Author: druginteractionchecker_lgaiz4

jute fiber extract 50 MG/ML Injectable Solution

Generic Name: COTTON
Brand Name: Cotton
  • Substance Name(s):
  • COTTON

WARNINGS

DO NOT INJECT INTRAVENOUSLY.

Epinephrine 1:1000 should be available.

Concentrated extracts must be diluted with sterile diluent prior to first use on a patient for treatment or intradermal testing.

All concentrates of glycerinated allergenic extracts have the ability to cause serious local and systemic reactions including death in sensitive patients.

Sensitive patients may experience severe anaphylactic reactions resulting in respiratory obstruction, shock, coma and /or death.(4) (See Adverse Reactions) An allergenic extract should be temporarily withheld from patients or the dose of the extract adjusted downward if any of the following conditions exist: (1) Severe symptoms of rhinitis and/or asthma (2) Infections or flu accompanied by fever and (3) Exposure to excessive amounts of clinically relevant allergen prior to a scheduled injection.

When switching patients to a new lot of the same extract the initial dose should be reduced 3/4 so that 25% of previous dose is administered.

OVERDOSAGE

Overdose can cause both local and systemic reactions.

An overdose may be prevented by careful observation and questioning of the patient about the previous injection.

If systemic or anaphylactic reaction, does occur, apply a tourniquet above the site of injection and inject intramuscularly or subcutaneously 0.3 to 0.5ml of 1:1000 Epinephrine Hydrochloride into the opposite arm.

The dose may be repeated in 5-10 minutes if necessary.

Loosen the tourniquet at least every 10 minutes.

The Epinephrine Hydrochloride 1:1000 dose for infants to 2 years is 0.05 to 0.1 ml, for children 2 to 6 years it is 0.15 ml, for children 6-12 years it is 0.2 ml.

Patients unresponsive to Epinephrine may be treated with Theophylline.

Studies on asthmatic subjects reveal that plasma concentrations of Theophylline of 5 to 20 µg/ml are associated with therapeutic effects.

Toxicity is particularly apparent at concentrations greater than 20 µg/ml.

A loading dose of Aminophylline of 5.8 mg/kg intravenously followed by 0.9 mg/kg per hour results in plasma concentrations of approximately 10 µg/ml for patients not previously receiving theophylline.

(Mitenko and Ogilive, Nicholoson and Chick,1973) Other beta-adrenergic drugs such as Isoproterenol, Isoetharine, or Albuterol may be used by inhalation.

The usual dose to relieve broncho-constriction in asthma is 0.5 ml of the 0.5% solution for Isoproterenol HCl.

The Albuterol inhaler delivers approximately 90 mcg of Albuterol from the mouthpiece.

The usual dosage for adults and children would be two inhalations repeated every 4-6 hours.

Isoetharine supplied in the Bronkometer unit delivers approximately 340 mcg Isoetharine.

The average dose is one to two inhalations.

Respiratory obstruction not responding to parenteral or inhaled bronchodilators may require oxygen, intubation and the use of life support systems.

DESCRIPTION

Allergenic extracts are sterile solutions consisting of the extractable components from various biological sources including pollens, inhalants, molds, animal epidermals and insects.

Aqueous extracts are prepared using cocas fluid containing NaCl 0.5%, NaHCO3 0.0275%, WFI, preservative 0.4% Phenol.

Glycerinated allergenic extracts are prepared with cocas fluid and glycerin to produce a 50% (v/v) allergenic extract.

Allergenic Extracts are supplied as concentrations designated as protein nitrogen units (PNU) or weight/volume (w/v) ratio.

Standardized extracts are designated in Bioequivalent Allergy Units (BAU) or Allergy Units (AU).

(See product insert for standardized extracts) For diagnostic purposes, allergenic extracts are to be administered by prick-puncture or intradermal routes.

Allergenic extracts are administered subcutaneously for immunotherapy injections.

HOW SUPPLIED

Allergenic extracts are supplied with units listed as: Weight/volume (W/V), Protein Nitrogen Units (PNU/ml), Allergy Units (AU/ml) or Bioequivalent Allergy Units (BAU/ml).

Sizes: Diagnostic Scratch: 5 ml dropper application vials Diagnostic Intradermal: 5 ml or 10 ml vials.

Therapeutic Allergens: 5 ml, 10 ml, 50 ml multiple dose vials.

INDICATIONS AND USAGE

Allergenic extracts are indicated for use in diagnostic testing and as part of a treatment regime for allergic disease, as established by allergy history and skin test reactivity.

Allergenic extracts are indicated for the treatment of allergen specific allergic disease for use as hyposensitization or immunotherapy when avoidance of specific allergens can not be attained.

The use of allergenic extracts for therapeutic purpose has been established by well-controlled clinical studies.

Allergenic extracts may be used as adjunctive therapy along with pharmacotherapy which includes antihistamines, corticosteroids, and cromoglycate, and avoidance measures.

Allergenic extracts for therapeutic use should be given using only the allergen selection to which the patient is allergic, has a history of exposure and are likely to be exposed to again.

BOXED WARNING

WARNING Diagnostic and therapeutic allergenic extracts are intended to be administered by a physician who is an allergy specialist and experienced in allergenic diagnostic testing and immunotherapy and the emergency care of anaphylaxis.

This product should not be injected intravenously.

Deep subcutaneous routes have been safe.

Sensitive patients may experience severe anaphylactic reactions resulting in respiratory obstruction, shock, coma and/or death.

(See Adverse Reactions) Serious adverse reactions should be reported to Nelco Laboratories immediately and a report filed to: MedWatch, The FDA Medical Product Problem Reporting Program, at 5600 Fishers Lane, Rockville, Md.

20852-9787, call 1-800-FDA-1088.

Extreme caution should be taken when using allergenic extracts for patients who are taking beta-blocker medications.

In the event of a serious adverse reaction associated with the use of allergenic extracts, patients receiving beta-blockers may not be responsive to epinephrine or inhaled brochodialators.(1) (See Precautions) Allergenic extracts should be used with caution for patients with unstable or steroid-dependent asthma or underlying cardiovascular disease.

(See Contraindications)

DOSAGE AND ADMINISTRATION

General Precautions Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permits.

The dosage of allergenic extracts is dependent upon the purpose of the administration.

