Drug Intercation

Oxytetracycline Hydrochloride 500 MG Oral Tablet

No Details Found

promethazine HCl 50 MG per 1 ML Injection

WARNINGS

Respiratory Depression Pediatrics Promethazine hydrochloride injection should not be used in pediatric patients less than 2 years of age because of the potential for fatal respiratory depression.

Post-marketing cases of respiratory depression, including fatalities, have been reported with use of promethazine in pediatric patients less than 2 years of age.

A wide range of weight-based doses of promethazine hydrochloride injection have resulted in respiratory depression in these patients.

Caution should be exercised when administering promethazine hydrochloride injection to pediatric patients 2 years of age and older.

It is recommended that the lowest effective dose of promethazine hydrochloride injection be used in pediatric patients 2 years of age and older.

Avoid concomitant administration of other drugs with respiratory depressant effects because of an association with respiratory depression, and sometimes death, in pediatric patients.

Other Because of the risk of potentially fatal respiratory depression, use of promethazine hydrochloride injection in patients with compromised respiratory function or patients at risk for respiratory failure (e.g.

COPD, sleep apnea) should be avoided.

Severe Tissue Injury, Including Gangrene Promethazine hydrochloride injection can cause severe chemical irritation and damage to tissues, regardless of the route of administration.

Irritation and damage can also result from perivascular extravasation, unintentional intra-arterial injection, and intraneuronal or perineuronal infiltration.

Adverse event reports include burning, pain, erythema, swelling, sensory loss, palsies, paralysis, severe spasms of distal vessels, thrombophlebitis, venous thrombosis, phlebitis, abscesses, tissue necrosis, and gangrene.

In some cases surgical intervention, including fasciotomy, skin graft, and/or amputation have been required.

Because of the risks of intravenous injection, the preferred route of administration of promethazine hydrochloride injection is deep intramuscular injection (see DOSAGE AND ADMINISTATION ).

Subcutaneous injection is contraindicated.

Due to close proximity of arteries and veins in the areas most commonly used for intravenous injection, extreme care should be exercised to avoid perivascular extravasation or unintentional intra-arterial injection as pain, severe chemical irritation, severe spasm of distal vessels, and resultant gangrene requiring amputation are likely under such circumstances.

Aspiration of dark blood does not preclude intra-arterial needle placement because blood is discolored upon contact with promethazine hydrochloride injection.

Use of syringes with rigid plungers or small-bore needles might obscure typical arterial backflow if this is relied upon.

In the event that a patient complains of pain during intravenous injection of promethazine hydrochloride injection, the injection should be stopped immediately to evaluate for possible arterial injection or perivascular extravasation.

There is no proven successful management of unintentional intra-arterial injection or perivascular extravasation after it occurs.

Sympathetic block and hepar inization have been employed dur ing the acute management of unintentional intra-arterial injection, because of the results of animal experiments with other known arteriolar irritants.

CNS Depression Promethazine hydrochloride injection may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery.

The impairment may be amplified by concomitant use of other central-nervous-system depressants such as alcohol, sedative-hypnotics (including barbiturates), general anesthetics, narcotics, narcotic analgesics, tricyclic antidepressants, and tranquilizers; therefore such agents should either be eliminated or given in reduced dosage in the presence of promethazine hydrochloride (see PRECAUTIONS – Information for Patients and Drug Interactions ).

Lower Seizure Threshold Promethazine hydrochloride injection may lower seizure threshold and should be used with caution in persons with seizure disorders or in persons who are using concomitant medications, such as narcotics or local anesthetics, which may also affect seizure threshold.

Bone-Marrow Depression Promethazine hydrochloride injection should be used with caution in patients with bone-marrow depression.

Leukopenia and agranulocytosis have been reported, usually when promethazine hydrochloride has been used in association with other known marrow-toxic agents.

Neuroleptic Malignant Syndrome A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with promethazine hydrochloride alone or in combination with antipsychotic drugs.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmias).

The diagnostic evaluation of patients with this syndrome is complicated.

In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS).

Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.

The management of NMS should include 1) immediate discontinuation of promethazine hydrochloride, antipsychotic drugs, if any, and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available.

There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

Since recurrences of NMS have been reported with phenothiazines, the reintroduction of promethazine hydrochloride should be carefully considered.

Sulfite Sensitivity Promethazine hydrochloride injection contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthma episodes, in certain susceptible people.

The overall prevalence of sulfite sensitivity in the general population is unknown and probably low.

Sulfite sensitivity is seen more frequently in asthmatic that in nonasthmatic people.

Visual Inspection This product is light sensitive and should be inspected before use and discarded if either color or particulate is observed.

Cholestatic Jaundice Administration of promethazine has been associated with reported cholestatic jaundice.

DRUG INTERACTIONS

Drug Interactions CNS Depressants Promethazine hydrochloride injection may increase, prolong, or intensify the sedative action of central-nervous-system depressants, such as alcohol, sedative/hypnotics (including barbiturates), general anesthetics, narcotics, narcotic analgesics, tricyclic antidepressants, and tranquilizers; therefore, such agents should be avoided or administered in reduced dosage to patients receiving promethazine hydrochloride.

When given concomitantly with promethazine hydrochloride injection, the dose of barbiturates should be reduced by at least one-half, and the dose of narcotics should be reduced by one-quarter to one-half.

Dosage must be individualized.

Excessive amounts of promethazine hydrochloride injection relative to a narcotic may lead to restlessness and motor hyperactivity in the patient with pain; these symptoms usually disappear with adequate control of the pain.

Epinephrine Because of the potential for promethazine hydrochloride to reverse epinephrine’s vasopressor effect, epinephrine should NOT be used to treat hypotension associated with promethazine hydrochloride injection overdose.

Anticholinergics Concomitant use of other agents with anticholinergic properties should be undertaken with caution.

Monoamine Oxidase Inhibitors (MAO) Inhibitors Drug interactions, including an increased incidence of extrapyramidal effects, have been reported when some MAO Inhibitors and phenothiazines are used concomitantly.

This possibility should be considered with promethazine hydrochloride injection.

OVERDOSAGE

Signs and symptoms of overdosage range from mild depression of the central nervous system and cardiovascular system to profound hypotension, respiratory depression, unconsciousness and sudden death.

Other reported reactions include hyperreflexia, hypertonia, ataxia, athetosis, and extensor-plantar reflexes (Babinski reflex).

Stimulation may be evident, especially in pediatric patients and geriatric patients.

Convulsions may rarely occur.

A paradoxical-type reaction has been reported in pediatric patients receiving single doses of 75 mg to 125 mg orally, characterized by hyperexcitability and nightmares.

Atropine-like signs and symptoms–dry mouth; fixed, dilated pupils; flushing; etc., as well as gastrointestinal symptoms, may occur.

Treatment Treatment of overdosage is essentially symptomatic and supportive.

Only in cases of extreme overdosage or individual sensitivity do vital signs, including respiration, pulse, blood pressure, temperature, and EKG, need to be monitored.

Attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation.

Diazepam may be used to control convulsions.

Acidosis and electrolyte losses should be corrected.

Note that any depressant effects of promethazine hydrochloride injection are not reversed by naloxone.

Avoid analeptics, which may cause convulsions.

The treatment of choice for resulting hypotension is administration of intravenous fluids, accompanied by repositioning if indicated.

In the event that vasopressors are considered for the management of severe hypotension which does not respond to intravenous fluids and repositioning, the administration of norepinephrine or phenylephrine should be considered.

