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tramadol


Category:

Analgesic .

Composition:

Each tablet contains:
Acetaminophen
Tramadol HCl

Chemistry:

Chemical name: (±)Cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol hydrochloride.
Molecular wheight of tramadol HCl: 299.8

Mechanism of Action:

Tramadol is a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood , from animal tests, at least two complementary mechanisms appear applicable . Binding of parent and M1 metabolite to µ -opioid receptors and weak inhibition of re-uptake of norepinephrine and serotonin .
Opioid activity 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 . The relationship between exposure of tramadol and M1 and efficacy has not been evaluated in the Ultram ER clinical studies.
A part from analgesia , tramadol administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation , sweating and pruritus) similar to that of other opioids. In contrast to morphine , tramadol has not been shown to cause histamine release . At therapeutic doses, tramadol has no effect on heart rate, left ventricular function or cardiac index. Orthostatic hypotension has been observed .

Pharmacokinetics:

The analgesic activity of tramadol is due to both parent drug and the M1 metabolite. tramadol is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation .
The pharmacokinetics of tramadol are approximately dose-proportional over a 100-400 mg dose range in healthy subjects . The observed tramadol AUC values for the 400 mg dose were 26% higher than predicted based on the AUC values for the 200 mg dose. The clinical significance of this finding has not been studied and is not known .

Absorption :

In healthy subjects, the bioavailability of a tramadol 200 mg tablet relative to a 50 mg every six hours dosing regimen of the immediate – release dosage form was approximately 85-90% . Consistent with the extended release nature of the formulation , there is a lag time in drug absorption following tramadol administration . The mean peak plasma concentrations of tramadol and M1 after administration of tramadol tablets to healthy volunteers are attained at about 12 h and 15 h , respectively , after dosing (See table 1 and Figure 2) . Following administration of the tramadol, steady-state plasma concentrations of both tramadol and M1 are achieved within four days with once daily dosing .

Food Effects :

After a single dose administration of 200 mg tramadol tablet with a high fat meal , the Cmax and AUC0-2 of tramadol decreased 28% and 16% , respectively , compared to fasting conditions. Mean Tmax was increased by 3 hr (from 14 hr under fasting conditions to 17 hr under fed conditions ) . While tramadol may be taken without regard to food, it is recommended that it be taken in a consistent manner .
Distribution :
The volume of distribution of tramadol was 2.6 and 2.9 liters/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 10 µg/ml. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.

Metabolism :

Tramadol is extensively metabolized after oral administration . The major metabolic pathways appear to be N-mediated by CYP3A4 and CYP2B6) and 0- (mediated by CYP2D6) demethylation and glucuronidation or sulfation in the liver . One metabolite (O-desmethyl) tramadol , denoted M1) is pharmacologically active in animal models . Formation of M1 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 precautions – Drug interations ) .

Elimination :

Tramadol is eliminated primarity through metabolism by the liver and the metabolites are eliminated primarily by the kidneys . Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites. The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 after administration of tramadol are approximately 7.9 and 8.8 hours, respectively .

Special Populations :

Renal
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 100 mg . There is no consistent trend observed for tramadol exposure related to renal function in patients with mild (CLct : 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 has not been studied in patients with severe renal impairment (CL ct < 30 ml/min) . The limited availability of dose strenghs of tramadol dose not permit the dosing flexibility required for safe use in patients with severe renal impairment . Therefore , tramadol should not be used in patients with severe renal impairment (see Precautions, use in renal and Hepatic Disease and Dosage and administration) . The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose .
Hepatic :

Pharmacokinetics of tramadol was studied in patients with mild or moderate hepatic impairment after receiving multiple doses of tramadol 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 has not been studied in patients with severe hepatic impairment . After the administration of tramadol immediate – release talblets 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 . The limited availability of dose strengths of tramadol does not permit the dosing flexibility required for safe use in patients with severe hepatic impairment . therefore, tramadol should not be used in patients with severe hepatic impairment
Gender :
Based on pooled multiple-dose pharmacokinetics studies for tramadol in 166 healthy subjects (111 males and 55 females) , the dose-normalied AUC values for tramadol were somewhat higher in females than in males. There was a considerable degree of overlap in values between male and female groups. Dosage adjustment based on gender is not recommended .

Indications:

Acute pain (treatment) – Tramadol and acetaminophen combination is indicated for short-term (five days or less) management of acute pain .

Contraindications:

tramadol should not be administered to patients who have previously demonstrated hypersensitivity to trarnadol, any other component of this product or opioids. tramadol is contraindicated in any situation where opioids are contraindicated, including acute intoxication with any of the following alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs. tramadol ER may worsen central nervous system and respiratory deprssion of these patients.

