Tramal (Tramadol HCL) 100mg capsule

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Description

Tramal (Tramadol HCL) 100mg tablets/capsule: Tramal (Tramadol HCL) is used to treat moderate to severe pain. Tramadol extended-release is used to treat moderate to severe chronic pain when treatment is needed around the clock. You buy Tramal (Tramadol HCL) 100mg tablets online without prescription from TopHealth- Online Pharmacy.

Other name: Tramadol hydrochloride

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Tramadol an opioid drug used to relieve severe pain following a heart attack , surgery, or serious illness. It is less likely to cause dependence with long-term use than most opioids.

Tramal 50 mg, solution for injection
Tramal 100 mg, solution for injection
Tramal (capsules)

QUALITATIVE AND QUANTITATIVE COMPOSITION
One ampoule of Tramal 50 mg, with 1 ml solution for injection, contains 50 mg tramadol hydrochloride.
One ampoule of Tramal 100 mg, with 2 ml solution for injection, contains
100 mg tramadol hydrochloride.
One Tramal capsule contains 50 mg tramadol hydrochloride.

DOSAGE FORMS
Solution for injection
Clear, colorless solution
Capsules
Two-tone (green/bright yellow), glossy, oblong capsule imprinted with the manufacturer’s logo.

CLINICAL PARTICULARS
Indications
Treatment of moderate to severe pain

Posology and Method of Administration
The various Tramal dosage forms allow the following modes of
Administration:
– oral (independent of meals, to be swallowed whole with sufficient fluid)
– intravenous
– intramuscular
– subcutaneous
– by infusion

Intravenous administration is slow with 1 ml Tramal (equivalent to 50 mg tramadol hydrochloride) per minute.
The dosage should be adjusted to the intensity of the pain and the sensitivity of the individual patient.
Unless otherwise prescribed, the dosage of Tramal in adults and adolescents above the age of 12 years is as follows:

Dosage form Single dose Daily dose
Tramal capsules
Tramal 50 mg,
solution for injection
1-2 capsules
i.v. 1-2 ampoules (to be injected slowly or diluted in infusion solution and infused) i.m. 1-2 ampoules
s.c. 1-2 ampoules
up to 8 capsules

up to 8 ampoules

Tramal 100 mg, solution for injection i.v. 1 ampoule (to be injected slowly or diluted in infusion solution and infused) i.m. 1 ampoule
s.c. 1 ampoule up to 4 ampoules

If after administration of a single dose of 50-100 mg active substance(equivalent to 1-2 Tramal hard-shell capsules or 1-2 Tramal 50 mg ampoules) adequate pain relief is not achieved within 30-60 minutes, a second single dose of 50 mg
may be given.
If in severe pain the demand is likely to be higher, the higher single dose of Tramal (100 mg tramadol) may be given as the initial dose. Depending on the intensity of the pain the effect Lasts for 4-8 hours. In general, 400 mg tramadol hydrochloride per day need not be exceeded. However, for the treatment of cancer pain and severe postoperative pain much higher doses may be necessary.
For the treatment of severe postoperative pain even higher doses may be necessary for on-demand analgesia in the early postoperative period. Requirements over 24 hours are generally not higher than on normal administration.

Geriatric patients
In acute pain Tramal is administered only once or a small number of times. Therefore it is not necessary to adjust the dose. In chronic pain dose adjustment is usually not necessary in elderly patients (up to 75 years) with no clinically manifest hepatic or renal insufficiency. In geriatric patients (above 75 years) elimination may be prolonged. Therefore, if necessary, the dosage intervals are to be extended according to the patient’s requirements.

Hepatic and renal insufficiency/dialysis
In acute pain Tramal is administered only once or a small number of times. Therefore it is not necessary to adjust the dose. Tramal should not be given to patients with severe hepatic and/or renal insufficiency. In less severe cases prolongation of the dosage interval should be considered.

