as
applicable) about the special warnings and precautions for use, drug interactions, undesirable
effects, and any relevant contra-indications of CALPOL T. Patients (and/or patient’s caregiver)
may also be informed about posology, method of administration and storage/handling information
as applicable.
10. DETAILS OF MANUFACTURER

The Manufacturing Site details are mentioned on the label and packaging.

For further information, please contact:

GlaxoSmithKline Pharmaceuticals Limited.
Registered Office:
Dr. Annie Besant Road, Worli,
Mumbai 400 030, India.

11. DETAILS OF PERMISSION OR LICENSE NUMBER WITH DATE

Manufacturing License number is indicated on the label and packaging.

12. DATE OF REVISION

11-Apr-2023

Trademarks are owned by or licensed to the GSK group of companies.

Version: CALT/PI/IN/2023/01

Adapted from ULTRACET USPI revised 02/2023.