EPINEPHRINE SHOULD NOT BE USED, since its use in a patient with partial adrenergic blockade may further lower the blood pressure.

Extrapyramidal reactions may be treated with anticholinergic antiparkinson agents, diphenhydramine, or barbiturates.

Oxygen may also be administered.

Limited experience with dialysis indicates that it is not helpful.

DESCRIPTION

Promethazine hydrochloride injection, USP is a sterile, pyrogen-free solution for deep intramuscular or intravenous administration.

Promethazine hydrochloride (10 H -phenothiazine-10-ethanamine, N , N , α-trimethyl-, monohydrochloride, (±)-) is a racemic compound and has the following structural formula: Each mL contains promethazine hydrochloride, either 25 mg or 50 mg, edetate disodium 0.1 mg, calcium chloride 0.04 mg, sodium metabisulfite 0.25 mg and phenol 5 mg in Water for Injection.

pH 4.0 to 5.5; buffered with acetic acid-sodium acetate.

Promethazine hydrochloride injection is a clear, colorless solution.

The product is light sensitive.

It should be inspected before use and discarded if either color or particulate is observed.

Promethazine hydrochloride structural formula

HOW SUPPLIED

Promethazine Hydrochloride Injection, USP is available as follows: NDC Number Strength Package 54868-4021-0 25 mg/mL 1 mL fill in a 1 mL ampule 25 ampules per carton 54868-2088-0 50 mg/mL 1 mL fill in a 1 mL ampule 25 ampules per carton Store at 20 º – 25 ºC (68º – 77ºF).

[See USP Controlled Room Temperature ] .

Protect from light.

Keep covered in carton until time of use.

Do not use if solution has developed color or contains a precipitate.

Manufactured by: HIKMA FARMACÊUTICA (PORTUGAL), S.A.

Estrada do Rio da Mó, nº 8, 8A e 8B – Fervença, 2705 – 906 Terrugem SNT PORTUGAL Distributed by: WEST-WARD PHARMACEUTICAL CORP.

465 Industrial Way West Eatontown, NJ 07724 USA Iss.: Oct 2009 Relabeling of “Additional Barcode Label” by: Physicians Total Care, Inc.

Tulsa, OK 74146

GERIATRIC USE

Geriatric Use ( patients approximately 60 years or older) Since therapeutic requirements for sedative drugs tend to be less in geriatric patients, the dosage should be reduced for these patients.

INDICATIONS AND USAGE

Promethazine hydrochloride injection is indicated for the following conditions: Amelioration of allergic reactions to blood or plasma.

In anaphylaxis as an adjunct to epinephrine and other standard measures after the acute symptoms have been controlled.

For other uncomplicated allergic conditions of the immediate type when oral therapy is impossible or contraindicated.

For sedation and relief of apprehension and to produce light sleep from which the patient can be easily aroused.

Active treatment of motion sickness.

Prevention and control of nausea and vomiting associated with certain types of anesthesia and surgery.

As an adjunct to analgesics for the control of postoperative pain.

Preoperative, postoperative, and obstetric (during labor) sedation.

Intravenously in special surgical situations, such as repeated bronchoscopy, ophthalmic surgery, and poor-risk patients, with reduced amounts of meperidine or other narcotic analgesic as an adjunct to anesthesia and analgesia.

PEDIATRIC USE

Pediatric Use Promethazine hydrochloride injection is contraindicated for use in pediatric patients less than 2 years of age, because of the potential for fatal respiratory depression.

Promethazine hydrochloride injection should be used with caution in pediatric patients 2 years of age and older (see WARNINGS – Respiratory Depression ).

Antiemetics are not recommended for treatment of uncomplicated vomiting in pediatric patients, and their use should be limited to prolonged vomiting of known etiology.

The extrapyramidal symptoms which can occur secondary to promethazine hydrochloride injection administration may be confused with the CNS signs of undiagnosed primary disease, e.g., encephalopathy or Reye´s syndrome or other hepatic diseases.

Excessively large dosages of antihistamines, including promethazine hydrochloride injection, in pediatric patients may cause sudden death (see OVERDOSAGE ).

Hallucinations and convulsions have occurred with therapeutic doses and overdoses of promethazine hydrochloride injection in pediatric patients.

In pediatric patients who are acutely ill associated with dehydration, there is an increased susceptibility to dystonias with the use of promethazine hydrochloride injection.

PREGNANCY

Pregnancy Teratogenic Effects –Pregnancy Category C Teratogenic effects have not been demonstrated in rat-feeding studies at doses of 6.25 and 12.5 mg/kg (approximately 2.1 and 4.2 times the maximum recommended human daily dose) of promethazine hydrochloride injection.

Daily doses of 25 mg/kg intraperitoneally have been found to produce fetal mortality in rats.

There are no adequate and well-controlled studies of promethazine hydrochloride injection in pregnant women.

Because animal reproduction studies are not always predictive of human response, promethazine hydrochloride injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Adequate studies to determine the action of the drug on parturition, lactation and development of the animal neonate have not been conducted.

Nonteratogenic Effects Promethazine hydrochloride injection administered to a pregnant woman within two weeks of delivery may inhibit platelet aggregation in the newborn.

NUSRING MOTHERS

Nursing Mothers It is not known whether promethazine hydrochloride injection is excreted in human milk.

Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from promethazine hydrochloride injection, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

BOXED WARNING

WARNINGS RESPIRATORY DEPRESSION – Pediatrics Promethazine hydrochloride injection should not be used in pediatric patients less than 2 years of age because of the potential for fatal respiratory depression.

Post-marketing cases of respiratory depression, including fatalities, have been reported with use of promethazine in pediatric patients less than 2 years of age.

Caution should be exercised when administering promethazine hydrochloride injection to pediatric patients 2 years of age and older (see WARNINGS – Respiratory Depression ).

SEVERE TISSUE INJURY, INCLUDING GANGRENE Promethazine hydrochloride injection can cause severe chemical irritation and damage to tissues regardless of the route of administration.

Irritation and damage can result from perivascular extravasation, unintentional intra-arterial injection, and intraneuronal or perineuronal infiltration.

Adverse reactions include burning, pain, thrombophlebitis, tissue necrosis, and gan grene.

In some cases, surgical intervention, including fasciotomy, skin graft, and/or amputation have been required (see WARNINGS – Severe Tissue Injury, Including Gangrene ).

Due to risks of intravenous injection, the preferred route of administration of promethazine hydrochloride injection is deep intramuscular injection.

Subcutaneous injection is contraindicated.

See DOSAGE AND ADMINISTRATION for important notes on administration.

INFORMATION FOR PATIENTS

Information for Patients Patients should be advised of the risk of respiratory depression, including potentially fatal respiratory depression in children less than 2 years of age (see WARNINGS – Respiratory Depression ).

Patients should be advised of the risk of severe tissue injury, including gangrene (see WARNINGS – Severe Tissue Injury, Including Gangrene ).

Patients should be advised to immediately report persistent or worsening pain or burning at the injection site.

Promethazine hydrochloride injection may cause marked drowsiness or impair the mental or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machiner y.

Pediatric patients should be supervised to avoid potential harm in bike riding or in other hazardous activities.

The concomitant use of alcohol, sedative/hypnotics (including barbiturates), general anesthetics, narcotics, narcotic analgesics, tricyclic antidepressants, and tranquilizers may enhance impairment (see WARNINGS – CNS Depression and PRECAUTIONS – Drug Interactions ).