Children
Children aged 1-11 years receive 1-2 mg tramadol hydrochloride per kg body weight as a single dose.
Tramal solution for injection
For this, Tramal 50 mg or Tramal 100 mg, solution for injection is (fluted with water for injections. The following table shows which concentrations are reached (1ml Tramal 50 mg or 100 mg, solution for injection contains 50 mg tramadol hydrochloride):

Diluting Tramal 50 mg or Tramal 100 mg in

water for Injections gives the following concentrations
Tramal 50 mg Tramal 100 mg
1ml 1ml 2ml 2 ml 25.0 mg/ml
1ml 2 ml 2 ml 4 ml 16.7 mg/ml
1ml 3 ml 2 ml 6 ml 12.5 mg/ml
1ml 4 ml 2 ml 8 ml 10.0 mg/ml
1ml 5 ml 2 ml 10 ml 8.3 mg/ml
1ml 6 ml 2 ml 12 ml 7.1 mg/ml
1ml 7 ml 2 ml 14 ml 6.3 mg/ml
1ml 8 ml 2 ml 16 ml 5.1 mg/ml
1ml 9 ml 2 ml 18 ml 5.0 mg/ml


Example for a child weighing 45 kg you would like to give a dose of 1.5 mg tramadol hydrochloride per kg body weight. To do so, 67,5 mg tramadol hydrochloride are required. Therefore 2 ml of Tramal 50 mg or 100 mg are diluted in 4 ml of water for injections. This gives a concentration of 16,7 mg tramadol hydrochloride per milliliter.
Then 4 ml of the solution (approx. 67 mg tramadol hydrochloride) are administered.

Note
The recommended dosages are guidelines. In principle, the lowest analgesically effective dose should be selected. In the treatment of chronic pain a fixed dosage schedule is recommended.
Tramal must not be given for longer than therapeutically absolutely necessary
If long-term pain treatment is necessary, checks should be carried out at regular brief intervals (if necessary with breaks in treatment) as to whether and in what doses further treatment with Tramal is necessary.

Contraindications
Tramal must not be used in known hypersensitivity towards tramadol or any other excipients (see “Excipients”), acute intoxication with alcohol, hypnotics, analgesics, opioids or psychotropics, or in patients who are receiving MAO inhibitors or have taken them within the last 14 days (see “Interactions with Other Medicinal Products and Other Forms of Interaction”). Tramal must not be used in epilepsy not adequately controlled by treatment. Tramal must not be used for narcotic withdrawal treatment.

Precautions and Warnings
Tramal must only be used with special care in cases of opioid dependence, head injury, shock, consciousness disorders of  uncertain origin, disorders of the  respiratory centre or function, increased cerebral pressure, in patients sensitive to opiates the medicinal product should only be used with caution.
Convulsions have been reported in patients receiving tramadol in the recom­mended dosage. The risk may be increased on administration of dosages exceeding the recommended daily dose (400 mg). On concomitant admini­stration of drugs that lower the convulsion threshold tramadol may increase the risk of convulsions (see “Interactions with Other Medicinal Products and Other Forms of Interaction”). Patients with epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling circumstances.
Tramadol has a low dependence potential. On long-term use tolerance, psychic and physical dependence may develop. In patients with a tendency to abuse medicines or who are dependent on medicines, treatment with Tramal should only be carried out for short periods and under strict medical supervision. Tramal is not suitable as a substitute in opiate-dependent patients. Although tramadol is an opiate agonist, it cannot suppress morphine withdrawal symptoms.
Tramal is not intended for use in children below the age of one year.

