Tramadol hydrochloride 37.5mg and Paracetamol 325mg film-coated tablets USP Taj Pharma

1.NAME OF THE MEDICINAL PRODUCT
Tramadol hydrochloride 37.5mg and Paracetamol 325mg film-coated tablets USP Taj Pharma

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains:
Tramadol hydrochloride USP      37.5 mg
equivalent to 32.94 mg tramadol
Paracetamol                                  325 mg
Excipients                                        q.s.
Colour: Yellow Iron Oxide

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM
Film-coated tablet.
Tablets are yellow-brown, oval, slightly biconvex.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications
Tramadol hydrochloride/Paracetamol tablets are indicated for the symptomatic treatment of moderate to severe pain.
The use of Tramadol hydrochloride/Paracetamol should be restricted to patients whose moderate to severe pain is considered to require a combination of tramadol and paracetamol (see also section 5.1).

4.2 Posology and method of administration
Posology

Adults and adolescents (12 years and older)
The use of Tramadol hydrochloride/Paracetamol should be restricted to patients whose moderate to severe pain is considered to require a combination of tramadol and paracetamol.

The dose should be individually adjusted according to intensity of the pain and the sensitivity of the individual patient. The lowest effective dose for analgesia should generally be selected.

An initial dose of two tablets of Tramadol hydrochloride/Paracetamol is recommended. Additional doses can be taken as needed, not exceeding 8 tablets (equivalent to 300 mg tramadol hydrochloride and 2600 mg paracetamol) per day.

The dosing interval should not be less than six hours.

Tramadol hydrochloride/Paracetamol should under no circumstances be administered for longer than is strictly necessary (see also section 4.4.). If repeated use or long term treatment with Tramadol hydrochloride/Paracetamol is required as a result of the nature and severity of the illness, then careful, regular monitoring should take place (with breaks in the treatment, where possible), to assess whether continuation of the treatment is necessary.

Paediatric population

The effective and safe use of Tramadol hydrochloride/Paracetamol has not been established in children below the age of 12 years. Treatment is therefore not recommended in this population.

Elderly patients
A dose adjustment is not usually necessary in patients up to 75 years without clinically manifest hepatic or renal insufficiency. In elderly patients over 75 years elimination may be prolonged. Therefore, if necessary the dosage interval is to be extended according to the patient’s requirements.

Renal insufficiency/dialysis
Because of the presence of tramadol, the use of Tramadol hydrochloride/Paracetamol is not recommended in patients with severe renal insufficiency (creatinine clearance < 10 ml/min). In cases of moderate renal insufficiency (creatinine clearance between 10 and 30 ml/min), the dosing should be increased to 12-hourly intervals. As tramadol is removed only very slowly by haemodialysis or by haemofiltration, post dialysis administration to maintain analgesia is not usually required.

Hepatic impairment
In patients with hepatic impairment the elimination of tramadol is delayed. In these patients prolongation of dosage intervals should be carefully considered according to the patient’s requirements (see section 4.4).

Because of the presence of paracetamol should not be used in patients with severe hepatic impairment (see section 4.3).

Method of administration
Oral use.

Tablets must be swallowed whole, with a sufficient quantity of liquid. They must not be crushed or chewed.

4.3 Contraindications
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Acute intoxication with alcohol, hypnotic medicinal products, centrally-acting analgesics, opioids or psychotropic medicinal products.

Tramadol hydrochloride/Paracetamol should not be administered to patients who are receiving monoamine oxidase inhibitors or within two weeks of their withdrawal (see section 4.5).

Severe hepatic impairment.

Epilepsy not controlled by treatment (see section 4.4).

4.4 Special Warnings and precautions for use
Warnings
– The maximum dose of 8 tablets of Tramadol hydrochloride/Paracetamol should not be exceeded in adults and adolescents 12 years and older. In order to avoid inadvertent overdose, patients should be advised not to exceed the recommended dose and not to use any other paracetamol (including over the counter) or tramadol hydrochloride containing products concurrently without the advice of a physician.

– In severe renal impairment (creatinine clearance <10 ml/min), Tramadol hydrochloride/Paracetamol is not recommended.

– In patients with severe hepatic impairment Tramadol hydrochloride/Paracetamol should not be used (see section 4.3). The hazards of paracetamol overdose are greater in patients with non-cirrhotic alcoholic liver disease. In moderate cases prolongation of dosage interval should be carefully considered.

– In severe respiratory impairment, Tramadol hydrochloride/Paracetamol is not recommended.

– Tramadol is not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, tramadol cannot suppress morphine withdrawal symptoms.