Allergenic extracts can be administered for diagnostic use or for therapeutic use.

When allergenic extracts are administered for diagnostic use, the dosage is dependent upon the method used.

Two methods commonly used are scratch testing and intradermal testing.

Both types of tests result in a wheal and flare response at the site of the test which usually develops rapidly and may be read in 20-30 minutes.

Diagnostic Use : Scratch Testing Method Scratch testing is considered a simple and safe method although less sensitive than the intradermal test.

Scratch testing can be used to determine the degree of sensitivity to a suspected allergen before using the intradermal test.

This combination lessens the severity of response to an allergen which can occur in a very sensitive patient.

The most satisfactory testing site is the patient’s back or volar surface of the arms from the axilla to 2.5 or 5cm above the wrist, skipping the anti-cubital space.

If using the back as a testing site, the most satisfactory area are from the posterior axillary fold to 2.5 cm from the spinal column, and from the top of the scapula to the lower rib margins.

Allergenic extracts for diagnostic use are to be administered in the following manner: To scratch surface of skin, use a circular scarifier.

Do not draw blood.

Tests sites should be 4 cm apart to allow for wheal and flare reaction.

1-30 scratch tests may be done at a time.

A separate sterile scratch instrument is to be used on each patient to prevent transmission of homologous serum hepatitis or other infectious agents from one patient to another.

The recommended usual dosage for Scratch testing is one drop of allergen applied to each scratch site.

Do not let dropper touch skin.

Always apply a control scratch with each test set.

Sterile Diluent (for a negative control) is used in exactly the same way as an active test extract.

Histamine may be used as a positive control.

Scratch or prick test sites should be examined at 15 and 30 minutes.

To prevent excessive absorption, wipe off antigens producing large reactions as soon as the wheal appears.

Record the size of the reaction.

Interpretation of Scratch Test Skin tests are graded in terms of the wheal and erythema response noted at 10 to 20 minutes.

Wheal and erythema size may be recorded by actual measurement as compared with positive and negative controls.

A positive reaction consists of an area of erythema surrounding the scarification that is larger than the control site.

For uniformity in reporting reactions, the following system is recommended.

(6) REACTION SYMBOL CRITERIA Negative – No wheal.

Erythema absent or very slight (not more than 1 mm diameter).

One Plus + Wheal absent or very slight erythema present (not more than 3 mm diameter).

Two Plus ++ Wheal not more than 3mm or erythema not more than 5mm diameter.

Three Plus +++ Wheal between 3mm and 5mm diameter, with erythema.

Possible pseudopodia and itching.

Four Plus ++++ A larger reaction with itching and pain.

Diagnostic Use: Intradermal Skin Testing Method Do not perform intradermal test with allergens which have evoked a 2+ or greater response to a Scratch test.

Clean test area with alcohol, place sites 5 cm apart using separate sterile tuberculin syringe and a 25 gauge needle for each allergen.

Insert needle tip, bevel up, into intracutaneous space.

Avoid injecting into blood vessel, pull back gently on syringe plunger, if blood enters syringe change position of needle.

The recommended dosage and range for intradermal testing is 0.05 ml of not more than 100 pnu/ml or 1:1000 w/v (only if puncture test is negative) of allergenic extract.

Inject slowly until a small bleb is raised.

It is important to make each bleb the same size.

Interpretation of Intradermal Test: The patient’s reaction is graded on the basis of size of wheal and flare as compared to control.

Use 0.05 ml sterile diluent as a negative control to give accurate interpretation.

The tests may be accurately interpreted only when the saline control site has shown a negative response.

Observe patient for at least 30 minutes.

Tests can be read in 15-20 minutes.

Edema, erythema and presence of pseudopods, pain and itching may be observed in 4 plus reactions.

For uniformity in reporting reactions the following system is recommended.

(6) REACTION SYMBOL CRITERIA Negative – No increase in size of bleb since injection.

No erythema.

One Plus + An increase in size of bleb to a wheal not more than 5mm diameter, with associated erythema.

Two Plus ++ Wheal between 5mm and 8mm diameter with erythema.

Three Plus +++ Wheal between 8mm and 12mm diameter with erythema and possible pseudopodia and itching or pain.

Four Plus ++++ Any larger reaction with itch and pain, and possible diffuse blush of the skin surrounding the reaction area.

Therapeutic Use: Recommended dosage & range Check the listed ingredients to verify that it matches the prescription ordered.

When using a prescription set, verify the patient’s name and the ingredients listed with the prescription order.

Assess the patient’s physical and emotional status prior to giving as injection.

Do not give injections to patients who are in acute distress.

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

Dosage of allergenic extracts is a highly individualized matter and varies according to the degree of sensitivity of the patient, his clinical response and tolerance to the extract administered during the early phases of an injection regimen.

The dosage must be reduced when transferring a patient from non-standardized or modified extract to standardized extract.

Any evidence of a local or generalized reaction requires a reduction in dosage during the initial stages of immunotherapy as well as during maintenance therapy.

After therapeutic injections patients should be observed for at least 20 minutes for reaction symptoms.

SUGGESTED DOSAGE SCHEDULE The following schedule may act as a guide.

This schedule has not been proven to be safe or effective.

Sensitive patients may begin with smaller doses of weaker solutions and the dosage increments can be less.

STRENGTH DOSE VOLUME Vial #1 1 0.05 1:100,000 w/v 2 0.10 10 pnu/ml 3 0.15 1 AU/ml 4 0.20 1 BAU/ml 5 0.30 6 0.40 7 0.50 Vial #2 8 0.05 1:10,000 w/v 9 0.10 100 pnu/ml 10 0.15 10 AU/ml 11 0.20 10 BAU/ml 12 0.30 13 0.40 14 0.50 Vial #3 15 0.05 1:1,000 w/v 16 0.10 1,000 pnu/ml 17 0.15 100 AU/ml 18 0.20 100 BAU/ml 19 0.30 20 0.40 21 0.50 Vial #4 22 0.05 1:100 w/v 23 0.07 10,000 pnu/ml 24 0.10 1,000 AU/ml 25 0.15 1,000 BAU/ml 26 0.20 27 0.25 Maintenance Refill 28 0.25 1:100 w/v 29 0.25 10,000 pnu/ml 30 0.25 1,000 AU/ml 31 0.25 1,000 BAU/ml 32 0.25 subsequent doses 33 0.25 Preparation Instructions: All dilutions may be made using sterile buffered diluent.