Interactions with Other Medicinal Products and Other Forms of Interaction
Tramal should not be combined with MAO inhibitors (see section 4.3 “Contraindications”).
On premedication with MAO inhibitors in the last 14 days prior to the use of the opioid pethidine, life-threatening interactions on the central nervous system, respiratory and cardiovascular function have been observed. The same interactions with MAO inhibitors cannot be ruled out during treatment with Tramal.
Concomitant administration of Tramal with other centrally depressant substances, including alcohol, may potentiate the CNS effects. The results of pharmacokinetic studies have so far shown that on the concomitant or previous administration of cimetidine (enzyme inhibitor) clinically relevant interactions are unlikely to occur. Simultaneous or previous admini­stration of carbamazepine (enzyme inducer) may reduce the analgesic effect and curtail the duration of action.
The combination of mixed agonist/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) and tramadol is not advisable, because the analgesic effect of a pure agonist may theoretically be reduced in such circumstances. Tramadol may induce convulsions and increase the potential of selective serotonin re-uptake inhibitors, tricyclic antidepressants, neuroleptics and other seizure-threshold-lowering drugs to cause convulsions. There have been isolated reports of serotonin syndrome in a temporal connection with the therapeutic use of tramadol in combination with other serotinerqic substances such as selective serotonin re-uptake inhibitors (SSRI). Symptoms of serotonin syndrome are, for example, confusion, restlessness, pyrexia, sweating, ataxia, hyperreflexia,  myoclonia and diarrhoea. When the serotoninergic medicines are withdrawn, there is usually a rapid improvement. Medicinal countermeasures depend on the nature and severity of the symptoms.
On the concomitant administration of tramadol and coumarin derivatives (e.g. warfarin) patients should be carefully monitored, as in some patients reduced prothrombin time values and ecchymosis have been observed. Other CYP3A4 inhibitors, such as ketoconazole and erythromycin, may inhibit the metabolism of tramadol (N-demethylation) and the active O-demethylated metabolite. The clinical significance of this  interaction to not known.

Pregnancy and Lactation
Animal studies have shown that very high doses of tramadol affect organ development, bone growth, and neonate mortality rate. Teratogenic effects have not been observed. Tramadol passes the placental barrier. Sufficient evidence of the safety of tramadol during pregnancy in humans is not available. Therefore Tramal should not be administered to pregnant women. When given before or during delivery, tramadol does not affect uterine contractility. In neonates it may induce changes in the respiratory rate which are usually not clinically relevant. About 0.1 % of the tramadol dose given to the mother is excreted in the breast-milk during lactation. Tramal should not be given to lactating women. After a single administration of  tramadol it is not usually necessary to interrupt breast-feeding.

Effects on Ability to Drive and Use Machines
Even when taken according to instructions, Tramal may affect reactions to such an extent that road safety or operating machinery may be affected. This applies particularly in conjunction with psychotropic substances.

Side-effects
The most common side-effects are nausea and dizziness in more than 10% of patients.

Cardiovascular system
Uncommon (< 1%): effect on cardiovascular regulation (palpitation, tachycardia, orthostatic hypotension
or cardiovascular collapse). These adverse effects may occur particularly on intravenous administration
and in patients who are physically stressed.
Rare (< 0.1%): bradycardia, hypertension

Central and peripheral nervous system
Very common (> 10%): dizziness
Common (1-10%): headache, muzziness
Rare (< 0.1%): changes in appetite, paraesthesia, tremor, respiratory depression, epileptiform seizures. If the recommended dosages are considerably exceeded or on the concomitant use of other centrally acting substances (see section “Interactions with Other Medicinal Products and Other Forms of Interaction”), respiratory depression may occur.
Epileptiform seizures mainly occurred after high tramadol dosages or on the concomitant use of drugs that may lower the seizure threshold (see sections ‘Precautions and Warnings” and “Interactions with Other Medicinal Products and Other Forms of Interaction”).

Psychic side-effects
Rare (< 0.1%): hallucinations, confusion, sleep disorders and nightmares.
After administration of Tramal retard a variety of psychic side-effects that vary in intensity and nature from patient to patient (depending on personality and duration of treatment) may occur. These include
changes in mood (usualry euphoria, occasionalry dysphoria), changes in activity (usualry depression.
occasionally increase), and changes in cognitive and sensory perception (e.g. decision-making.
perception disorders).
Dependence may occur.
Visual disorders
Rare (< 0.1%): blurred vision

Respiratory organs
Deterioration of asthma has been reported. However, a causal connection has not been established.