– Convulsions have been reported in tramadol-treated patients susceptible to seizures or taking other medications that lower the seizure threshold, especially selective serotonin re-uptake inhibitors, tricyclic antidepressants, antipsychotics, centrally acting analgesics or local anaesthesia. Epileptic patients controlled by a treatment or patients susceptible to seizures should be treated with Tramadol hydrochloride/Paracetamol only if there are compelling circumstances. Convulsions have been reported in patients receiving tramadol at the recommended dose levels. The risk may be increased when doses of tramadol exceed the recommended upper dose limit.

Precautions for use
Tolerance and physical and/or psychological dependence may develop, even at therapeutic doses. The clinical need for analgesic treatment should be reviewed regularly (see 4.2). In opioid-dependent patients and patients with a history of drug abuse or dependence, treatment should only be for short period and under medical supervision.

Tramadol hydrochloride/Paracetamol should be used with caution in patients with cranial trauma, in patients prone to convulsive disorder, biliary tract disorders, in a state of shock, in an altered state of consciousness for unknown reasons, with problems affecting the respiratory centre or the respiratory function, or with an increased intracranial pressure.

Paracetamol overdosage may cause hepatic toxicity in some patients.

Symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal may occur even at therapeutic doses and for short term treatment (see section 4.8). Withdrawal symptoms may be avoided by taper it at the time of discontinuation especially after long treatment periods. Rarely, cases of dependence and abuse have been reported (see section 4.8).

In one study, use of tramadol during general anaesthesia with enflurane and nitrous oxide was reported to enhance intra-operative recall. Until further information is available, use of tramadol during light plans of anaesthesia should be avoided.

4.5 Interaction with other medicinal products and other forms of interaction
Concomitant use is contraindicated with:

– Non-selective MAO Inhibitors
Risk of serotoninergic syndrome: diarrhoea, tachycardia, hyperhidrosis, trembling, confusional state, even coma.

– Selective-A MAO Inhibitors
Extrapolation from non-selective MAO inhibitors, risk of serotoninergic syndrome: diarrhoea, tachycardia, hyperhidrosis, trembling, confusional state, even coma.

– Selective-B MAO Inhibitors
Central excitation symptoms evocative of a serotoninergic syndrome: diarrhoea, tachycardia, hyperhidrosis, trembling, confusional state, even coma.

In case of recent treatment with MAO inhibitors, a delay of two weeks should occur before treatment with tramadol

Concomitant use is not recommended with:

– Alcohol
Alcohol increases the sedative effect of opioid analgesics. The effect on alertness can make driving of vehicles and the use of machines dangerous. Avoid intake of alcoholic drinks and of medicinal products containing alcohol.

– Carbamazepine and other enzyme inducers
Risk of reduced efficacy and shorter duration due to decreased plasma concentrations of tramadol.

– Opioid agonists-antagonists (buprenorphine, nalbuphine, pentazocine)

Decrease of the analgesic effect by competitive blocking effect at the receptors, with the risk of occurrence of withdrawal syndrome.

Concomitant use which needs to be taken into consideration
– Tramadol can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and other seizure threshold-lowering medicinal products (such as bupropion, mirtazapine, tetrahydrocannabinol), to cause convulsions.

– Concomitant therapeutic use of tramadol and serotonergic drugs such as selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors (see section 4.3), tricyclic antidepressants and mirtazapine may cause serotonin toxicity. Serotonin syndrome is likely if when one of the following is observed:

– Spontaneous clonus

– Inducible or ocular clonus with, agitation or diaphoresis

– Tremor and hyperreflexia,

– Hypertonia and body temperature >38°C and inducible or ocular clonus.

Withdrawal of the serotonergic drugs usually brings about a rapid improvement. Treatment depends on the type and severity of the symptoms.

– Other opioid derivatives (including antitussive medicinal products and substitutive treatments), benzodiazepines and barbiturates: increased risk of respiratory depression which can be fatal in cases of overdose.

– Other central nervous system depressants, such as other opioid derivatives (including antitussive drugs and substitutive treatments), barbiturates, benzodiazepines, other anxiolytics, hypnotics, sedative antidepressants, sedative antihistamines, neuroleptics, centrally-acting antihypertensive medicinal products, thalidomide and baclofen. These active substances can cause increased central depression. The effect on alertness can make driving of vehicles and the use of machines dangerous.

– Caution should be exercised during concomitant treatment with Tramadol hydrochloride/Paracetamol and coumarin derivatives (e.g. warfarin) due to reports of increased INR with major bleeding and ecchymoses in some patients.