Patients should be advised to report any involuntary muscle movements (see ADVERSE REACTIONS – Paradoxical Reactions ).

Patients should be advised to avoid prolonged exposure to the sun (see ADVERSE REACTIONS – Dermatologic ).

DOSAGE AND ADMINISTRATION

Important Notes on Administration Promethazine hydrochloride injection can cause severe chemical irritation and damage to tissues regardless of the route of administration.

Irritation and damage can result from perivascular extravasation, unintentional intra-arterial injection, and intraneuronal or perineuronal infiltration (see WARNINGS – Severe Tissue Injury, Including Gangrene ).

The preferred parenteral route of administration for promethazine hydrochloride injection is by deep intramuscular injection.

Under no circumstances should promethazine hydrochloride injection be given by intra-arterial injection due to the likelihood of severe anteriospasm and the possibility of resultant gangrene (see WARNINGS – Severe Tissue Injury, Including Gangrene ).

Subcutaneous injection is contraindicated as it may result in tissue necrosis When administered intravenously, promethazine hydrochloride injection should be given in a concentration no greater than 25 mg per mL and at a rate not to exceed 25 mg per minute.

It is preferable to inject through the tubing of an intravenous infusion set that is known to be functioning satisfactorily.

In the event that a patient complains of pain during the intravenous injection fo promethazine hydrochloride injection, the injection should be stopped immediately to evaluate for a possible aterial injection or perivascular extravasation.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Do not use promethazine hydrochloride injection if solution has developed color or contains precipitate.

To avoid the possibility of physical and/or chemical incompatibility, consult specialized literature before diluting with any injectable solution or combining with any other medication.

Do not use if there is a precipitate or any sign of incompatibility.

Allergic Conditions The average adult dose is 25 mg.

This dose may be repeated within two hours if necessary, but continued therapy, if indicated, should be via the oral route as soon as existing circumstances permit.

After initiation of treatment, dosage should be adjusted to the smallest amount adequate to relieve symptoms.

The average adult dose for amelioration of allergic reactions to blood or plasma is 25 mg.

Sedation In hospitalized adult patients, nighttime sedation may be achieved by a dose of 25 to 50 mg of promethazine hydrochloride injection.

Nausea and Vomiting For control of nausea and vomiting, the usual adult dose is 12.5 to 25 mg, not to be repeated more frequently than every four hours.

When used for control of postoperative nausea and vomiting, the dosage of analgesics and barbiturates should be reduced accordingly (see PRECAUTIONS – Drug Interactions ).

Antiemetics should not be used in vomiting of unknown etiology in children and adolescents (see PRECAUTIONS – Pediatric Use ).

Preoperative and Postoperative Use As an adjunct to preoperative or postoperative medication, 25 to 50 mg of promethazine hydrochloride injection in adults may be combined with appropriately reduced doses of analgesics and atropine-like drugs as desired.

Dosage of concomitant analgesic or hypnotic medication should be reduced accordingly (see PRECAUTIONS – Drug Interactions ).

Promethazine hydrochloride is contraindicated for use in pediatric patients less than two years of age.

Obstetrics Promethazine hydrochloride injection in doses of 50 mg will provide sedation and relieve apprehension in the early stages of labor.

When labor is definitely established, 25 to 75 mg (average dose, 50 mg) promethazine hydrochloride injection may be given with an appropriately reduced dose of any desired narcotic (see PRECAUTIONS – Drug Interactions ).

If necessary, promethazine hydrochloride injection with a reduced dose of analgesic may be repeated once or twice at four-hour intervals in the course of a normal labor.

A maximum total dose of 100 mg of promethazine hydrochloride injection may be administered during a 24-hour period to patients in labor.

Pediatric Patients Promethazine hydrochloride injection is c ontraindicated for use in pediatric patients less than 2 years of age (s ee WARNINGS – Respiratory Depression ).

Caution should be exercised when administering promethazine hydrochloride injection to pediatric patients 2 years of age or older.

It is recommended that the lowest effective dose of promethazine hydrochloride be used in pediatric patients 2 years of age and older and concomitant administration of other drugs with respiratory depressant effects be avoided (see WARNINGS – Respiratory Depression ).

In pediatric patients 2 years of age and older, the dosage should not exceed half that of the suggested adult dose.

As an adjunct to premedication, the suggested dose is 1.1 mg per kg of body weight in combination with an appropriately reduced dose of narcotic or barbiturate and the appropriate dose of an atropine-like drug (see PRECAUTIONS – Drug Interactions ).

Antiemetics should not be used in vomiting of unknown etiology in pediatric patients.

Antihemophilic Factor, Human Recombinant 1 UNT Injection

No Details Found

Betaine 1000 MG Powder for Oral Solution

No Details Found

DRUG INTERACTIONS

7 Concomitant use of drugs that increase bleeding risk, antibiotics, antifungals, botanical (herbal) products, and inhibitors and inducers of CYP2C9, 1A2, or 3A4.

( 7 ) Consult labeling of all concurrently used drugs for complete information about interactions with warfarin sodium or increased risks for bleeding.

( 7 ) 7.1 General Information Drugs may interact with warfarin sodium through pharmacodynamic or pharmacokinetic mechanisms.

Pharmacodynamic mechanisms for drug interactions with warfarin sodium are synergism (impaired hemostasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and alteration of the physiologic control loop for vitamin K metabolism (hereditary resistance).

Pharmacokinetic mechanisms for drug interactions with warfarin sodium are mainly enzyme induction, enzyme inhibition, and reduced plasma protein binding.

It is important to note that some drugs may interact by more than one mechanism.

More frequent INR monitoring should be performed when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs, including drugs intended for short-term use (e.g., antibiotics, antifungals, corticosteroids) [see Boxed Warning ].

Consult the labeling of all concurrently used drugs to obtain further information about interactions with warfarin sodium or adverse reactions pertaining to bleeding.

7.2 CYP450 Interactions CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4.

The more potent warfarin S -enantiomer is metabolized by CYP2C9 while the R -enantiomer is metabolized by CYP1A2 and 3A4.

Inhibitors of CYP2C9, 1A2, and/or 3A4 have the potential to increase the effect (increase INR) of warfarin by increasing the exposure of warfarin.

Inducers of CYP2C9, 1A2, and/or 3A4 have the potential to decrease the effect (decrease INR) of warfarin by decreasing the exposure of warfarin.

Examples of inhibitors and inducers of CYP2C9, 1A2, and 3A4 are below in Table 2; however, this list should not be considered all-inclusive.

Consult the labeling of all concurrently used drugs to obtain further information about CYP450 interaction potential.

The CYP450 inhibition and induction potential should be considered when starting, stopping, or changing dose of concomitant medications.

Closely monitor INR if a concomitant drug is a CYP2C9, 1A2, and/or 3A4 inhibitor or inducer.

Table 2: Examples of CYP450 Interactions with Warfarin Enzyme Inhibitors Inducers CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 7.3 Drugs that Increase Bleeding Risk Examples of drugs known to increase the risk of bleeding are presented in Table 3.

Because bleeding risk is increased when these drugs are used concomitantly with warfarin, closely monitor patients receiving any such drug with warfarin.

Table 3: Drugs that Can Increase the Risk of Bleeding Drug Class Specific Drugs Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 7.4 Antibiotics and Antifungals There have been reports of changes in INR in patients taking warfarin and antibiotics or antifungals, but clinical pharmacokinetic studies have not shown consistent effects of these agents on plasma concentrations of warfarin.