The calculation may be based on the following ratio: Volume desired x Concentration desired = Volume needed x Concentration available.

Example 1: If a 1:10 w/v extract is available and it is desired to use a 1:1,000 w/v extract substitute as follows: Vd x Cd = Vn x Ca 10ml x 0.001 = Vn x 0.1 0.1 ml = Vn Using a sterile technique, remove 0.10 ml of extract from the 1:10 vial and place it into a vial containing 9.90 ml of sterile diluent.

The resulting ratio will be a 10 ml vial of 1:1,000 w/v.

Example 2: If a 10,000 pnu/ml extract is available and it is desired to use a 100 pnu/ml extract substitute as follows: 10ml x 100 = Vn x 10,000 0.1 ml = Vn Using a sterile technique, remove 0.10 ml of extract from the 10,000 pnu/ml vial and place it into a vial containing 9.90 ml of sterile diluent.

The resulting concentration will be a 10 ml vial of 100 pnu/ml.

Example 3: If a 10,000 AU/ml or BAU/ml extract is available and it is desired to use a 100 AU/ml or BAU/ml extract substitute as follows: Vd x Cd = Vn x Ca 10ml x 100 = Vn x 10,000 0.1 ml = Vn Using a sterile technique, remove 0.10 ml of extract from the 10,000 AU/ml or BAU/ml vial and place it into a vial containing 9.90 ml of sterile diluent.

The resulting concentration will be 10ml vial of 100 AU/ml or BAU/ml.

Intervals between doses: The optimal interval between doses of allergenic extract has not been definitely established.

The amount of allergenic extract is increased at each injection by not more than 50%-100% of the previous amount and the next increment is governed by the response to the last injection.

There are three generally accepted methods of pollen hyposensitizing therapy.

1.

PRESEASONAL Treatment starts each year 6 to 8 weeks before onset of seasonal symptoms.

Maximal dose reached just before symptoms are expected.

Injections discontinued during and following season until next year.

2.

CO-SEASONAL Patient is first treated during season with symptoms.

Low initial doses are employed to prevent worsening of condition.

This is followed by an intensive schedule of therapy (i.e.

injections given 2 to 3 times per week).

Fewer Allergists are resorting to this Co-seasonal therapy because of the availability of more effective, symptomatic medications that allow the patient to go through a season relatively symptom free.

3.

PERENNIAL Initially this is the same as pre seasonal.

The allergen is administered twice weekly or weekly for about 20 injections to achieve the maximum tolerated dose.

Then, maintenance therapy may be administered once a week or less frequently.

Duration of Treatment: The usual duration of treatment has not been established.

A period of two or three years of injection therapy constitutes an average minimum course of treatment.

Aluminum Hydroxide 200 MG / Magnesium Hydroxide 200 MG / Simethicone 25 MG Chewable Tablet

WARNINGS

Ask a doctor ​before use if you have kidney disease a magnesium restricted Ask a doctor or pharmacist before use if you are presently taking a prescription drug.

Antacids may interact with certain prescription drugs.

INDICATIONS AND USAGE

INDICATIONS & USAGE Uses relieves heartburn acid indigestion sour stomach upset stomach & gas associated with these conditions

INACTIVE INGREDIENTS

INACTIVE INGREDIENT citric acid anhydrous, corn starch, D&C red 30 lake, D&C yellow 10 lake, destrose, flavors, glycerin, magnesium stearate, maltodextrin, mannitol, pregelatinized starch, saccharin sodium, sorbitol, sugar

PURPOSE

OTC – Purposes Antacid Antigas

KEEP OUT OF REACH OF CHILDREN

OTC – Keep out of reach of children.

DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION Dosage: chew 1 – 4 tablets 4 times a day or as directed by a doctor.

do not take more than 16 tablets in a 24 hour period.

do not use the maximum dose for more than 2 weeks.

each tablet contains: magnesium 85 mg

DO NOT USE

OTC – TAMPER EVIDENT: IF IMPRINTED SEAL UNDER CAP IS TORN OR MISSING

STOP USE

OTC – Do not take more than 16 tablets in a 24-hour period, or use the maximum dosage of this product for more than 2 weeks, except under the advice and supervision of a doctor.

ACTIVE INGREDIENTS

OTC – ACTIVE INGREDIENT Active ingredients (in each tablet) Purpose Aluminum Hydroxide (equiv.

to dried gel, USP) 200mg ………

Antacid Magnesium Hydroxide 200mg …………

Antacid Simethicone 25 mg …………..

Antigas

Magnesium Sulfate 1000 MG Oral Granules

Generic Name: MAGNESIUM SULFATE
Brand Name: PEPSOM SPORTS WINTERGREEN
  • Substance Name(s):
  • MAGNESIUM SULFATE, UNSPECIFIED

WARNINGS

Warnings For external use only

INDICATIONS AND USAGE

Uses For relieving muscle strains and soreness from working out

INACTIVE INGREDIENTS

Inactive ingredients: Carrot juice extract, silicon dioxide, wintergreen.

PURPOSE

Purpose Soaking Solution

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children If swallowed, get medical help or contact a Poison Control Center right away.

ASK DOCTOR

Ask a doctor before use if you have redness or swelling present evidence of an infection diabetes

DOSAGE AND ADMINISTRATION

Directions Bath- Soaking Aid Dissolve 2 cups into a tub of hot water and soak for 15-30 minutes.

Foot or Wrist Soak Dissolve 2 cups into a foot-soaking tub half-full of water, soaking the injured area for 20-30 minutes.

Repeat 2-3 times per day until relief is obtained.

ACTIVE INGREDIENTS

Active Ingredient Magnesium Sulfate U.S.P.

100% (Epsom salt) label

Dilantin 125 MG per 5 ML Oral Suspension

Generic Name: PHENYTOIN
Brand Name: Dilantin-125
  • Substance Name(s):
  • PHENYTOIN

DRUG INTERACTIONS

7 Phenytoin is extensively bound to plasma proteins and is prone to competitive displacement.

Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19 and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism.

Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity.

Monitoring of phenytoin serum levels is recommended when a drug interaction is suspected.

Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes.

Multiple drug interactions because of extensive plasma protein binding, saturable metabolism and potent induction of hepatic enzymes (7.1, 7.2).

7.1 Drugs that Affect Phenytoin Concentrations Table 2 includes commonly occurring drug interactions that affect phenytoin concentrations.

However, this list is not intended to be inclusive or comprehensive.

Individual prescribing information from relevant drugs should be consulted.

The addition or withdrawal of these agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome.

Table 2: Drugs That Affect Phenytoin Concentrations Interacting Agent Examples Drugs that may increase phenytoin serum levels Antiepileptic drugs Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate Azoles Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole Antineoplastic agents Capecitabine, fluorouracil Antidepressants Fluoxetine, fluvoxamine, sertraline Gastric acid reducing agents H2 antagonists (cimetidine), omeprazole Sulfonamides Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim Other Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin Drugs that may decrease phenytoin serum levels AntacidsAntacids may affect absorption of phenytoin.

Calcium carbonate, aluminum hydroxide, magnesium hydroxide Prevention or Management: Phenytoin and antacids should not be taken at the same time of day Antineoplastic agents (usually in combination) Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate Antiviral agents Fosamprenavir, nelfinavir, ritonavir Antiepileptic drugs Carbamazepine, vigabatrin Other Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St.

John’s wortThe induction potency of St.

John’s wort may vary widely based on preparation., sucralfate, theophylline Drugs that may either increase or decrease phenytoin serum levels Antiepileptic drugs Phenobarbital, valproate sodium, valproic acid 7.2 Drugs Affected by Phenytoin Table 3 includes commonly occurring drug interactions affected by phenytoin.

However, this list is not intended to be inclusive or comprehensive.

Individual drug package inserts should be consulted.

The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome.

Table 3: Drugs Affected by Phenytoin Interacting Agent Examples Drugs whose efficacy is impaired by phenytoin Azoles Fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole Antineoplastic agents Irinotecan, paclitaxel, teniposide Delavirdine Phenytoin can substantially reduce the concentrations of delavirdine.

This can lead to loss of virologic response and possible resistance [see Contraindications (4)].

Neuromuscular blocking agents Cisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin.

Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown.

Prevention or Management: Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.

Warfarin Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin Other Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D Drugs whose level is decreased by phenytoin Antiepileptic drugs The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine Antilipidemic agents Atorvastatin, fluvastatin, simvastatin Antiviral agents Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite.

Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir Calcium channel blockers Nifedipine, nimodipine, nisoldipine, verapamil Other Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, folic acid, methadone, mexiletine, praziquantel, quetiapine 7.3 Drug Enteral Feeding/Nutritional Preparations Interaction Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected phenytoin serum levels.

It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation.

More frequent serum phenytoin level monitoring may be necessary in these patients.

7.4 Drug/Laboratory Test Interactions Care should be taken when using immunoanalytical methods to measure serum phenytoin concentrations.

OVERDOSAGE

10 The lethal dose in pediatric patients is not known.

The lethal dose in adults is estimated to be 2 to 5 grams.

The initial symptoms are nystagmus, ataxia, and dysarthria.

Other signs are tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting.

The patient may become comatose and hypotensive.

Death is caused by respiratory and circulatory depression.

There are marked variations among individuals with respect to phenytoin serum levels where toxicity may occur.

Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL, dysarthria and lethargy appear when the serum concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity.

As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery.

Irreversible cerebellar dysfunction and atrophy have been reported.

Treatment: Treatment is nonspecific since there is no known antidote.

The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed.

Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins.

Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients.

In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind.

DESCRIPTION

11 DILANTIN (phenytoin) is related to the barbiturates in chemical structure, but has a five-membered ring.

The chemical name is 5,5-diphenyl-2,4 imidazolidinedione, having the following structural formula: Each 5 mL of the oral suspension contains 125 mg of phenytoin, USP; alcohol, USP (maximum content not greater than 0.6 percent); banana flavor; carboxymethylcellulose sodium, USP; citric acid, anhydrous, USP; glycerin, USP; magnesium aluminum silicate, NF; orange oil concentrate; polysorbate 40, NF; purified water, USP; sodium benzoate, NF; sucrose, NF; vanillin, NF; and FD&C yellow No.

6.

Chemical Structure

HOW SUPPLIED

16 /STORAGE AND HANDLING 16.1 How Supplied DILANTIN-125 Oral Suspension is supplied as follows: Package Configuration Strength NDC 8-oz bottles 125 mg phenytoin/5mL 0071-2214-20 DILANTIN-125 Suspension (phenytoin oral suspension, USP), 125 mg phenytoin/5 mL contains a maximum alcohol content not greater than 0.6 percent in an orange suspension with an orange-vanilla flavor.

16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); see USP controlled room temperature.

Protect from light.

Do not freeze.

RECENT MAJOR CHANGES

Warnings and Precautions (5.11) 11/2016

GERIATRIC USE

8.5 Geriatric Use Phenytoin clearance tends to decrease with increasing age [see Clinical Pharmacology (12.3)].

Lower or less frequent dosing may be required [see Dosage and Administration (2.7)].

DOSAGE FORMS AND STRENGTHS

3 DILANTIN-125 is available as a 125 mg phenytoin/5 mL oral suspension of orange color with an orange-vanilla flavor.

DILANTIN-125 is available as a 125 mg phenytoin/5 mL oral suspension.

(3)

MECHANISM OF ACTION

12.1 Mechanism of Action The precise mechanism by which phenytoin exerts its therapeutic effect has not been established but is thought to involve the voltage-dependent blockade of membrane sodium channels resulting in a reduction in sustained high-frequency neuronal discharges.

INDICATIONS AND USAGE

1 DILANTIN is indicated for the treatment of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures.

DILANTIN is indicated for the treatment of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures.

(1)

PEDIATRIC USE

8.4 Pediatric Use Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily.

A recommended daily maintenance dosage is usually 4 to 8 mg/kg.

Children over 6 years and adolescents may require the minimum adult dosage (300 mg/day) [see Dosage and Administration (2.3)].

PREGNANCY

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as DILANTIN, during pregnancy.

Physicians are advised to recommend that pregnant patients taking Dilantin enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry.

This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves.

Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/ Risk Summary In humans, prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes.

An increased incidence of major malformations (such as orofacial clefts and cardiac defects) and abnormalities characteristic of fetal hydantoin syndrome (dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities [including microcephaly], and cognitive deficits) has been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy.

There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy.

Administration of phenytoin to pregnant animals resulted in an increased incidence of fetal malformations and other manifestations of developmental toxicity (including embryofetal death, growth impairment, and behavioral abnormalities) in multiple species at clinically relevant doses [see Data].

In the U.S.

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

The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (including phenytoin) during pregnancy is about 10%, or two- to three-fold that in the general population.

Clinical Considerations Disease-associated maternal risk An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics.

Periodic measurement of serum phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage [see Dosage and Administration (2.4, 2.8)].

However, postpartum restoration of the original dosage will probably be indicated [see Clinical Pharmacology (12.3)].

Fetal/Neonatal Adverse Reactions A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero.

This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.

Data Animal data Administration of phenytoin to pregnant rats, rabbits, and mice during organogenesis resulted in embryofetal death, fetal malformations, and decreased fetal growth.

Malformations (including craniofacial, cardiovascular, neural, limb, and digit abnormalities) were observed in rats, rabbits, and mice at doses as low as 100, 75, and 12.5 mg/kg, respectively.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Withdrawal Precipitated Seizure: May precipitate status epilepticus.

Dose reductions or discontinuation should be done gradually.

(5.1) Suicidal Behavior and Ideation: Monitor patients for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

(5.2) Serious Dermatologic Reactions: Discontinue DILANTIN at the first sign of a rash, unless the rash is clearly not drug-related.

If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.

(5.3) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity: If signs or symptoms of hypersensitivity are present, evaluate the patient immediately.

Discontinue if an alternative etiology cannot be established.

(5.4) Hepatic Injury: Cases of acute hepatotoxicity have been reported with DILANTIN.

If this occurs, immediately discontinue.

(4, 5.6) Hematopoietic Complications: If occurs, follow-up observation is indicated and an alternative antiepileptic treatment should be used.

(5.7) 5.1 Withdrawal Precipitated Seizure, Status Epilepticus Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus.

When in the judgment of the clinician the need for dosage reduction, discontinuation, or substitution of alternative anticonvulsant medication arises, this should be done gradually.

However, in the event of an allergic or hypersensitivity reaction, more rapid substitution of alternative therapy may be necessary.

In this case, alternative therapy should be an anticonvulsant not belonging to the hydantoin chemical class.

5.2 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including DILANTIN, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.

Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo.

In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated.

There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed.

Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.

The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.

The risk did not vary substantially by age (5–100 years) in the clinical trials analyzed.

Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

Table 1 Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing DILANTIN or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.

Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.

Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.

Behaviors of concern should be reported immediately to healthcare providers.

5.3 Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment.

The onset of symptoms is usually within 28 days, but can occur later.

DILANTIN should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related.

If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.

If a rash occurs, the patient should be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms [see Warnings and Precautions (5.4)].

Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine.

Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin.

Consideration should be given to avoiding phenytoin as an alternative for carbamazepine in patients positive for HLA-B*1502.

The use of HLA-B*1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management.

The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied.

5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including DILANTIN.

Some of these events have been fatal or life-threatening.

DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection.

Eosinophilia is often present.

Because this disorder is variable in its expression, other organ systems not noted here may be involved.

It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident.

If such signs or symptoms are present, the patient should be evaluated immediately.

DILANTIN should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

5.5 Hypersensitivity DILANTIN and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity [see Contraindications (4)].

Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients.

Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to DILANTIN.

5.6 Hepatic Injury Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with DILANTIN.

These events may be part of the spectrum of DRESS or may occur in isolation [see Warnings and Precautions (5.4)].

Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia.

The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes.

In these patients with acute hepatotoxicity, DILANTIN should be immediately discontinued and not readministered.

5.7 Hematopoietic Complications Hematopoietic complications, some fatal, have occasionally been reported in association with administration of DILANTIN.

These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression.

There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s disease.

Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology.

Lymph node involvement may occur with or without symptoms and signs of DRESS [see Warnings and Precautions (5.4)].

In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs.

5.8 Effects on Vitamin D and Bone The chronic use of phenytoin in patients with epilepsy has been associated with decreased bone mineral density (osteopenia, osteoporosis, and osteomalacia) and bone fractures.

Phenytoin induces hepatic metabolizing enzymes.

This may enhance the metabolism of vitamin D and decrease vitamin D levels, which may lead to vitamin D deficiency, hypocalcemia, and hypophosphatemia.

Consideration should be given to screening with bone-related laboratory and radiological tests as appropriate and initiating treatment plans according to established guidelines.

5.9 Renal or Hepatic Impairment, or Hypoalbuminemia Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients.

5.10 Exacerbation of Porphyria In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease.

5.11 Teratogenicity and Other Harm to the Newborn DILANTIN may cause fetal harm when administered to a pregnant woman.

Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse development outcomes [see Use in Specific Populations (8.1)].

Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), and abnormalities characteristic of fetal hydantoin syndrome, including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits, have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy.

There have been several reported cases of malignancies, including neuroblastoma.

The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs, including phenytoin, during pregnancy is about 10%, or two- to three-fold that in the general population.

A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero.

This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.

5.12 Slow Metabolizers of Phenytoin A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly.

Slow metabolism may be caused by limited enzyme availability and lack of induction; it appears to be genetically determined.

If early signs of dose-related CNS toxicity develop, serum levels should be checked immediately.

5.13 Hyperglycemia Hyperglycemia, resulting from the drug’s inhibitory effects on insulin release, has been reported.

Phenytoin may also raise the serum glucose level in diabetic patients.

5.14 Serum Phenytoin Levels above Therapeutic Range Serum levels of phenytoin sustained above the therapeutic range may produce confusional states referred to as “delirium,” “psychosis,” or “encephalopathy,” or rarely irreversible cerebellar dysfunction and/or cerebellar atrophy.

Accordingly, at the first sign of acute toxicity, serum levels should be immediately checked.

Dose reduction of phenytoin therapy is indicated if serum levels are excessive; if symptoms persist, termination is recommended.