– Other drugs known to inhibit CYP3A4, such as ketoconazole and erythromycin, might inhibit the metabolism of tramadol (N-demethylation) probably also the metabolism of the active O-demethylated metabolite. The clinical importance of such an interaction has not been studied.

– In a limited number of studies the pre- or postoperative application of the antiemetic 5-HT3 antagonist ondansetron increased the requirement of tramadol in patients with postoperative pain.

4.6 Fertility, Pregnancy and lactation
Pregnancy
Since Tramadol hydrochloride/Paracetamol is a fixed combination of active ingredients including tramadol, it should not be used during pregnancy.

Data regarding paracetamol:
Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage.

Data regarding tramadol:
Tramadol should not be used during pregnancy as there is inadequate evidence available to assess the safety of tramadol in pregnant women. Tramadol administered before or during birth does not affect uterine contractility. In neonates it may induce changes in the respiratory rate which are usually not clinically relevant. Long-term treatment during pregnancy may lead to withdrawal symptoms in the newborn after birth, as a consequence of habituation.

Breast-feeding
Since Tramadol hydrochloride/Paracetamol is a fixed combination of active ingredients including tramadol, it should not be used more than once during breast feeding or alternatively, breast-feeding should be discontinued during treatment with tramadol.

Data regarding paracetamol:
Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data on paracetamol does not contraindicate it for breast feeding by women using single ingredient medicinal products containing only paracetamol.

Data regarding tramadol:
Approximately 0.1% of the maternal dose of tramadol is excreted in breast milk. In the immediate post-partum period, for maternal oral daily dosage up to 400 mg, this corresponds to a mean amount of tramadol ingested by breast-fed infants of 3% of the maternal weight-adjusted dosage. For this reason tramadol should not be used during lactation or alternatively, breast-feeding should be discontinued during treatment with tramadol. Discontinuation of breast-feeding is generally not necessary following a single dose of tramadol.

Fertility
Post marketing surveillance does not suggest an effect of tramadol on fertility.

Animal studies did not show an effect of tramadol on fertility. No study on fertility was accomplished with the combination of tramadol and paracetamol.

4.7 Effects on ability to drive and use machines
Tramadol hydrochloride may cause drowsiness or dizziness, which may be enhanced by alcohol or other CNS depressants. If affected, the patient should not drive or operate machinery.

4.8 Undesirable Effects
Undesirable effects that may occur during treatment with Tramadol hydrochloride/Paracetamol are classified into the following groups in order of frequency:
– very common (≥1/10)
– common (≥1/100 to <1/10)
– uncommon (≥1/1,000 to <1/100)
– rare (≥1/10,000 to <1/1,000)
– very rare (<1/10,000)
– not known (cannot be estimated from the available data)

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The most commonly reported undesirable effects during the clinical trials performed with the paracetamol/tramadol combination were nausea, dizziness and somnolence, observed in more than 10% of the patients.

Frequency of undesirable effects listed by individual organ systems:

	Very common	Common	Uncommon	Rare	Very rare	Unknown
Metabolism and nutrition disorders						hypoglycaemia
Psychiatric disorders		confusional state, mood altered, anxiety, nervousness, euphoric mood, sleep disorders	depression, hallucinations, nightmares, amnesia	drug dependence	abuse*
Nervous system disorders	dizziness, somnolence	headache, trembling	involuntary muscular contractions, paraesthesia	ataxia, convulsions, syncope
Eye disorders				blurred vision
Ear and labyrinth disorders			tinnitus
Cardiac disorders			palpitations, tachycardia, arrythmia
Vascular disorders			hypertension, hot flush
Respiratory, thoracic and mediastinal disorders			dyspnoea
Gastrointestinal disorders	nausea	vomiting, constipation, dry mouth, diarrhoea abdominal pain, dyspepsia, flatulence	dysphagia, melaena.
Skin and subcutaneous tissue disorders		hyperhidrosis, pruritus	dermal reactions (e.g. rash, urticaria)
Renal and urinary disorders			albuminuria, micturition disorders (dysuria and urinary retention).
General disorders and administration site conditions			chills, chest pain
Investigations			transaminases increase

*Reported in post marketing surveillance.

Although not observed during clinical trials, the occurrence of the following undesirable effects known to be related to the administration of tramadol or paracetamol cannot be excluded:

Tramadol
– Postural hypotension, bradycardia, collapse (tramadol).

– Post-marketing surveillance of tramadol has revealed rare alterations of warfarin effect, including elevation of prothrombin times.