Closely monitor INR when starting or stopping any antibiotic or antifungal in patients taking warfarin.

7.5 Botanical (Herbal) Products and Foods More frequent INR monitoring should be performed when starting or stopping botanicals.

Few adequate, well-controlled studies evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and warfarin sodium exist.

Due to a lack of manufacturing standardization with botanical medicinal preparations, the amount of active ingredients may vary.

This could further confound the ability to assess potential interactions and effects on anticoagulation.

Some botanicals may cause bleeding events when taken alone (e.g., garlic and Ginkgo biloba) and may have anticoagulant, antiplatelet, and/or fibrinolytic properties.

These effects would be expected to be additive to the anticoagulant effects of warfarin sodium.

Conversely, some botanicals may decrease the effects of warfarin sodium (e.g., co-enzyme Q 10 , St.

John’s wort, ginseng).

Some botanicals and foods can interact with warfarin sodium through CYP450 interactions (e.g., echinacea, grapefruit juice, ginkgo, goldenseal, St.

John’s wort).

The amount of vitamin K in food may affect therapy with warfarin sodium.

Advise patients taking warfarin sodium to eat a normal, balanced diet maintaining a consistent amount of vitamin K.

Patients taking warfarin sodium should avoid drastic changes in dietary habits, such as eating large amounts of green leafy vegetables.

OVERDOSAGE

10 10.1 Signs and Symptoms Bleeding (e.g., appearance of blood in stools or urine, hematuria, excessive menstrual bleeding, melena, petechiae, excessive bruising or persistent oozing from superficial injuries, unexplained fall in hemoglobin) is a manifestation of excessive anticoagulation.

10.2 Treatment The treatment of excessive anticoagulation is based on the level of the INR, the presence or absence of bleeding, and clinical circumstances.

Reversal of warfarin sodium anticoagulation may be obtained by discontinuing warfarin sodium therapy and, if necessary, by administration of oral or parenteral vitamin K 1 .

The use of vitamin K 1 reduces response to subsequent warfarin sodium therapy and patients may return to a pretreatment thrombotic status following the rapid reversal of a prolonged INR.

Resumption of warfarin sodium administration reverses the effect of vitamin K, and a therapeutic INR can again be obtained by careful dosage adjustment.

If rapid re-anticoagulation is indicated, heparin may be preferable for initial therapy.

Prothrombin complex concentrate (PCC), fresh frozen plasma, or activated Factor VII treatment may be considered if the requirement to reverse the effects of warfarin sodium is urgent.

A risk of hepatitis and other viral diseases is associated with the use of blood products; PCC and activated Factor VII are also associated with an increased risk of thrombosis.

Therefore, these preparations should be used only in exceptional or life-threatening bleeding episodes secondary to warfarin sodium overdosage.

DESCRIPTION

11 Warfarin sodium tablets contain warfarin sodium, an anticoagulant that acts by inhibiting vitamin K-dependent coagulation factors.

The chemical name of warfarin sodium is 3-(α-acetonylbenzyl)-4-hydroxycoumarin sodium salt, which is a racemic mixture of the R – and S -enantiomers.

Crystalline warfarin sodium is an isopropanol clathrate.

Its empirical formula is C 19 H 15 NaO 4 , and its structural formula is represented by the following: Crystalline warfarin sodium occurs as a white, odorless, crystalline powder that is discolored by light.

It is very soluble in water, freely soluble in alcohol, and very slightly soluble in chloroform and ether.

Warfarin sodium tablets, USP for oral use also contain: All strengths: Anhydrous lactose, corn starch, and magnesium stearate 1 mg: D&C Red No.

6 Barium Lake 2 mg: FD&C Blue No.

2 Aluminum Lake, FD&C Red No.

40 Aluminum Lake 2.5 mg: D&C Yellow No.

10 Aluminum Lake, FD&C Blue No.

2 Aluminum Lake 3 mg: D&C Yellow No.

10 Aluminum Lake, FD&C Blue No.

2 Aluminum Lake, FD&C Red No.

40 Aluminum Lake 4 mg: FD&C Blue No.

1 Aluminum Lake 5 mg: D&C Red No.

6 Barium Lake, D&C Yellow No.

10 Aluminum Lake 6 mg: D&C Yellow No.

10 Aluminum Lake, FD&C Blue No.

2 Aluminum Lake 7.5 mg: D&C Yellow No.

10 Aluminum Lake 10 mg: Dye Free Chemical Structure

CLINICAL STUDIES

14 14.1 Atrial Fibrillation In five prospective, randomized, controlled clinical trials involving 3711 patients with non-rheumatic AF, warfarin significantly reduced the risk of systemic thromboembolism including stroke (see Table 4 ).

The risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%), which was stopped early due to published positive results from two of these trials.

The incidence of major bleeding in these trials ranged from 0.6% to 2.7% (see Table 4 ).

Table 4: Clinical Studies of Warfarin in Non-Rheumatic AF Patients All study results of warfarin vs.

control are based on intention-to-treat analysis and include ischemic stroke and systemic thromboembolism, excluding hemorrhagic stroke and transient ischemic attacks.

N Thromboembolism % Major Bleeding Study Warfarin-Treated Patients Control Patients PT Ratio INR % Risk Reduction p -value Warfarin-Treated Patients Control Patients AFASAK 335 336 1.5-2.0 2.8-4.2 60 0.027 0.6 0.0 SPAF 210 211 1.3-1.8 2.0-4.5 67 0.01 1.9 1.9 BAATAF 212 208 1.2-1.5 1.5-2.7 86 <0.05 0.9 0.5 CAFA 187 191 1.3-1.6 2.0-3.0 45 0.25 2.7 0.5 SPINAF 260 265 1.2-1.5 1.4-2.8 79 0.001 2.3 1.5 Trials in patients with both AF and mitral stenosis suggest a benefit from anticoagulation with warfarin sodium [see Dosage and Administration (2.2) ].

14.2 Mechanical and Bioprosthetic Heart Valves In a prospective, randomized, open-label, positive-controlled study in 254 patients with mechanical prosthetic heart valves, the thromboembolic-free interval was found to be significantly greater in patients treated with warfarin alone compared with dipyridamole/aspirin-treated patients (p<0.005) and pentoxifylline/aspirin-treated patients (p<0.05).

The results of this study are presented in Table 5.

Table 5: Prospective, Randomized, Open-Label, Positive-Controlled Clinical Study of Warfarin in Patients with Mechanical Prosthetic Heart Valves Patients Treated With Event Warfarin Dipyridamole/Aspirin Pentoxifylline/Aspirin py=patient years Thromboembolism 2.2/100 py 8.6/100 py 7.9/100 py Major Bleeding 2.5/100 py 0.0/100 py 0.9/100 py In a prospective, open-label, clinical study comparing moderate (INR 2.65) versus high intensity (INR 9.0) warfarin therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency in the two groups (4.0 and 3.7 events per 100 patient years, respectively).

Major bleeding was more common in the high intensity group.

The results of this study are presented in Table 6.

Table 6: Prospective, Open-Label Clinical Study of Warfarin in Patients with Mechanical Prosthetic Heart Valves Event Moderate Warfarin Therapy INR 2.65 High Intensity Warfarin Therapy INR 9.0 py=patient years Thromboembolism 4.0/100 py 3.7/100 py Major Bleeding 0.95/100 py 2.1/100 py In a randomized trial in 210 patients comparing two intensities of warfarin therapy (INR 2.0 to 2.25 vs.