INFORMATION FOR PATIENTS

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

Administration Information Advise patients taking phenytoin of the importance of adhering strictly to the prescribed dosage regimen, and of informing the physician of any clinical condition in which it is not possible to take the drug orally as prescribed, e.g., surgery, etc.

Instruct patients to use an accurately calibrated measuring device when using this medication to ensure accurate dosing.

Withdrawal of Antiepileptic Drugs Advise patients not to discontinue use of DILANTIN without consulting with their healthcare provider.

DILANTIN should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus [see Warnings and Precautions (5.1)].

Suicidal Ideation and Behavior Counsel patients, their caregivers, and families that AEDs, including DILANTIN, may increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.

Behaviors of concern should be reported immediately to healthcare providers [see Warnings and Precautions (5.2)].

Potential Signs of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Other Systemic Reactions Advise patients of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions.

These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy, facial swelling, and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice.

Advise the patient that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician.

In addition, advise the patient that these signs and symptoms should be reported even if mild or when occurring after extended use [see Warnings and Precautions (5.3, 5.4, 5.5, 5.6, 5.7)].

Effects of Alcohol Use and Other Drugs and Over-the-Counter Drug Interactions Caution patients against the use of other drugs or alcoholic beverages without first seeking their physician’s advice [see Drug Interactions (7.1, 7.2)].

Inform patients that certain over-the-counter medications (e.g., antacids, cimetidine, and omeprazole), vitamins (e.g., folic acid), and herbal supplements (e.g., St.

John’s wort) can alter their phenytoin levels.

Hyperglycemia Advise patients that DILANTIN may cause an increase in blood glucose levels [see Warnings and Precautions (5.13)].

Gingival Hyperplasia Advise patients of the importance of good dental hygiene in order to minimize the development of gingival hyperplasia and its complications.

Neurologic Effects Counsel patients that DILANTIN may cause dizziness, gait disturbance, decreased coordination and somnolence.

Advise patients taking DILANTIN not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with DILANTIN.

Use in Pregnancy Inform pregnant women and women of childbearing potential that use of DILANTIN during pregnancy can cause fetal harm, including an increased risk for cleft lip and/or cleft palate (oral clefts), cardiac defects, dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits.

When appropriate, counsel pregnant women and women of childbearing potential about alternative therapeutic options.

Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using DILANTIN, keeping in mind that there is a potential for decreased hormonal contraceptive efficacy [see Drug Interactions (7.2)].

Instruct patients to notify their physician if they become pregnant or intend to become pregnant during therapy, and to notify their physician if they are breast feeding or intend to breast feed during therapy [see Use in Specific Populations (8.1, 8.2)].

Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant.

This registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1)].

DOSAGE AND ADMINISTRATION

2 Adult starting dose in patients who have received no previous treatment is 5mL three times daily, with dose adjustments as necessary, up to 25 mL daily.

(2.2) Pediatric starting dose is 5 mg/kg/day in two to three equally divided doses, with dosage adjustments as necessary, up to a maximum of 300 mg daily.

Maintenance dosage is 4 to 8 mg/kg/day.

(2.3) Serum blood level determinations may be necessary for optimal dosage adjustments—the clinically effective serum total concentration is 10–20 mcg/mL (unbound phenytoin concentration is 1–2 mcg/mL).

(2.1) 2.1 Important Administration Instructions FOR ORAL ADMINISTRATION ONLY; NOT FOR PARENTERAL USE A calibrated measuring device is recommended to measure and deliver the prescribed dose accurately.

A household teaspoon or tablespoon is not an adequate measuring device.

2.2 Adult Dosage The recommended starting dosage for adult patients who have received no previous treatment is 5 mL (125 mg/5 mL), or one teaspoonful, by mouth three times daily.

Adjust the dosage to suit individual requirements, up to a maximum of 25 mL daily [see Dosage and Administration (2.4)].

2.3 Pediatric Dosage The recommended starting dosage for pediatric patients is 5 mg/kg/day by mouth in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily in divided doses.

A recommended daily maintenance dosage is usually 4 to 8 mg/kg/day in equally divided doses.

Children over 6 years and adolescents may require the minimum adult dosage (300 mg/day).

2.4 Dosage Adjustments Dosage should be individualized to provide maximum benefit.

In some cases, serum blood level determinations may be necessary for optimal dosage adjustments.

Trough levels provide information about clinically effective serum level range and confirm patient compliance, and are obtained just prior to the patient’s next scheduled dose.

Peak levels indicate an individual’s threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration.

Therapeutic effect without clinical signs of toxicity occurs more often with serum total concentrations between 10 and 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL), although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin.

In patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of unbound phenytoin concentrations may be more relevant [see Dosage and Administration (2.6)].

With recommended dosages, a period of seven to ten days may be required to achieve phenytoin steady-state blood levels, and changes in dosage (increase or decrease) should not be carried out at intervals shorter than seven to ten days.

2.5 Switching Between Phenytoin Formulations The free acid form of phenytoin is used in DILANTIN-125 Suspension and DILANTIN Infatabs.

DILANTIN extended capsules and parental DILANTIN are formulated with the sodium salt of phenytoin.

Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa.

2.6 Dosing in Patients with Renal or Hepatic Impairment or Hypoalbuminemia Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients [see Warnings and Precautions (5.9) and Use in Specific Populations (8.6)].

2.7 Geriatric Dosage Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required [see Clinical Pharmacology (12.3)].

2.8 Dosing during Pregnancy Decreased serum concentrations of phenytoin may occur during pregnancy because of altered phenytoin pharmacokinetics.

Periodic measurement of serum phenytoin concentrations should be performed during pregnancy, and the DILANTIN dosage should be adjusted as necessary.

Postpartum restoration of the original dosage will probably be indicated [see Use in Specific Populations (8.1)].

Because of potential changes in protein binding during pregnancy, the monitoring of phenytoin serum levels should be based on the unbound fraction.

oxyCODONE 7.5 MG / acetaminophen 325 MG Oral Tablet

Generic Name: OXYCODONE HYDROCHLORIDE AND ACETAMINOPHEN
Brand Name: OXYCODONE AND ACETAMINOPHEN
  • Substance Name(s):
  • OXYCODONE HYDROCHLORIDE
  • ACETAMINOPHEN

WARNINGS

OVERDOSAGE

DESCRIPTION

Each tablet, for oral administration, contains oxycodone hydrochloride and acetaminophen in the following strengths: Oxycodone Hydrochloride USP ………………………………………………………………..5 mg* Acetaminophen USP …………………………………………………………………………….325 mg *5 mg oxycodone HCl is equivalent to 4.4815 mg of oxycodone.