– Rare cases: allergic reactions with respiratory symptoms (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis.

– Rare cases: changes in appetite, motor weakness, and respiratory depression.

– Psychic side-effects may occur following administration of tramadol which vary individually in intensity and nature (depending on personality and duration of medication). These include changes in mood, (usually elation occasionally dysphoria), changes in activity (usually suppression occasionally increase) and changes in cognitive and sensorial capacity (e.g. decision behaviour perception disorders).

– Worsening of asthma has been reported though a causal relationship has not been established.

– Symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms. Other symptoms that have very rarely been seen if tramadol hydrochloride is discontinued abruptly include: panic attacks, severe anxiety, hallucinations, paraesthesia, tinnitus and unusual CNS symptoms.

Paracetamol
– Adverse effects of paracetamol are rare but hypersensitivity including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to paracetamol.

– There have been several reports that suggest that paracetamol may produce hypoprothrombinemia when administered with warfarin-like compounds. In other studies, prothrombin time did not change.

– Very rare cases of serious skin reactions have been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

4.9 Overdose
Tramadol hydrochloride/Paracetamol is a fixed combination of active ingredients. In case of overdose, the symptoms may include the signs and symptoms of toxicity of tramadol or paracetamol or of both these active ingredients.

Symptoms of overdose from tramadol
In principle, on intoxication with tramadol, symptoms similar to those of other centrally acting analgesics (opioids) are to be expected. These include in particular, miosis, vomiting, cardiovascular collapse, consciousness disorders up to coma, convulsions and respiratory depression up to respiratory arrest.

Symptoms of overdose from paracetamol
An overdose is of particular concern in young children. Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalophathy, coma and death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Liver damage is possible in adults who have taken 7.5-10 g or more of paracetamol. It is considered that excess quantities of a toxic metabolite (usually adequately detoxified by glutathione when normal doses of paracetamol are ingested), become irreversibly bound to liver tissue.

Emergency treatment
– Transfer immediately to a specialised unit.

– Maintain respiratory and circulatory functions.

– Prior to starting treatment, a blood sample should be taken as soon as possible after overdose in order to measure the plasma concentration of paracetamol and tramadol and in order to perform hepatic tests.

– Perform hepatic tests at the start (of overdose) and repeat every 24 hours. An increase in hepatic enzymes (ASAT, ALAT) is usually observed, which normalizes after one or two weeks.

– Empty the stomach by causing the patient to vomit (when the patient is conscious) by irritation or gastric lavage.

– Supportive measures such as maintaining the patency of the airway and maintaining cardiovascular function should be instituted; naloxone should be used to reverse respiratory depression; fits can be controlled with diazepam.

– Tramadol is minimally eliminated from the serum by haemodialysis or haemofiltration. Therefore treatment of acute intoxication with Tramadol hydrochloride/Paracetamol with haemodialysis or haemofiltration alone is not suitable for detoxification.

Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention and any adult or adolescent who had ingested around 7.5 g or more of paracetamol in the preceding 4 hours or any child who has ingested ≥150 mg/kg of paracetamol in the preceding 4 hours should undergo gastric lavage. Paracetamol concentrations in blood should be measured later than 4 hours after overdose in order to be able to assess the risk of developing liver damage (via the paracetamol overdose nomogram). Administration of oral methionine or intravenous N-acetylcysteine (NAC) which may have a beneficial effect up to at least 48 hours after the overdose, may be required. Administration of intravenous N-acetylcysteine (NAC) is most beneficial when initiated within 8 hours of overdose ingestion. However, NAC should still be given if the time to presentation is greater than 8 hours after overdose and continued for a full course of therapy. NAC treatment should be started immediately when massive overdose is suspected. General supportive measures must be available.

Irrespective of the reported quantity of paracetamol ingested, the antidote for paracetamol, NAC, should be administered orally or intravenously, as quickly as possible, if possible, within 8 hours following the overdose.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: other opioids, tramadol, combinations,

Analgesics
Tramadol is an opioid analgesic that acts on the central nervous system. Tramadol is pure non selective agonists of the μ, δ, and κ opioid receptors with a higher affinity for the µ receptors. Other mechanisms which contribute to its analgesic effect are inhibition of neuronal reuptake of noradrenaline and enhancement of serotonin release. Tramadol has an antitussive effect. Unlike morphine, a broad range of analgesic doses of tramadol has no respiratory depressant effect. Similarly, the gastro-intestinal motility is not modified. The cardiovascular effects are generally slight. The potency of tramadol is considered to be one-tenth to one-sixth that of morphine.