INR 2.5 to 4.0) for a three-month period following tissue heart valve replacement, thromboembolism occurred with similar frequency in the two groups (major embolic events 2.0% vs.

1.9%, respectively, and minor embolic events 10.8% vs.

10.2%, respectively).

Major hemorrhages occurred in 4.6% of patients in the higher intensity INR group compared to zero in the lower intensity INR group.

14.3 Myocardial Infarction WARIS (The Warfarin Re-Infarction Study) was a double-blind, randomized study of 1214 patients 2 to 4 weeks post-infarction treated with warfarin to a target INR of 2.8 to 4.8.

The primary endpoint was a composite of total mortality and recurrent infarction.

A secondary endpoint of cerebrovascular events was assessed.

Mean follow-up of the patients was 37 months.

The results for each endpoint separately, including an analysis of vascular death, are provided in Table 7.

Table 7: WARIS – Endpoint Analysis of Separate Events Event Warfarin (N=607) Placebo (N=607) RR (95% CI) % Risk Reduction ( p -value) RR=Relative risk; Risk reduction=(1 – RR); CI=Confidence interval; MI=Myocardial infarction; py=patient years Total Patient Years of Follow-up 2018 1944 Total Mortality Vascular Death 94 (4.7/100 py) 82 (4.1/100 py) 123 (6.3/100 py) 105 (5.4/100 py) 0.76 (0.60, 0.97) 0.78 (0.60, 1.02) 24 (p=0.030) 22 (p=0.068) Recurrent MI 82 (4.1/100 py) 124 (6.4/100 py) 0.66 (0.51, 0.85) 34 (p=0.001) Cerebrovascular Event 20 (1.0/100 py) 44 (2.3/100 py) 0.46 (0.28, 0.75) 54 (p=0.002) WARIS II (The Warfarin, Aspirin, Re-Infarction Study) was an open-label, randomized study of 3630 patients hospitalized for acute myocardial infarction treated with warfarin to a target INR 2.8 to 4.2, aspirin 160 mg per day, or warfarin to a target INR 2.0 to 2.5 plus aspirin 75 mg per day prior to hospital discharge.

The primary endpoint was a composite of death, nonfatal reinfarction, or thromboembolic stroke.

The mean duration of observation was approximately 4 years.

The results for WARIS II are provided in Table 8.

Table 8: WARIS II – Distribution of Events According to Treatment Group Event Aspirin (N=1206) Warfarin (N=1216) Aspirin plus Warfarin (N=1208) Rate Ratio (95% CI) p -value No.

of Events CI=confidence interval ND=not determined Major Bleeding Major bleeding episodes were defined as nonfatal cerebral hemorrhage or bleeding necessitating surgical intervention or blood transfusion.

8 33 28 3.35 The rate ratio is for aspirin plus warfarin as compared with aspirin.

(ND) 4.00 The rate ratio is for warfarin as compared with aspirin.

(ND) ND ND Minor Bleeding Minor bleeding episodes were defined as non-cerebral hemorrhage not necessitating surgical intervention or blood transfusion.

39 103 133 3.21 (ND) 2.55 (ND) ND ND Composite Endpoints Includes death, nonfatal reinfarction, and thromboembolic cerebral stroke.

241 203 181 0.81 (0.69-0.95) 0.71 (0.60-0.83) 0.03 0.001 Reinfarction 117 90 69 0.56 (0.41-0.78) 0.74 (0.55-0.98) <0.001 0.03 Thromboembolic Stroke 32 17 17 0.52 (0.28-0.98) 0.52 (0.28-0.97) 0.03 0.03 Death 92 96 95 0.82 There were approximately four times as many major bleeding episodes in the two groups receiving warfarin than in the group receiving aspirin alone.

Major bleeding episodes were not more frequent among patients receiving aspirin plus warfarin than among those receiving warfarin alone, but the incidence of minor bleeding episodes was higher in the combined therapy group.

HOW SUPPLIED

16 /STORAGE AND HANDLING Warfarin Sodium Tablets, USP are single-scored, flat, beveled, capsule-shaped tablets, engraved numerically with 1, 2, 2½, 3, 4, 5, 6, 7½, or 10 on one side and engraved with “WARFARIN” on top of “TARO” on the other side.

They are packaged with potencies and colors as follows: Bottles of 100 Bottles of 1000 Bottles of 5000 Cartons of 100 10×10 blister packs 1 mg Pink NDC 51672-4027-1 NDC 51672-4027-3 NDC 51672-4027-7 NDC 51672-4027-0 2 mg Lavender NDC-51672-4028-1 NDC-51672-4028-3 NDC-51672-4028-7 NDC-51672-4028-0 2.5 mg Green NDC 51672-4029-1 NDC 51672-4029-3 NDC 51672-4029-7 NDC 51672-4029-0 3 mg Tan NDC 51672-4030-1 NDC 51672-4030-3 NDC 51672-4030-7 NDC 51672-4030-0 4 mg Blue NDC 51672-4031-1 NDC 51672-4031-3 NDC 51672-4031-7 NDC 51672-4031-0 5 mg Peach NDC 51672-4032-1 NDC 51672-4032-3 NDC 51672-4032-7 NDC 51672-4032-0 6 mg Teal NDC 51672-4033-1 NDC 51672-4033-3 NDC 51672-4033-7 NDC 51672-4033-0 7.5 mg Yellow NDC 51672-4034-1 NDC 51672-4034-3 NDC 51672-4034-0 10 mg White (dye free) NDC 51672-4035-1 NDC 51672-4035-3 NDC 51672-4035-0 Protect from light and moisture.

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP.

Store the hospital unit-dose blister packages in the carton until contents have been used.

Special Handling Procedures for proper handling and disposal of potentially hazardous drugs should be considered.

Guidelines on this subject have been published [see References (15) ].

Pharmacy and clinical personnel who are pregnant should avoid exposure to crushed or broken tablets [see Use in Specific Populations (8.1) ].

RECENT MAJOR CHANGES

Dosage and Administration, Renal Impairment ( 2.5 ) 5/2017 Warnings and Precautions, Calciphylaxis ( 5.3 ) 9/2016 Warnings and Precautions, Acute kidney injury ( 5.4 ) 5/2017

GERIATRIC USE

8.5 Geriatric Use Of the total number of patients receiving warfarin sodium in controlled clinical trials for which data were available for analysis, 1885 patients (24.4%) were 65 years and older, while 185 patients (2.4%) were 75 years and older.

No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant effects of warfarin [see Clinical Pharmacology (12.3) ].

Warfarin sodium is contraindicated in any unsupervised patient with senility.

Conduct more frequent monitoring for bleeding with administration of warfarin sodium to elderly patients in any situation or with any physical condition where added risk of hemorrhage is present.

Consider lower initiation and maintenance doses of warfarin sodium in elderly patients [see Dosage and Administration (2.2 , 2.3) ].

DOSAGE FORMS AND STRENGTHS

3 Warfarin Sodium Single-Scored Tablets, USP Strength Color Engraved 1 mg pink 1 2 mg lavender 2 2.5 mg green 2½ 3 mg tan 3 4 mg blue 4 5 mg peach 5 6 mg teal 6 7.5 mg yellow 7½ 10 mg white (dye-free) 10 Scored tablets: 1, 2, 2½, 3, 4, 5, 6, 7½, or 10 mg ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Warfarin acts by inhibiting the synthesis of vitamin K-dependent clotting factors, which include Factors II, VII, IX, and X, and the anticoagulant proteins C and S.

Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K-dependent clotting factors.

Vitamin K promotes the biosynthesis of γ-carboxyglutamic acid residues in the proteins that are essential for biological activity.

Warfarin is thought to interfere with clotting factor synthesis by inhibition of the C1 subunit of vitamin K epoxide reductase (VKORC1) enzyme complex, thereby reducing the regeneration of vitamin K 1 epoxide [see Clinical Pharmacology (12.5) ].

INDICATIONS AND USAGE

1 Warfarin sodium tablets, USP are indicated for: Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE).

Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation (AF) and/or cardiac valve replacement.

Reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as stroke or systemic embolization after myocardial infarction.

Warfarin sodium is a vitamin K antagonist indicated for: Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism ( 1 ) Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement ( 1 ) Reduction in the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction ( 1 ) Limitations of Use Warfarin sodium has no direct effect on an established thrombus, nor does it reverse ischemic tissue damage.

( 1 ) Limitations of Use Warfarin sodium has no direct effect on an established thrombus, nor does it reverse ischemic tissue damage.

Once a thrombus has occurred, however, the goals of anticoagulant treatment are to prevent further extension of the formed clot and to prevent secondary thromboembolic complications that may result in serious and possibly fatal sequelae.

PEDIATRIC USE

8.4 Pediatric Use Adequate and well-controlled studies with warfarin sodium have not been conducted in any pediatric population, and the optimum dosing, safety, and efficacy in pediatric patients is unknown.

Pediatric use of warfarin sodium is based on adult data and recommendations, and available limited pediatric data from observational studies and patient registries.

Pediatric patients administered warfarin sodium should avoid any activity or sport that may result in traumatic injury.

The developing hemostatic system in infants and children results in a changing physiology of thrombosis and response to anticoagulants.

Dosing of warfarin in the pediatric population varies by patient age, with infants generally having the highest, and adolescents having the lowest milligram per kilogram dose requirements to maintain target INRs.

Because of changing warfarin requirements due to age, concomitant medications, diet, and existing medical condition, target INR ranges may be difficult to achieve and maintain in pediatric patients, and more frequent INR determinations are recommended.

Bleeding rates varied by patient population and clinical care center in pediatric observational studies and patient registries.

Infants and children receiving vitamin K-supplemented nutrition, including infant formulas, may be resistant to warfarin therapy, while human milk-fed infants may be sensitive to warfarin therapy.

PREGNANCY

8.1 Pregnancy Risk Summary Warfarin sodium tablets, USP are contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism, and for whom the benefits of warfarin sodium may outweigh the risks [see Warnings and Precautions (5.7) ].

Warfarin sodium can cause fetal harm.

Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring.

Because these data were not collected in adequate and well-controlled studies, this incidence of major birth defects is not an adequate basis for comparison to the estimated incidences in the control group or the U.S.

general population and may not reflect the incidences observed in practice.

Consider the benefits and risks of warfarin sodium and possible risks to the fetus when prescribing warfarin sodium to a pregnant woman.

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Fetal/Neonatal Adverse Reactions In humans, warfarin crosses the placenta, and concentrations in fetal plasma approach the maternal values.

Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring.

Warfarin embryopathy is characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) and growth retardation (including low birth weight).

Central nervous system and eye abnormalities have also been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, midline cerebellar atrophy, and ventral midline dysplasia characterized by optic atrophy.

Mental retardation, blindness, schizencephaly, microcephaly, hydrocephalus, and other adverse pregnancy outcomes have been reported following warfarin exposure during the second and third trimesters of pregnancy [see Contraindications (4) ].

BOXED WARNING

WARNING: BLEEDING RISK Warfarin sodium can cause major or fatal bleeding [see Warnings and Precautions (5.1) ].

Perform regular monitoring of INR in all treated patients [see Dosage and Administration (2.1) ].

Drugs, dietary changes, and other factors affect INR levels achieved with warfarin sodium therapy [see Drug Interactions (7) ].

Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding [see Patient Counseling Information (17) ].

WARNING: BLEEDING RISK See full prescribing information for complete boxed warning.

Warfarin sodium can cause major or fatal bleeding.

( 5.1 ) Perform regular monitoring of INR in all treated patients.

( 2.1 ) Drugs, dietary changes, and other factors affect INR levels achieved with warfarin sodium therapy.

( 7 ) Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding.

( 17 )

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Tissue necrosis: Necrosis or gangrene of skin or other tissues can occur, with severe cases requiring debridement or amputation.

Discontinue warfarin sodium and consider alternative anticoagulants if necessary.

( 5.2 ) Calciphylaxis: Fatal and serious cases have occurred.

Discontinue warfarin sodium and consider alternative anticoagulation therapy.

( 5.3 ) Acute kidney injury may occur during episodes of excessive anticoagulation and hematuria.

( 5.4 ) Systemic atheroemboli and cholesterol microemboli: Some cases have progressed to necrosis or death.

Discontinue warfarin sodium if such emboli occur.

( 5.5 ) Heparin-induced thrombocytopenia (HIT): Initial therapy with warfarin sodium in HIT has resulted in cases of amputation and death.

Warfarin sodium may be considered after platelet count has normalized.

( 5.6 ) Pregnant women with mechanical heart valves: Warfarin sodium may cause fetal harm; however, the benefits may outweigh the risks.

( 5.7 ) 5.1 Hemorrhage Warfarin sodium can cause major or fatal bleeding.

Bleeding is more likely to occur within the first month.

Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age greater than or equal to 65, history of highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, anemia, malignancy, trauma, renal impairment, certain genetic factors [see Clinical Pharmacology (12.5) ], certain concomitant drugs [see Drug Interactions (7) ], and long duration of warfarin therapy.

Perform regular monitoring of INR in all treated patients.

Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shortest duration of therapy appropriate for the clinical condition.

However, maintenance of INR in the therapeutic range does not eliminate the risk of bleeding.

Drugs, dietary changes, and other factors affect INR levels achieved with warfarin sodium therapy.

Perform more frequent INR monitoring when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs [see Drug Interactions (7) ].

Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding [see Patient Counseling Information (17) ].

5.2 Tissue Necrosis Warfarin sodium can cause necrosis and/or gangrene of skin and other tissues, which is an uncommon but serious risk (<0.1%).

Necrosis may be associated with local thrombosis and usually appears within a few days of the start of warfarin sodium therapy.

In severe cases of necrosis, treatment through debridement or amputation of the affected tissue, limb, breast, or penis has been reported.

Careful clinical evaluation is required to determine whether necrosis is caused by an underlying disease.

Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective.

Discontinue warfarin sodium therapy if necrosis occurs.

Consider alternative drugs if continued anticoagulation therapy is necessary.

5.3 Calciphylaxis Warfarin sodium can cause fatal and serious calciphylaxis or calcium uremic arteriolopathy, which has been reported in patients with and without end-stage renal disease.

When calciphylaxis is diagnosed in these patients, discontinue warfarin sodium and treat calciphylaxis as appropriate.

Consider alternative anticoagulation therapy.

5.4 Acute Kidney Injury In patients with altered glomerular integrity or with a history of kidney disease, acute kidney injury may occur with warfarin sodium, possibly in relation to episodes of excessive anticoagulation and hematuria [see Use in Specific Populations (8.6) ].