Warnings:

Seizure risk
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 its patients taking:
  • Selective serotonin re-uptake inhibitors (SSRI antidepressants or anorectics),
  • Tricyclic antidepressant. (TCAs). and other tricyclic compounds (e.g.. cyclobenzaprine, promethazine, etc.), or
  • Other oploids

  • Administration of tramadol may enhance the seizure risk in patients taking
  • MAO inhibitors
  • Narcoleptics, or
  • Other drugs that reduce the seizure threshold.


Risk of convulsions 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 tramadol for patients who are suicidal or addiction-prone.
  • Prescribe tramadol with caution for patients taking tranquilizers or antidepressant drugs and patients who use alcohol in excess.
  • Tell your patients not to exceed the recommended dose and to limit their intake of alcohol

Tramadol products in excessive doses, either alone or- in combination with other CNS depressants, including alcohol, are a major cause of drug-related deaths. Fatalities within the first hour of overdosage are not uncommon. Tramadol should not be taken in doses higher than those recommended by the physician. The judicious prescribing of tramadol is essential to the safe use of this drug. With patients -who are depressed or suicidal, consideration should be given to the use of non-narcotic analgesics. Patients should be cautioned about the concomitant use of tramadol products and alcohol because of potentially serious CNS- additive effects of these agents. Because of its added depressant effects, tramadol should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Patients should be advised of the additive depressant effects of these combinations.
Many of the tramadol-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation or attempts as well as histories of misuse of tranquilizers, alcohol, and other CNS-active drugs. Some deaths have occurred as a consequence of the accidental ingestion of excessive quantities of tramadol alone or in combination with other drugs. Patients taking tramadol should be warned not to exceed the dose recommended by their physician.
Anaphylactoid Reactions
Serious and rarely fatal anaphylactoid 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 codeine and other opioids may be at increased risk and therefore should not receive tramadol .
Respiratory Depression
Administer tramadol cautiously in patients at risk for respiratory depression. In these patients alternative nonopioid analgesics should be considered. When large doses of tramadol are administered with anesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures.
Interaction With Central Nervous System (CNS) Depressants
tramadol should be used with caution and in reduced dosages when administered to patients receiving CNS atiepressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. tramadol increases the risk of CNS and respiratory depression in these patients
Increased Intracranial Pressure or Head Trauma
tramadol should be used with caution in patients with increased intracranial pressure or head injury. The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in these patients. Additionally, papillary changes (miosis) from tramadol may obscure the existence, extent, or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving tramadol .
Use in Ambulatory Patients
tramadol may impair the mental and or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. The patient using this drug should be cautioned accordingly.
Use with MAO inhibitors and serotonin Re-uptake Inhibitors
Use tramadolwith great caution in patients taking monoamine oxidase inhibitors. Animal studies have shown increased deaths with combined administration. Concomitant use of tramadol with MAO inhibitors or SSRIs increases the risk of adverse events, including seizure and serotonin syndrome.
Withdrawal
Withdrawal symptoms may occur if tramadol is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. Clinical experience suggests that withdrawal symptoms may be reduced by tapering tramadol.
Misuse, Abuse and Diversion of Opioids
Tramadol is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion
Tramadol can be abused in a manner similar to other opioid agonists. legal or illicit. This should be considered when prescribing or dispensing tramadol in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.
tramadol could be abused by crushing, chewing, snorting. or injecting the dissolved product. These practices will result in the uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare: However, data are not available to establish the true incidence of addiction in chronic pain patients. Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.
Interactions with Alcohol and Drugs of Abuse
Tramadol may be expected to have additive effects when used in conjunction with alcohol, other opioida, or illicit
drugs that cause central nervous system depression.
DRUG ABUSE AND ADDICTION
tramadol is a mu-agonist opioid. Tramadol, Iike, other opiolds used in analgesia, can be abused and Is subject to criminal diversion.
Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common. “Drug-seeking” behavior is very common in addicts and drug abusers. 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’ to obtain ad. ditional prescriptions is common among drug abusers and people suffering from untreated addiction.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians 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 and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. tramadol, like other opioids, may be diverted for non-medical use. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. 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. tramadol is intended for oral use only. The crushed tablet poses a hazard of overdose and death. This risk is increased with concurrent abuse of alcohol and other substances. With parenteral abuse, the tablet excipients can be I expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and I valvular heart injury Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HlV
Risk of Overdosage
Serious potential consequences of overdosage with tramadol are central nervous system depression, respiratory depression and death. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment

Precautions:

Acute Abdominal Condition
The administration of tramadol may complicate the clinical assessment of patients with acute abdominal conditions.
Use in Renal and Hepatic Disease
Impaired renal function results in a decreased rate and extant of excretion of tramadol and its active metabolite, tramadol has not been studied in patients with severe renal impairment (CLcr < 30 mL/min). The limited availability of dose strengths and once daily dosing of tramadol. do not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, tramadol should not be used in patients with severe renal impairment. Metabolism of tramadol and MI is reduced in patients with advanced cirrhosis of the liter. The pharmacokinetics of tramadol has not been studied on patients with severe hepatic impairment. The limited availability of dose strengths and once daily dosing of tramadol do not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore. tramadol should not be used in patients with severe hepatic impairment
INFORMATION FOR PATIENTS
  • • Patients should be informed that tramadol is for Such oral use only and should be swallowed whole. tablets should not be chewed, crushed, or split.
  • • Patients should be informed that tramadol may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a the car or operating machinery
  • • Patients should be informed that tramadol should not be taken with alcohol containing beverages.
  • • Patients should be informed that tramadol should will be used with caution when taking medications such as Be a tranquilizers. hypnotics or other opiate containing an- lose analgesics.
  • • Female patients should be instructed to inform the prescriber if they are pregnant, think they might become not pregnant, or are trying to become pregnant .
  • • Patients should be educated regarding the single-dose and 24-hour dosing regimen, as exceeding these recommendations can result in respiratory depression, seizures or death,

Use in Drug and Alcohol Addiction
tramadol is an opioid with no approved use in the management of addictive disorders. Its proper usage in individuals with drug or alcohol dependence, either active or in remission, is for the management of pain requiring opioid to analgesia.

Usage in pregnancy:

Pragnancy category C.

Breast-feeding:

Tramadol is not recommended for obstetrical preperative medication or for post-delivery analgesia in nursing mothers because its safety in iniants and newborns has not been studied. Following a single IV 100-mg dose of tramadol , the cumulative excretion in breast milk within sixteen hours postdose was 100 µg of tramadol (0.1% of the maternal dose) and 27 µg of M1 .

Pediatrics:

The safety and efficacy of tramadol in patients under 18 years of age have not been established .
The use of tramadol in the pediatric population is not recommended .

Geriatrics:

Nine – hundred- one elderly (65 years of age or older) subjects were exposed to tramadol in clinical trials . Of those subjects , 156 were 75 years of age and older . In general , higher incidence rates of adverse events were observed for patients older than 65 years of age compared with patients 65 years and younger , particularly for the following adverse events L constipation , fatigue, weakness, postural hypotension and dyspepsia . for this reason , tramadol should be used with great caution in patients older than 75 years of age (see clinical pharmacology and dosage and administration) .
Tramadol was administered to a total of 3108 patients during studies conducted in the U.S. These included four double-blind studies in patients with osteoarthritis and / or chronic low back pain and one open-label study in patients with chronic non-malignant pain . A total of 901 patients were 65 years or older . The frequency of adverse events generally increased with doses from 100 mg to 400 mg in the two pooled, twelve-week , randomized , double-blind, placebo – controlled studies in patients with chronic non-malignant pain ( see table 2) .
The following adverse events were reported from all the chronic pain studies (N=3108) .
The lists below include adverse events not otherwise noted in table 2 .

Drug Interactions:

Drug interactions
Use With Carbarnazepine
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 tramadol and carbamazepine is not recommended. Use With Quinidine Coadministration of quinidine with tramadol resulted in a 50-60% increase in tramadol exposure and a 50—60% decrease in Ml exposure. The clinical consequences of these findings are unknown.
Use With MAO Inhibitors
Interactions with MAO Inhibitors, due to interference with detoxification mechanisms, have been reported for some centrally acting drugs.
Use With Digoxin and Warfarin
Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity and alteration of warfarin effect, including elevation of prothrombin times.
Potential for Other Drugs to Affect Tramadol
in vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline mold result in some inhibition of the metabolism of tramadol.
Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin. or inducers. such as rifampin and St. John’s Wort. with tramadol may affect the metabolism of tramadol leading to altered tramadol exposure.
Potential for Tramadal to Affect Other Drugs
It vitro drug interaction studies in human liver m(crosomes indicate that tramadol has no effect an quinidine metabolism, In vitro studies indicate that tramadol is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when administered concomitantly at therapeutic doses. tamadol is a mild inducer of selected drug metabolism ways measured in animals.