Mechanism of action
The precise mechanism of the analgesic properties of paracetamol is unknown and may involve central and peripheral effects.

Tramadol hydrochloride/Paracetamol is positioned as a step II analgesic in the WHO pain ladder and should be utilised accordingly by the physician.

5.2 Pharmacokinetic properties
Tramadol is administered in racemic form and the [-] and [+] forms of tramadol and its metabolite M1, are detected in the blood. Although tramadol is rapidly absorbed after administration, its absorption is slower (and its half-life longer) than that of paracetamol.

After a single oral administration of a tramadol/paracetamol (37.5 mg/325 mg) tablet, peak plasma concentrations of 64.3/55.5 ng/ml [(+)-tramadol/(-)-tramadol] and 4.2 µg/ml (paracetamol) are reached after 1.8 h [(+)-tramadol/(-)-tramadol] and 0.9 h (paracetamol) respectively. The mean elimination half-lives t_1/2 are 5.1/4.7 h [(+)-tramadol/(-)-tramadol] and 2,5 h (paracetamol).

During pharmacokinetic studies in healthy volunteers after single and repeated oral administration of Tramadol hydrochloride/Paracetamol, no clinical significant change was observed in the kinetic parameters of each active ingredient compared to the parameters of the active ingredients used alone.

Absorption
Racemic tramadol is rapidly and almost completely absorbed after oral administration. The mean absolute bioavailability of a single 100 mg dose is approximately 75%. After repeated administration, the bioavailability is increased and reaches approximately 90%.

After administration of Tramadol hydrochloride/Paracetamol, the oral absorption of paracetamol is rapid and nearly complete and takes place mainly in the small intestine. Peak plasma concentrations of paracetamol are reached in one hour and are not modified by concomitant administration of tramadol.

The oral administration of Tramadol hydrochloride/Paracetamol with food has no significant effect on the peak plasma concentration or extent of absorption of either tramadol or paracetamol so that Tramadol hydrochloride/Paracetamol can be taken independently of meal times.

Distribution
Tramadol has a high tissue affinity (V_d,β=203 ± 40 l). It has a plasma protein binding of about 20%.

Paracetamol 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 paracetamol is bound to plasma proteins.

Biotransformation
Tramadol is extensively metabolized after oral administration. About 30% of the dose is excreted in urine as unchanged drug, whereas 60% of the dose is excreted as metabolites.

Tramadol is metabolised through O-demethylation (catalysed by the enzyme CYP2D6) to the metabolite M1, and through N-demethylation (catalysed by CYP3A) to the metabolite M2. M1 is further metabolised through N-demethylation and by conjugation with glucuronic acid. The plasma elimination half-life of M1 is 7 hours. The metabolite M1 has analgesic properties and is more potent than the parent drug. The plasma concentrations of M1 are several-fold lower than those of tramadol and the contribution to the clinical effect are unlikely to change on multiple dosing.

Paracetamol is principally metabolized in the liver through two major hepatic routes: glucuronidation and sulphation. The latter route can be rapidly saturated at doses above the therapeutic doses. A small fraction (less than 4%) is metabolized by cytochrome P450 to an active intermediate (the N-acetyl benzoquinoneimine) which, under normal conditions of use, is rapidly detoxified by reduced glutathione and excreted in urine after conjugation to cysteine and mercapturic acid. However, during massive overdose, the quantity of this metabolite is increased.

Elimination
Tramadol and its metabolites are eliminated mainly by the kidneys.

The half-life of paracetamol is approximately 2 to 3 hours in adults. It is shorter in children and slightly longer in the newborn and in cirrhotic patients. Paracetamol is mainly eliminated by dose-dependent formation of glucuro- and sulpho-conjugate derivatives. Less than 9% of paracetamol is excreted unchanged in urine. In renal insufficiency, the half-life of both compounds is prolonged.

5.3 Preclinical safety data
No preclinical study has been performed with the fixed combination (tramadol and paracetamol) to evaluate its carcinogenic or mutagenic effects or its effects on fertility.

No teratogenic effect that can be attributed to the medicine has been observed in the progeny of rats treated orally with the combination tramadol/paracetamol.

The combination tramadol/paracetamol has proven to be embryotoxic and foetotoxic in the rat at materno-toxic dose (50/434 mg/kg tramadol/paracetamol), i.e., 8.3 times the maximum therapeutic dose in man. No teratogenic effect has been observed at this dose. The toxicity to the embryo and the foetus results in a decreased foetal weight and an increase in supernumerary ribs. Lower doses, causing less severe materno-toxic effect (10/87 and 25/217 mg/kg tramadol/paracetamol) did not result in toxic effects in the embryo or the foetus.