More frequent monitoring of anticoagulation is advised in patients with compromised renal function.

5.5 Systemic Atheroemboli and Cholesterol Microemboli Anticoagulation therapy with warfarin sodium may enhance the release of atheromatous plaque emboli.

Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms depending on the site of embolization.

The most commonly involved visceral organs are the kidneys followed by the pancreas, spleen, and liver.

Some cases have progressed to necrosis or death.

A distinct syndrome resulting from microemboli to the feet is known as “purple toes syndrome.” Discontinue warfarin sodium therapy if such phenomena are observed.

Consider alternative drugs if continued anticoagulation therapy is necessary.

5.6 Limb Ischemia, Necrosis, and Gangrene in Patients with HIT and HITTS Do not use warfarin sodium as initial therapy in patients with heparin-induced thrombocytopenia (HIT) and with heparin-induced thrombocytopenia with thrombosis syndrome (HITTS).

Cases of limb ischemia, necrosis, and gangrene have occurred in patients with HIT and HITTS when heparin treatment was discontinued and warfarin therapy was started or continued.

In some patients, sequelae have included amputation of the involved area and/or death.

Treatment with warfarin sodium may be considered after the platelet count has normalized.

5.7 Use in Pregnant Women with Mechanical Heart Valves Warfarin sodium can cause fetal harm when administered to a pregnant woman.

While warfarin sodium is contraindicated during pregnancy, the potential benefits of using warfarin sodium may outweigh the risks for pregnant women with mechanical heart valves at high risk of thromboembolism.

In those individual situations, the decision to initiate or continue warfarin sodium should be reviewed with the patient, taking into consideration the specific risks and benefits pertaining to the individual patient’s medical situation, as well as the most current medical guidelines.

Warfarin sodium exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1) ].

5.8 Other Clinical Settings with Increased Risks In the following clinical settings, the risks of warfarin sodium therapy may be increased: Moderate to severe hepatic impairment Infectious diseases or disturbances of intestinal flora (e.g., sprue, antibiotic therapy) Use of an indwelling catheter Severe to moderate hypertension Deficiency in protein C-mediated anticoagulant response: warfarin sodium reduces the synthesis of the naturally occurring anticoagulants, protein C and protein S.

Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration.

Concomitant anticoagulation therapy with heparin for 5 to 7 days during initiation of therapy with warfarin sodium may minimize the incidence of tissue necrosis in these patients.

Eye surgery: In cataract surgery, warfarin sodium use was associated with a significant increase in minor complications of sharp needle and local anesthesia block but not associated with potentially sight-threatening operative hemorrhagic complications.

As warfarin sodium cessation or reduction may lead to serious thromboembolic complications, the decision to discontinue warfarin sodium before a relatively less invasive and complex eye surgery, such as lens surgery, should be based upon the risks of anticoagulant therapy weighed against the benefits.

Polycythemia vera Vasculitis Diabetes mellitus 5.9 Endogenous Factors Affecting INR The following factors may be responsible for increased INR response: diarrhea, hepatic disorders, poor nutritional state, steatorrhea, or vitamin K deficiency.

The following factors may be responsible for decreased INR response: increased vitamin K intake or hereditary warfarin resistance.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Instructions for Patients Advise patients to: Strictly adhere to the prescribed dosage schedule [see Dosage and Administration (2.1) ].

If the prescribed dose of warfarin sodium is missed, take the dose as soon as possible on the same day but do not take a double dose of warfarin sodium the next day to make up for missed doses [see Dosage and Administration (2.6) ].

Obtain prothrombin time tests and make regular visits to their physician or clinic to monitor therapy [see Dosage and Administration (2.1) ].

Be aware that if therapy with warfarin sodium is discontinued, the anticoagulant effects of warfarin sodium may persist for about 2 to 5 days [see Clinical Pharmacology (12.2) ].

Avoid any activity or sport that may result in traumatic injury [see Use in Specific Populations (8.4) ].

And to tell their physician if they fall often as this may increase their risk for complications.

Eat a normal, balanced diet to maintain a consistent intake of vitamin K.

Avoid drastic changes in dietary habits, such as eating large amounts of leafy, green vegetables [see Drug Interactions (7.5) ].

Contact their physician to report any serious illness, such as severe diarrhea, infection, or fever [see Warnings and Precautions (5) and Adverse Reactions (6) ].

Immediately contact their physician when experiencing pain and discoloration of the skin (a purple bruise like rash) mostly on areas of the body with a high fat content, such as breasts, thighs, buttocks, hips and abdomen [see Warnings and Precautions (5.2) ].

Immediately contact their physician when experiencing any unusual symptom or pain since warfarin sodium may cause small cholesterol or athero emboli.

On feet it may appear as a sudden cool, painful, purple discoloration of toe(s) or forefoot [see Warnings and Precautions (5.5) ].

Immediately contact their physician when taking warfarin sodium after any heparin formulation therapy and experiencing bloody or black stools or appearence of bruises, or bleeding [see Warnings and Precautions (5.6) ].

To tell all of their healthcare professionals and dentists that they are taking warfarin sodium.

This should be done before they have any surgery or dental procedure [see Dosage and Administration (2.7) ].

Carry identification stating that they are taking warfarin sodium.

Bleeding Risks Advise patients to: Notify their physician immediately if any unusual bleeding or symptoms occur.

Signs and symptoms of bleeding include: pain, swelling or discomfort, prolonged bleeding from cuts, increased menstrual flow or vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or dark brown urine, red or tar black stools, headache, dizziness, or weakness [see Box Warning and Warnings and Precautions (5.1) ].

Concomitant Medications and Botanicals (Herbals) Advise patients to: Not take or discontinue any other drug, including salicylates (e.g., aspirin and topical analgesics), other over-the-counter drugs, and botanical (herbal) products except on advice of your physician [see Drug Interactions (7) ].

Pregnancy and Nursing Advise patients to: Notify their physician if they are pregnant or planning to become pregnant or considering breast feeding [see Use in Specific Populations (8.1 , 8.2 , 8.3) ].

Avoid warfarin sodium during pregnancy except in pregnant women with mechanical heart valves, who are at risk of thromboembolism [see Contraindications (4) ].

Use effective measures to avoid pregnancy while taking warfarin sodium.

This is very important because their unborn baby could be seriously harmed if they take warfarin sodium while they are pregnant [see Use in Specific Populations (8.1 , 8.3) ].

DOSAGE AND ADMINISTRATION

2 Individualize dosing regimen for each patient, and adjust based on INR response.

( 2.1 , 2.2 ) Knowledge of genotype can inform initial dose selection.

( 2.3 ) Monitoring: Obtain daily INR determinations upon initiation until stable in the therapeutic range.

Obtain subsequent INR determinations every 1 to 4 weeks.

( 2.4 ) Review conversion instructions from other anticoagulants.

( 2.8 ) 2.1 Individualized Dosing The dosage and administration of warfarin sodium must be individualized for each patient according to the patient’s International Normalized Ratio (INR) response to the drug.

Adjust the dose based on the patient’s INR and the condition being treated.

Consult the latest evidence-based clinical practice guidelines regarding the duration and intensity of anticoagulation for the indicated conditions.

2.2 Recommended Target INR Ranges and Durations for Individual Indications An INR of greater than 4.0 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding.

Venous Thromboembolism (including deep venous thrombosis [DVT] and PE) Adjust the warfarin dose to maintain a target INR of 2.5 (INR range, 2.0 to 3.0) for all treatment durations.