Oxycodone Hydrochloride USP ……………………………………………………………..7.5 mg* Acetaminophen USP …………………………………………………………………………….325 mg *7.5 mg oxycodone HCl is equivalent to 6.7228 mg of oxycodone.

Oxycodone Hydrochloride USP ……………………………………………………………..7.5 mg* Acetaminophen USP …………………………………………………………………………….500 mg *7.5 mg oxycodone HCl is equivalent to 6.7228 mg of oxycodone.

Oxycodone Hydrochloride USP ……………………………………………………………….10 mg* Acetaminophen USP ……………………………………………………………………………..325 mg *10 mg oxycodone HCl is equivalent to 8.9637 mg of oxycodone.

All strengths of oxycodone and acetaminophen tablets USP also contain the following inactive ingredients: crospovidone, microcrystalline cellulose, povidone, pregelatinized starch, silicon dioxide and stearic acid.

Oxycodone, 4,5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride, is a semisynthetic opioid analgesic which occurs as a white, odorless, crystalline powder having a saline, bitter taste.

It is derived from the opium alkaloid thebaine.

Oxycodone hydrochloride may be represented by the following structural formula: Acetaminophen, 4′-hydroxyacetanilide, is a non-opiate, non-salicylate analgesic and antipyretic which occurs as a white, odorless, crystalline powder, possessing a slightly bitter taste.

It may be represented by the following structural formula: Chemical Structure Chemical Structure

HOW SUPPLIED

Each oxycodone and acetaminophen tablet USP 7.5 mg/325 mg contains oxycodone hydrochloride 7.5 mg (equivalent to 6.7228 mg oxycodone) and acetaminophen 325 mg.

It is available as a white to off-white caplet shaped tablet debossed with “M522” on one side and “7.5/325” on the other side.

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NDC 42549-615-02 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, with a child-resistant closure (as required).

DEA Order Form Required.

Mallinckrodt Inc., Hazelwood, MO 63042 USA.

Printed in U.S.A.

COVIDIEN™ Mallinckrodt Rev 05/2009

GERIATRIC USE

Geriatric Use Special precaution should be given when determining the dosing amount and frequency of oxycodone and acetaminophen tablets for geriatric patients, since clearance of oxycodone may be slightly reduced in this patient population when compared to younger patients.

INDICATIONS AND USAGE

Oxycodone and acetaminophen tablets USP are indicated for the relief of moderate to moderately severe pain.

PEDIATRIC USE

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

PREGNANCY

Pregnancy

NUSRING MOTHERS

Nursing Mothers Ordinarily, nursing should not be undertaken while a patient is receiving oxycodone and acetaminophen tablets because of the possibility of sedation and/or respiratory depression in the infant.

Oxycodone is excreted in breast milk in low concentrations, and there have been rare reports of somnolence and lethargy in babies of nursing mothers taking an oxycodone/acetaminophen product.

Acetaminophen is also excreted in breast milk in low concentrations.

INFORMATION FOR PATIENTS

Information for Patients/Caregivers The following information should be provided to patients receiving oxycodone and acetaminophen tablets by their physician, nurse, pharmacist, or caregiver: Patients should be aware that oxycodone and acetaminophen tablets contain oxycodone, which is a morphine-like substance.

Patients should be instructed to keep oxycodone and acetaminophen tablets in a secure place out of the reach of children.

In the case of accidental ingestions, emergency medical care should be sought immediately.

When oxycodone and acetaminophen tablets are no longer needed, the unused tablets should be destroyed by flushing down the toilet.

Patients should be advised not to adjust the medication dose themselves.

Instead, they must consult with their prescribing physician.

Patients should be advised that oxycodone and acetaminophen tablets may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery).

Patients should not combine oxycodone and acetaminophen tablets with alcohol, opioid analgesics, tranquilizers, sedatives, or other CNS depressants unless under the recommendation and guidance of a physician.

When co-administered with another CNS depressant, oxycodone and acetaminophen tablets can cause dangerous additive central nervous system or respiratory depression, which can result in serious injury or death.

The safe use of oxycodone and acetaminophen tablets during pregnancy has not been established; thus, women who are planning to become pregnant or are pregnant should consult with their physician before taking oxycodone and acetaminophen tablets.

Nursing mothers should consult with their physicians about whether to discontinue nursing or discontinue oxycodone and acetaminophen tablets because of the potential for serious adverse reactions to nursing infants.

Patients who are treated with oxycodone and acetaminophen tablets for more than a few weeks should be advised not to abruptly discontinue the medication.

Patients should consult with their physician for a gradual discontinuation dose schedule to taper off the medication.

Patients should be advised that oxycodone and acetaminophen tablets are a potential drug of abuse.

They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed.

DOSAGE AND ADMINISTRATION

Dosage should be adjusted according to the severity of the pain and the response of the patient.

It may occasionally be necessary to exceed the usual dosage recommended below in cases of more severe pain or in those patients who have become tolerant to the analgesic effect of opioids.

If pain is constant, the opioid analgesic should be given at regular intervals on an around-the-clock schedule.

Oxycodone and acetaminophen tablets are given orally.

The total daily dose of acetaminophen should not exceed 4 grams.

Strength Usual Adult Dosage Maximal Daily Dose Oxycodone and acetaminophen tablets 5 mg/325 mg 1 tablet every 6 hours as needed for pain 12 Tablets Oxycodone and acetaminophen tablets 7.5 mg/325 mg 1 tablet every 6 hours as needed for pain 8 Tablets Oxycodone and acetaminophen tablets 7.5 mg/500 mg 1 tablet every 6 hours as needed for pain 8 Tablets Oxycodone and acetaminophen tablets 10 mg/325 mg 1 tablet every 6 hours as needed for pain 6 Tablets

Diurex Aquagels 50 MG Oral Capsule

Generic Name: PAMABROM
Brand Name: Diurex
  • Substance Name(s):
  • PAMABROM

WARNINGS

Warnings

INDICATIONS AND USAGE

Uses For the relief of temporary water weight gain bloating swelling full feeling associated with the premenstrual and menstrual periods.