Results of standard mutagenicity tests did not reveal a potential genotoxic risk for tramadol in man.

Results of carcinogenicity tests do not suggest a potential risk of tramadol for man.

Animal studies with tramadol revealed, at very high doses, effects on organ development, ossification and neonatal mortality, associated with maternotoxicity. Fertility reproductive performance and development of offspring were unaffected. Tramadol crosses the placenta. No effect on fertility has been observed after oral administration of tramadol up to doses of 50 mg/kg in the male rat and 75 mg/kg in the female rat.

Extensive investigations showed no evidence of a relevant genotoxic risk of paracetamol at therapeutic (i.e. non-toxic) doses.

Long-term studies in rats and mice yielded no evidence of relevant tumorigenic effects at non-hepatotoxic dosages of paracetamol.

Animal studies and extensive human experience to date yield no evidence of reproductive toxicity.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients
Tablet core:
Pregelatinised maize starch
Sodium starch glycolate (type A)
Microcrystalline cellulose (E460)
Magnesium stearate (E572)

Film-coating:
Hypromellose (E464)
Titanium dioxide (E171)
Macrogol 400
Yellow iron oxide (E172)
Polysorbate 80

6.2 Incompatibilities
Not applicable.

6.3 Shelf life
3 years.

6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container
Blister (PVC/PVDC white foil, aluminium foil): 2 film-coated tablets (blisters with 2 tablets) or 10, 20, 30, 40, 50, 60, 70, 80, 90 and 100 film-coated tablets (blisters with 10 tablets), in a box.

Child-resistant blister (PVC/PVDC white foil, paper/aluminium foil): 2 film-coated tablets (blisters with 2 tablets) or 10, 20, 30, 40, 50, 60, 70, 80, 90 and 100 film-coated tablets (blisters with 10 tablets), in a box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling
No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Package leaflet: Information for the patient

Tramadol hydrochloride 37.5mg and Paracetamol 325mg film-coated tablets USP Taj Pharma

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.
– Keep this leaflet. You may need to read it again.
– If you have any further questions, ask your doctor or pharmacist.
– This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
– If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

What is in this leaflet
1. What Tramadol HCl and Paracetamol is and what it is used for
2. Before you are given Tramadol HCl and Paracetamol
3. How you will be given Tramadol HCl and Paracetamol
4. Possible side effects
5. How Tramadol HCl and Paracetamol is stored
6. Further Information

1. What Tramadol HCl and Paracetamol is and what it is used for
Tramadol HCl and Paracetamol is a combination of two analgesics (pain killers) tramadol and paracetamol that act together to relieve your pain. Tramadol HCl and Paracetamol is intended for use in the treatment of moderate to severe pain when your doctor recommends that a combination of tramadol and paracetamol is needed.

2. Before you are given Tramadol HCl and Paracetamol
Do not take Tramadol HCl and Paracetamol if you:
• are allergic to paracetamol, tramadol or any of the other ingredients of this medicine (listed in section 6)
• drink alcohol
• take any medicine that can make you sleepy or less alert; these include opioids containing pain relievers such as morphine and codeine
• are also taking MAO inhibitors (certain medicines used for treatment of depression or Parkinson’s disease) or have taken them in the last 14 days before treatment with Tramadol HCl and Paracetamol
• suffer from severe liver problems
• have epilepsy that is not adequately controlled on your current medicine.

Warnings and precautions
Talk to your doctor or pharmacist before taking Tramadol HCl and Paracetamol.
Take special care with Tramadol HCl and Paracetamol if you:
• have kidney problems
• have liver problems or alcoholic liver disease or you have noticed your eyes and skin turning yellow, which may suggest jaundice or problems with bile ducts
• have difficulty breathing, for example, asthma or lung problems
• are dependent on any other medicines used to relieve moderate to severe pain, for example, morphine
• are epileptic or if have you experienced fits or seizures
• have suffered from a head injury, shock or severe headaches which may or may not be associated with vomiting
• take other medicines containing paracetamol or tramadol.

Other medicines and Tramadol HCl and Paracetamol
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
• Important: This medicine contains paracetamol and tramadol. Tell your doctor if you are taking any other medicine containing paracetamol or tramadol, so that you do not exceed the maximum daily doses.
• You must not take Tramadol HCl and Paracetamol together with monoamine oxidase inhibitors (“MAOIs”) (see section “Do not take Tramadol HCl and Paracetamol”).