Side effects:

Adverse events with incidence rates of 1.0% to < 5.0%
Eye disorders : Vision blurred
Gastrointestinal disorders : abdominal pain upper , dyspepsia , abdominal pain , sore throat General disorders L weakness, pain , feeling hot , influenza like illness , fall , rigors , lethargy , pyrexia , chest pain .
Infections and infestations : nasopharyngitis , upper respiratory tract infection , sinusitis , influenza , gastroenteritis viral , urinary tract infection , bronchitis .
Investigations : blood creatine phophokinase increased , weight decreased .
Metabolism and nutrition disorders : appetite decreased musculokeletal , connective tissue and bone disorders : arthralgia , back pain , pain in limb , neck pain .
Nervous system disorders : tremor, paresthesia , hypoesthesia .
Psychiatric disorders : nervousness , anxiety , depression Restlessness , respiratory , thoracic and mediastinal disorders : Sneezing , cough , rhinorrhea, nasal congestion , dyspnea, sinus congestion .
Skin and subcutaneous tissue disorders : Sweating increased , dermatitis .
Vascular disorders L hot flushes, vasodilatation
Adverse events with incidence rates of 0.5% to < 1.0% and serious adverse events reported in at least 2 patients .
Cardiac disorders : palpitations , myocardial infarction
Ear and labyrinth disorders : tinnitus , vertigo
Gastrointestinal disorders : flatulence, toothache, constipation aggravated , appendicitis , pancreatitis .
General disorders : feeling jittery , edema lower limb , shivering , joint swelling , malaise, drug withdrawal syndrome, peripheral swelling .
Hepato –biliary disorders : cholelithiasis, cholecystitis .
Infections and infestations : cellulitis, ear infection , gastroenteritis, pneumonia , viral infection
Injury and poisoning : joint sprain , muscle injury
Investigations : alanine aminotransferase increased , blood pressure increased , aspartate aminotransferase increased, heart rate increased, blood glucose increased , liver function tests abnormal .
Musculoskeletal , connective tissue and bone disorders: muscle cramps , muscle spasms , joint stiffiness , muscle twitching , myalgia , osteroarthritis aggravated
Nervous system disorders : migraine , sedation , syncope , disturbance in attention , dizziness aggravated
Psychiatric disorders : euphoric mood , irritability , libido decreased , sleep disorder , agitation , disorientation , abnormal dreams
Renal and urinary disorders : difficulty in micturition , urinary frequency , hematuria , dysuria , urinary retention
Respiratory , thoracic and mediastinal disorders : yawning skin and subcutaneous tissue disorders : contusion , piloerection , clamminess , night sweats , urticaria
Vascularedisorders : Hypertension aggravated , hypertension , peripheral ischemia .

Overdosage:

Over Dosage :
Acute over dosage with tramadol can be manifested by respiratory depression , somnolence progressing to stupor or coma , skeletal muscle faccidity , cold and clammy skin , constricted pupils , bradycardia , hypotension , and death.
Deaths due to overdose have been reported with abuse and misuse of tramadol , by ingesting , inhaling , or injecting the crushed tablets. Review of case reports has indicated that the risk of fatal over dose in further increased when tramadol is abused concurrently with alcohol or other CNS depressants , including other opioids .
In the treatment of tramadol over dosage, primary attention should be given to the re-establishment of a patent airway and institution of assisted or controlled ventilation . Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying over dose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation .
While naloxone will reverse some , but not all , symptoms caused by over dosage with tramadol , the risk of seizures is also increased with naloxone administration . In animals convulsions following the administration of toxic doses of tramadol could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an over dose 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

Dosage and Administration:

Oral Sosage Forms :
Tramadol hydrochloride and Acetaminophen Tablets
Usual adult and adolescent dose
Analgesic –
Oral , two tablets (75 mg tramadol , 650 mg acetaminophen) every four to six hours as needed for up to five days .
Note : Patients with impaired renal function (creatinine clearance less than 30 ml/min) , the dosing interval should be increased not to exceed 2 tablets every twelve hours .
Usual adult prescribing limits
Oral , 8 tablets per day (4 tablets per day in patients with creatinine clearance of less than 30 ml/min for up to five days ) .
Usual Pdiatric Dose
Children up to 16 years of age – Safety and efficacy have not been established.
Usual Geriatic Dose
See Usual adult and adolescent dose .
Note : In elderly patients , dose selection should be cautious , reflecting the greater frequency of decreased hepatic , renal , cardiac function , concomitant disease and multiple drug therapy .

Storage:

Store below 30 degree centigrade.

How Supplied:

References:
1- USP DI 2005
2- PDR 2008
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