Gastrointestinal tract
Very common (> 10%): nausea
Common (1-10%): vomiting, constipation, dry mouth
Uncommon (< 1%): urge to vomit, gastrointestinal irritation (e.g. feeling of pressure in the stomach, bloating)

Skin and skin appendages
Common (1-10%): sweating
Uncommon (< 1%): dermal reactions (e.g. pruritus, rash, urticaria)

Musculoskeletal system
Rare (< 0.1%): motorial weakness

Liver and biliary tract
In a few isolated cases elevated liver enzyme values have been reported in a temporal connection with the therapeutic use of tramadol.

Urinary tract
Rare (< 0.1%): micturition disorders (difficulties in passing water)

Generalised
Rare (< 0.1%): allergic reactions (e.g. dyspnoea, bronchospasm. rhonchi, angioneurotic oedema) and anaphylaxis
Withdrawal symptoms similar to those of opiates may occur. These symptoms include: agitation, anxiety,
nervousness, sleep disorders, hyperkinesia, tremor, and gastrointestinal symptoms, dther symptoms
observed in very rare cases after discontinuation of tramadol include: attacks of panic, severe anxiety,
hallucinations, paraesthesia. tinnitus, and unusual CNS symptoms.

Overdose

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

Therapy
The general emergency measures apply in keeping open the respiratory tract (aspiration!), maintaining respiration and circulation depending on the symptoms. The stomach is to be emptied by inducing vomiting (conscious patient) or rinsing. An antidote for respiratory depression is naloxone. In animal experiments naloxone had no effect on convulsions. In such cases diazepam should be given intra­venously.
Tramadol can only minimally be removed by means of dialysis. Therefore haemodialysis or haemo-filtration alone is not suitable for the treatment of acute intoxication with Tramal retard.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic Properties
ATC code: N 02 AX 02: analgesics
Tramadol is a centrally acting opioid analgesic. It is a non-selective pure agonist µ, ∂ and K-opioid receptors with a higher affinity for the µ-receptor. Other mechanisms that contribute to its analgesic effect are the inhibition of the neuronal re-uptake of noradrenaline and enhancement of serotonin release.
Tramadol has an antitussive effect. In contrast to morphine, analgesic doses of tramadol over a wide range have no respiratory depressant effect. Nor is gastrointestinal motility affected. The cardiovascular effects tend to be slight. The potency of tramadol is reported to be 1/10 to 1/6 that of morphine.

Pharmacokinetic Properties
More than 90% of Tramal retard is absorbed after oral administration. Absolute bioavailability is a mean of about 70%, irrespective of the concomitant intake of food. The difference between absorbed and non-metabolised tramadol is probably due to the low first-pass effect. After oral administration the first-pass effect is a maximum of 30%.
Tramadol has a high tissue affinity (Vd.b= 203 ± 40 l). Serum protein binding is about 20%.
After administration of Tramal retard 100 mg the peak plasma concentration Cmax. after 4.9 h is
141 ±40 ng/ml.
Tramadol passes the blood/brain and placental barriers. Very small amounts of the substance and its O-desmethyl derivative are found in the breast-milk (0.1% and 0.02% respectively of the applied dose).
The elimination half-life tag is approx. 6 h, irrespective of the mode of administration. In patients above the age of 75 years it may be prolonged by a factor of approx. 1.4. In humans tramadol is mainly metabolised by means of N- and O-demethylation and conjugation of the O-demethylation products with glucuronic acid. Only O-desmethyltramadol is pharmacologically active. There are considerable interindividual quantitative differences between the other metabolites. So far. 11 metabolites have been found in the urine. Animal experiments have shown that O-desme­thyltramadol is more potent than the parent substance by the factor 2-4. Its half-life t½β (six healthy volunteers) is 7.9 h (range 5.4 – 9.6 h) and is approximately that of tramadol. Inhibition of the iso-enzyme CYP3A4 and/or CYP2D6 involved in the biotransformation of tramadol may affect the plasma concentration of tramadol or its active metabolites. So far no clinically relevant interactions have been reported.
Tramadol and its metabolites are almost completely excreted via the kidneys. Cumulative urinary excretion is 90% of the total radioactivity of the administered dose. In cases of impaired hepatic and renal function the half-life may be slightly prolonged. In patients with cirrhosis of the liver, elimination half-lives of 13.3 ± 4.9 h (tramadol) and 18.5 ± 4.9 h (O-desmethyltramadol) have been determined, in an extreme case 22.3 h and 36 h respectively. In patients with renal insufficiency (creatinine clea­rance < 5 ml/min) the values were 11 ± 3.2 h and 16.9 ± 3 h, in an extreme case 19.5 h and 43.2 h respectively.
Tramadol has a linear pharmacokinetic profile within the therapeutic dose range. The relation between serum concentrations and the analgesic effect is dose-dependent, but varies considerably in isolated cases. A serum concentration of 100-300 ng/ml is usually effective.