Tramadol HCl and Paracetamol is not recommended with the following medicines, as it may affect how well they work:
• carbamazepine (a medicine used to treat epilepsy or some types of pain)
• buprenorphine, nalbuphine or pentazocine (opioid-type pain relievers). The pain-relieving effect may be reduced.

Tramadol HCl and Paracetamol may increase the risk of side effects if you also take the following medicines:
• triptans (used for migraine) or selective serotonin re-uptake inhibitors (SSRIs, used for depression). Check with your doctor if you experience confusion, restlessness, fever, sweating, uncoordinated movement of limbs or eyes, uncontrollable jerking of muscles or diarrhoea.
• tranquilizers, sleeping pills, other pain relievers such as morphine and codeine (also as cough medicine), baclofen (a muscle relaxant), medicines used to lower blood pressure, antidepressants or medicines to treat allergies. Check with your doctor if you feel drowsy or feel faint.
• antidepressants, anaesthetics, medicines that affect the state of mind, or bupropion (used to help stop smoking). The risk of having a fit may increase. Your doctor will tell you whether Tramadol HCl and Paracetamol is suitable for you.
• warfarin or phenprocoumon (for blood thinning). The effectiveness of such medicines may be altered and bleeding may occur (see section 4).

The effectiveness of Tramadol HCl and Paracetamol may be altered if you also take the following medicines:
• metoclopramide, domperidone or ondansetron (medicines used to treat nausea and vomiting/being sick)
• cholestyramine (medicine used to reduce cholesterol in the blood)
• ketoconazole or erythromycin (medicines used against infections).

Tramadol HCl and Paracetamol with food, drink and alcohol
Tramadol HCl and Paracetamol can be taken with or without food.
• Tramadol HCl and Paracetamol may make you feel drowsy. Alcohol may make you feel drowsier. Alcohol: increases the sedative effect of opioid analgesics, the effect on alertness can make driving of vehicles and the use of machines dangerous, avoid intake of alcoholic drinks and of medicinal products containing alcohol.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy
Since Tramadol HCl and Paracetamol is a fixed combination of active ingredients including tramadol, it should not be used during pregnancy.

Breast-feeding
Tramadol is excreted into breast milk. For this reason, you should not take Tramadol HCl and Paracetamol more than once during breast-feeding, or alternatively, if you take Tramadol HCl and Paracetamol more than once, you should stop breast-feeding.

Driving and using machines
Do not drive, operate machinery or perform other activities for which you need to be alert until you know how Tramadol HCl and Paracetamol affects you. Tramadol HCl and Paracetamol may make you feel drowsy.

3. How you will be given Tramadol HCl and Paracetamol
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

The usual starting dose is two tablets. If required, further doses can be taken after every six hours, as recommended by your doctor.
Do not take more than 8 tablets per day (equivalent to 300 mg tramadol hydrochloride and 2600 mg paracetamol).
The dosage should be adjusted to the intensity of your pain and your individual pain sensitivity. In general the lowest pain-relieving dose should be taken.

Severe liver disease (insufficiency)
Patients with severe liver insufficiency should not take Tramadol hydrochloride /Paracetamol. If in your case the insufficiency is mild or moderate, your doctor may recommend prolonging the dosage interval.

Use in children
Tramadol HCl and Paracetamol is not recommended for use in children under 12 years.

Elderly patients
In elderly patients (above 75 years) the excretion of tramadol may be delayed. If this applies to you, your doctor may recommend prolonging the dosage interval.

The tablets must be swallowed with some liquid. The tablets should not be chewed or crushed. The tablets should be taken for as short a time as possible. If you think that the effect of Tramadol HCl and Paracetamol is too strong (i.e. you feel very drowsy or have difficulty with breathing) or too weak (i.e. you have inadequate pain relief), contact your doctor or pharmacist. If your symptoms do not get any better, see your doctor.

If you take more Tramadol HCl and Paracetamol than you should
Immediate medical advice should be sought in the event of an overdose, even if you feel well, because of the risk of delayed, serious liver damage. If you take more Tramadol HCl and Paracetamol than you should you could experience severe disturbance of blood supply to organs, consciousness disorders up to coma, convulsions, or you might have difficulty breathing, feel unwell, vomit, lose weight or feel abdominal pain.

If you forget to take Tramadol HCl and Paracetamol
Do not take a double dose to make up for a forgotten tablet. If you miss a dose of Tramadol HCl and Paracetamol, take your next tablet at the usual time.