The duration of treatment is based on the indication as follows: For patients with a DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended.

For patients with an unprovoked DVT or PE, treatment with warfarin is recommended for at least 3 months.

After 3 months of therapy, evaluate the risk-benefit ratio of long-term treatment for the individual patient.

For patients with two episodes of unprovoked DVT or PE, long-term treatment with warfarin is recommended.

For a patient receiving long-term anticoagulant treatment, periodically reassess the risk-benefit ratio of continuing such treatment in the individual patient.

Atrial Fibrillation In patients with non-valvular AF, anticoagulate with warfarin to target INR of 2.5 (range, 2.0 to 3.0).

In patients with non-valvular AF that is persistent or paroxysmal and at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, or 2 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended.

In patients with non-valvular AF that is persistent or paroxysmal and at an intermediate risk of ischemic stroke (i.e., having 1 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended.

For patients with AF and mitral stenosis, long-term anticoagulation with warfarin is recommended.

For patients with AF and prosthetic heart valves, long-term anticoagulation with warfarin is recommended; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.

Mechanical and Bioprosthetic Heart Valves For patients with a bileaflet mechanical valve or a Medtronic Hall (Minneapolis, MN) tilting disk valve in the aortic position who are in sinus rhythm and without left atrial enlargement, therapy with warfarin to a target INR of 2.5 (range, 2.0 to 3.0) is recommended.

For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, therapy with warfarin to a target INR of 3.0 (range, 2.5 to 3.5) is recommended.

For patients with caged ball or caged disk valves, therapy with warfarin to a target INR of 3.0 (range, 2.5 to 3.5) is recommended.

For patients with a bioprosthetic valve in the mitral position, therapy with warfarin to a target INR of 2.5 (range, 2.0 to 3.0) for the first 3 months after valve insertion is recommended.

If additional risk factors for thromboembolism are present (AF, previous thromboembolism, left ventricular dysfunction), a target INR of 2.5 (range, 2.0 to 3.0) is recommended.

Post-Myocardial Infarction For high-risk patients with MI (e.g., those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on transthoracic echocardiography, those with AF, and those with a history of a thromboembolic event), therapy with combined moderate-intensity (INR, 2.0 to 3.0) warfarin plus low-dose aspirin (≤100 mg/day) for at least 3 months after the MI is recommended.

Recurrent Systemic Embolism and Other Indications Oral anticoagulation therapy with warfarin has not been fully evaluated by clinical trials in patients with valvular disease associated with AF, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology.

However, a moderate dose regimen (INR 2.0 to 3.0) may be used for these patients.

2.3 Initial and Maintenance Dosing The appropriate initial dosing of warfarin sodium varies widely for different patients.

Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by: Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities Genetic factors (CYP2C9 and VKORC1 genotypes) [see Clinical Pharmacology (12.5) ] Select the initial dose based on the expected maintenance dose, taking into account the above factors.

Modify this dose based on consideration of patient-specific clinical factors.

Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3) ].

Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation.

Individualize the duration of therapy for each patient.

In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed [see Dosage and Administration (2.2) ].

Dosing Recommendations without Consideration of Genotype If the patient’s CYP2C9 and VKORC1 genotypes are not known, the initial dose of warfarin sodium is usually 2 to 5 mg once daily.

Determine each patient’s dosing needs by close monitoring of the INR response and consideration of the indication being treated.

Typical maintenance doses are 2 to 10 mg once daily.

Dosing Recommendations with Consideration of Genotype Table 1 displays three ranges of expected maintenance warfarin sodium doses observed in subgroups of patients having different combinations of CYP2C9 and VKORC1 gene variants [see Clinical Pharmacology (12.5) ].

If the patient’s CYP2C9 and/or VKORC1 genotype are known, consider these ranges in choosing the initial dose.

Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 may require more prolonged time (>2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP variants.

Table 1: Three Ranges of Expected Maintenance Warfarin Sodium Daily Doses Based on CYP2C9 and VKORC1 Genotypes Ranges are derived from multiple published clinical studies.

VKORC1 −1639G>A (rs9923231) variant is used in this table.

Other coinherited VKORC1 variants may also be important determinants of warfarin dose.

VKORC1 CYP2C9 *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3 GG 5-7 mg 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg AG 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg AA 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 2.4 Monitoring to Achieve Optimal Anticoagulation Warfarin sodium has a narrow therapeutic range (index), and its action may be affected by factors such as other drugs and dietary vitamin K.

Therefore, anticoagulation must be carefully monitored during warfarin sodium therapy.

Determine the INR daily after the administration of the initial dose until INR results stabilize in the therapeutic range.

After stabilization, maintain dosing within the therapeutic range by performing periodic INRs.

The frequency of performing INR should be based on the clinical situation but generally acceptable intervals for INR determinations are 1 to 4 weeks.

Perform additional INR tests when other warfarin products are interchanged with warfarin sodium, as well as whenever other medications are initiated, discontinued, or taken irregularly.

Heparin, a common concomitant drug, increases the INR [see Dosage and Administration (2.8) and Drug Interactions (7) ].

Determinations of whole blood clotting and bleeding times are not effective measures for monitoring of warfarin sodium therapy.

2.5 Renal Impairment No dosage adjustment is necessary for patients with renal failure.

Monitor INR more frequently in patients with compromised renal function to maintain INR within the therapeutic range [see Warnings and Precautions (5.4) and Use in Specific Populations (8.6) ].

2.6 Missed Dose The anticoagulant effect of warfarin sodium persists beyond 24 hours.

If a patient misses a dose of warfarin sodium at the intended time of day, the patient should take the dose as soon as possible on the same day.

The patient should not double the dose the next day to make up for a missed dose.

2.7 Treatment During Dentistry and Surgery Some dental or surgical procedures may necessitate the interruption or change in the dose of warfarin sodium therapy.

Consider the benefits and risks when discontinuing warfarin sodium even for a short period of time.

Determine the INR immediately prior to any dental or surgical procedure.

In patients undergoing minimally invasive procedures who must be anticoagulated prior to, during, or immediately following these procedures, adjusting the dosage of warfarin sodium to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation.

2.8 Conversion From Other Anticoagulants Heparin Since the full anticoagulant effect of warfarin sodium is not achieved for several days, heparin is preferred for initial rapid anticoagulation.

During initial therapy with warfarin sodium, the interference with heparin anticoagulation is of minimal clinical significance.

Conversion to warfarin sodium may begin concomitantly with heparin therapy or may be delayed 3 to 6 days.

To ensure therapeutic anticoagulation, continue full dose heparin therapy and overlap warfarin sodium therapy with heparin for 4 to 5 days and until warfarin sodium has produced the desired therapeutic response as determined by INR, at which point heparin may be discontinued.

As heparin may affect the INR, patients receiving both heparin and warfarin sodium should have INR monitoring at least: 5 hours after the last intravenous bolus dose of heparin, or 4 hours after cessation of a continuous intravenous infusion of heparin, or 24 hours after the last subcutaneous heparin injection.

Warfarin sodium may increase the activated partial thromboplastin time (aPTT) test, even in the absence of heparin.

A severe elevation (>50 seconds) in aPTT with an INR in the desired range has been identified as an indication of increased risk of postoperative hemorrhage.

Other Anticoagulants Consult the labeling of other anticoagulants for instructions on conversion to warfarin sodium.