Preclinical Safety Data
On repeated oral and parenteral administration of tramadol for 6-26 weeks in rats and dogs and oral administration for 12 months in dogs, haematological, clinico-chemical and histological tests showed no evidence of any substance-related changes. Central nervous manifestations only occurred after high doses far above the therapeutic dose: restlessness, salivation, spasms, reduced weight increase. Rats and dogs tolerated oral doses of 20 mg/kg and 10 mg/kg body weight respectively, and dogs rectal doses of 20 mg/kg body weight, without any effects.
In rats tramadol dosages from 50 mg/kg dairy upwards had toxic effects in the dams and there was an increase in neonate mortality. In the offspring retardation in the form of ossification disorders and delayed vaginal and eye opening occurred. Male fertility was not affected. After high doses (from 50 mg/kg/day upwards) females exhibited a reduced pregnancy rate. In rabbits there were toxic effects in dams from 125 mg/kg upwards and skeletal anomalies in the offspring. In some in-vitro test systems there was evidence of mutagenic effects. In-vivo studies showed no such effects. According to knowledge gained so far. tramadol can be classified as non-mutagenic. Studies on the tumorigenic potential of tramadol hydrochloride have been carried out in rats and mice. The study in rats showed no evidence of any substance-related increase in the incidence of tumours. In the study in mice there was an increased incidence of liver-cell adenomas in male animals (a dose-dependent, non-significant increase from 15 mg/kg upwards) and an increase in pulmonary tumours in females of all dosage groups (significant, but not dose-dependent).

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic Properties
ATC code: N 02 AX 02: analgesics
Tramadol is a centrally acting opioid analgesic. It is a non-selective pure agonist µ, ∂ and K-opioid receptors with a higher affinity for the µ-receptor. Other mechanisms that contribute to its analgesic effect are the inhibition of the neuronal re-uptake of noradrenaline and enhancement of serotonin release.
Tramadol has an antitussive effect. In contrast to morphine, analgesic doses of tramadol over a wide range have no respiratory depressant effect. Nor is gastrointestinal motility affected. The cardiovascular effects tend to be slight. The potency of tramadol is reported to be 1/10 to 1/6 that of morphine.