If you stop taking Tramadol HCl and Paracetamol
If you have been using Tramadol HCl and Paracetamol for some time, you should talk to your doctor if you want to stop because your body may have got used to it. If you do suddenly stop using Tramadol/ Paracetamol you may feel unwell. You may experience anxiety, agitation, nervousness, sleeplessness, hyperactivity, tremors and/or an upset stomach.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible Side Effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.

The very common side effects (may affect more than 1 in 10 people):
• nausea,
• dizziness,
• drowsiness.
These are usually mild and not troublesome.

Common side effects (may affect up to 1 in 10 people):
• vomiting,
• digestion problems (constipation, flatulence, diarrhoea),
• stomach pain,
• dry mouth,
• headache,
• shaking,
• confusion,
• sleep disorders,
• mood changes (anxiety, nervousness, euphoria (a sense of feeling “high” all the time)),
• increased sweating,
• itching.

Uncommon side effects (may affect up to 1 in 100 people):
• high blood pressure, heart rhythm and heart rate disorders,
• difficulty or pain on passing urine, protein in the urine,
• skin reactions (hives, rashes)
• ringing in the ear,
• depression,
• nightmares,
• hallucinations (hearing, seeing or sensing things that are not really there),
• loss of memory,
• difficulty swallowing,
• blood in the stools,
• shivering,
• hot flushes,
• pain in the chest,
• involuntary muscle twitching,
• unusual tingling feeling (“pins and needles”),
• shortness of breath,
• raised liver enzymes.

Rare side effects (may affect up to 1 in 1,000 people) :
• drug dependence,
• fits, difficulties in carrying out coordinated movements,
• blurred vision,
• transient loss of consciousness.

Very rare side effect (may affect up to 1 in 10,000 people):
• drug abuse.

Unknown side effect (frequency cannot be estimated from the available data):
• decrease in blood sugar level.

The following are recognised side effects which have been reported by people using medicines that contain only tramadol hydrochloride or paracetamol. However, if you experience any of these while taking Tramadol HCl and Paracetamol, you should tell your doctor:
• feeling faint when getting up from a lying or sitting position, slow heart rate, fainting, changes in appetite, muscle weakness, slower or weaker breating, mood changes, changes in activitiy, changes in perception, worsening of asthma.
• in some rare cases a skin rash, indicating an allergic reaction, may develop with sudden swelling of the face and neck, difficulties breathing or drop of blood pressure and fainting. If this happens to you, stop treatment and see a doctor immediately. You must not take the medicine again.

In rare cases, using a medicine of the type of tramadol may make you become dependent on it, making it hard to stop taking it.
On rare occasions, people who have been taking tramadol for some time may feel unwell if they stop treatment abruptly. They may feel agitated, anxious, nervous or shaky. They may be hyperactive, have difficulty sleeping and have stomach or bowel disorders. Very few people may also get panic attacks, hallucinations, unusual perception such as itching, tingling, numbness and ringing in the ears (tinnitus). If you do notice any of these effects, or any other unusual symptoms, please tell your doctor or pharmacist as soon as possible.
In exceptional cases blood tests may reveal certain abnormalities, for instance, low counts of blood platelets, which may result in nose bleeds or bleeding gums.
Very rare cases of serious skin reactions have been reported for paracetamol containing medicines.

Use of Tramadol HCl and Paracetamol together with medicines used to thin the blood (e.g. phenoprocoumon, warfarin) may increase the bleeding risk. Any prolonged or unexpected bleeding should be reported to your doctor immediately.

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. By reporting side effects you can help provide more information on the safety of this medicine.

5. How Tramadol HCl and Paracetamol is stored
Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the packaging after EXP. The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Further information

What Tramadol HCl and Paracetamol contains
• The active substances are tramadol hydrochloride and paracetamol.

Each film-coated tablet contains:
Tramadol hydrochloride USP      37.5 mg
equivalent to 32.94 mg tramadol
Paracetamol                                  325 mg
Excipients                                        q.s.
Colour: Yellow Iron Oxide

The other ingredients are:
– Tablet core: pregelatinised maize starch, sodium starch glycolate (type A), microcrystalline cellulose (E460) and magnesium stearate (E572).
– Film-coating: hypromellose, titanium dioxide (E171), macrogol 400, yellow iron oxide (E172) and polysorbate 80.

What Tramadol HCl and Paracetamol looks like and contents of the pack
Film-coated tablets are yellow-brown, oval, slightly biconvex.
Boxes of 2 film-coated tablets (blisters with 2 tablets) or 10, 20, 30, 40, 50, 60, 70, 80, 90 and 100 film-coated tablets (blisters with 10 tablets) are available.
Not all pack sizes may be marketed.