Pharmacokinetic Properties
More than 90% of Tramal is absorbed after oral administration. Absolute bioavailability is a mean of about 70%, irrespective of the concomitant intake of food. The difference between absorbed and available non-metabolised tramadol is probably due to the low first-pass effect. The first-pass effect after oral administration is a maximum of 30%. After oral administration of 100 mg in a solid oral form Cmax is 280 ± 49 ng/ml after 2 hours. Tramadol has a high tissue affinity (Vd.b= 203 ± 40 l). Plasma protein binding is about 20%.
Tramadol passes the blood/brain and placental barriers. Very small amounts of the substance and its O-desmethyl derivative are found in the breast-milk (0.1 % and 0.02% respectively of the applied dose).
The elimination half-life t½βis approx. 6 h, irrespective of the mode of administration. In patients above the age of 75 years it may be prolonged by a factor of approx. 1.4. In humans tramadol is mainly metabolised by means of N- and O-demethylation and conjugation of the O-demethylation products with glucuronic acid. Only O-desmethyl-tramadol is pharmacologically active. There are considerable interindividual quantitative differences between the other metabolites. So far, 11 metabolites have been found in the urine. Animal experiments have shown that O-desmethyltramadol is more potent than the parent substance by the factor 2-4. Its half-life t½β (six healthy volunteers) is 7.9 h (range 5.4 – 9.6 h) and is approximately that of tramadol.
Inhibition of the iso-enzyme CYP3A4 and/or CYP2D6 involved in the biotransformation of tramadol may affect the plasma concentration of tramadol or its active metabolites. So far no clinically relevant interactions have been reported. Tramadol and its metabolites are almost completely excreted via the kidneys. Cumulative urinary excretion is 90% of the total radioactivity of the administered dose. In cases of impaired hepatic and renal function the half-life may be slightly prolonged. In patients with cirrhosis of the liver, elimination half-lives of 13.3 ± 4.9 h (tramadol) and 18.5 ± 4.9 h (O-desmethyltramadol) have been determined, in an extreme case 22.3 h and 36 h respectively. In patients with renal insufficiency (creatinine clearance < 5 ml/min) the values were 11 ± 3.2 h and 16.9 ± 3 h, in an extreme case 19.5 h and 43.2 h respectively. Tramadol has a linear pharmacokinetic profile within the therapeutic dose range. The relation between serum concentrations and the analgesic effect is dose-dependent, but varies considerably in isolated cases. A serum concentration of 100-300 ng/ml is usually effective.

Preclinical Safety Data
On repeated oral and parenteral administration of tramadol for 6-26 weeks in rats and dogs and oral administration for 12 months in dogs, haematological, clinico-chemical and histological tests showed no evidence of any substance-related changes. Central nervous manifestations only occurred after high doses far above the therapeutic dose: restlessness, salivation, spasms, reduced weight increase. Rats and dogs tolerated oral doses of 20 mg/kg and 10 mg/kg body weight respectively, and dogs rectal doses of 20 mg/kg body weight, without any effects.
In rats tramadol dosages from 50 mg/kg daily upwards had toxic effects in the dams and there was an increase in neonate mortality. In the offspring retardation in the form of ossification disorders and delayed vaginal and eye opening occurred. Male fertility was not affected. After high doses (from 50 mg/kg/day upwards) females exhibited a reduced pregnancy rate. In rabbits there were toxic effects in dams from 125 mg/kg upwards and skeletal anomalies in the offspring.
In some in-vitro test systems there was evidence of mutagenic effects. In-vivo studies showed no such effects. According to knowledge gained so far. tramadol can be classified as non-mutagenic.
Studies on the tumorigenic potential of tramadol hydrochloride have been carried out in
rats and mice. The study in rats showed no evidence of any substance-related increase in the incidence of tumours. In the study in mice there was an increased incidence of liver-cell adenomas in male animals (a dose-dependent, non-significant increase from 15 mg/kg upwards) and an increase in pulmonary tumours in females of all dosage groups (significant, but not dose-dependent).

PHARMACEUTICAL PARTICULARS
Excipients
Tramal capsules:
Microcrystalline cellulose, sodium carboxymethylcellulose (type A) (Ph.Eur.), colloidal
anhydrous silica, magnesium stearate (Ph.Eur.), gelatin, indigotine, ferric oxides and
hydroxides (E 172), titanium dioxide (E 171), sodium lauryl sulphate
Tramal 50 mg, solution for injection:
Sodium acetate, water for injections
Tramal 100 mg, solution for injection:
Sodium acetate, water for injections

 

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