INFORMATION FOR PATIENTS

Other information **Contents sealed: Each Diurex Aquagel, clear translucent blue colored, oval shaped soft gel capsule bears the identifying mark “ALVA” and is sealed in a clear plastic blister with a foil backing.

Do not use if seal appears broken or if product contents do not match product description.

You may report serious side effects to the phone number provided under Questions? below.

INACTIVE INGREDIENTS

Inactive ingredients FD&C Blue #1, gelatin, glycerin, hypromellose, polyethylene glycol, povidone, propylene glycol, purified water, sorbitol and titanium dioxide.

PURPOSE

Purpose Diuretic

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

DOSAGE AND ADMINISTRATION

Directions Read all package directions and warnings before use.

Use only as directed.

Adults: One (1) soft gel capsule after breakfast with a full glass of water.

Dose may be repeated after 6 hours, not to exceed four (4) soft gel capsules in 24 hours.

Start taking 5 or 6 days before onset of period and continue until desired relief is obtained or end of period.

Drink 6 to 8 glasses of water daily.

For use by normally healthy adults only.

Persons under 18 years of age should use only as directed by a doctor.

PREGNANCY AND BREAST FEEDING

If pregnant or breastfeeding, ask a health professional before use.

STOP USE

Stop use and ask a doctor if symptoms last for more than ten consecutive days.

ACTIVE INGREDIENTS

Active ingredient (in each soft gel capsule) Solubilized pamabrom, 50 mg

ASK DOCTOR OR PHARMACIST

Ask a doctor or pharmacist before use if you are taking any other medication.

Clindamycin 150 MG Oral Capsule

Generic Name: CLINDAMYCIN HYDROCHLORIDE
Brand Name: Clindamycin hydrochloride
  • Substance Name(s):
  • CLINDAMYCIN HYDROCHLORIDE

WARNINGS

See WARNING box.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including clindamycin hydrochloride, and may range in severity from mild diarrhea to fatal colitis.

Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C.

difficile.

C.

difficile produces toxins A and B, which contribute to the development of CDAD.

Hypertoxin producing strains of C.

difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

CDAD must be considered in all patients who present with diarrhea following antibiotic use.

Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C.

difficile may need to be discontinued.

Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C.

difficile, and surgical evaluation should be instituted as clinically indicated.

A careful inquiry should be made concerning previous sensitivities to drugs and other allergens.

Usage in Meningitis-Since clindamycin does not diffuse adequately into the cerebrospinal fluid, the drug should not be used in the treatment of meningitis.

DRUG INTERACTIONS

Drug Interactions Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents.

Therefore, it should be used with caution in patients receiving such agents.

Antagonism has been demonstrated between clindamycin and erythromycin in vitro.

Because of possible clinical significance, these two drugs should not be administered concurrently.

OVERDOSAGE

Significant mortality was observed in mice at an intravenous dose of 855 mg/kg and in rats at an oral or subcutaneous dose of approximately 2618 mg/kg.

In the mice, convulsions and depression were observed.

Hemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum.

DESCRIPTION

Clindamycin hydrochloride is the hydrated hydrochloride salt of clindamycin.

Clindamycin is a semisynthetic antibiotic produced by a 7(S)-chloro-substitution of the 7(R)-hydroxyl group of the parent compound lincomycin.

Clindamycin hydrochloride capsules, USP contain clindamycin hydrochloride, USP equivalent to 150 mg or 300 mg of clindamycin.

Inactive ingredients: 150 mg – black iron oxide, corn starch, D&C Yellow #10, FD&C Blue no.

1, gelatin, lactose monohydrate, magnesium stearate, potassium hydroxide, propylene glycol, shellac, talc, and titanium dioxide; 300 mg – black iron oxide, corn starch, FD&C Blue no.

1, gelatin, lactose monohydrate, magnesium stearate, potassium hydroxide, propylene glycol, shellac, talc, and titanium dioxide.

The structural formula is represented below: C18H33ClN2O5S•HCl M.W.

461.45 The chemical name for clindamycin hydrochloride is Methyl 7-chloro-6, 7, 8-trideoxy-6-(1-methyl-trans-4-propyl-L-2-pyrrolidinecarboxamido)-1-thio-L-threo-α-D-galacto-octopyranoside monohydrochloride.

structure

HOW SUPPLIED

Clindamycin hydrochloride capsules, USP are available in the following strengths, colors and sizes: Clindamycin hydrochloride capsules, USP, 150 mg are size ‘1’ capsules with turquoise blue opaque cap and light green body imprinted with “RX692” on cap and body in black ink containing white to off white powder.

They are supplied as follows: NDC 00440-7300-40 Bottles of 40 Store at 20° – 25° C (68° – 77° F) [See USP Controlled Room Temperature].

TO report SUSPECTED ADVERSE REACTIONS, contact the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

GERIATRIC USE

Geriatric Use Clinical studies of clindamycin did not include sufficient numbers of patients age 65 and over to determine whether they respond differently from younger patients.

However, other reported clinical experience indicates that antibiotic-associated colitis and diarrhea (due to Clostridium difficile) seen in association with most antibiotics occur more frequently in the elderly (> 60 years) and may be more severe.

These patients should be carefully monitored for the development of diarrhea.

Pharmacokinetic studies with clindamycin have shown no clinically important differences between young and elderly subjects with normal hepatic function and normal (age-adjusted) renal function after oral or intravenous administration.

INDICATIONS AND USAGE

Clindamycin hydrochloride capsules, USP are indicated in the treatment of serious infections caused by susceptible anaerobic bacteria.

Clindamycin hydrochloride capsules, USP are also indicated in the treatment of serious infections due to susceptible strains of streptococci, pneumococci, and staphylococci.

Its use should be reserved for penicillin-allergic patients or other patients for whom, in the judgment of the physician, a penicillin is inappropriate.

Because of the risk of colitis, as described in the WARNING box, before selecting clindamycin hydrochloride capsules, USP are the physician should consider the nature of the infection and the suitability of less toxic alternatives (e.g., erythromycin).

Anaerobes: Serious respiratory tract infections such as empyema, anaerobic pneumonitis, and lung abscess; serious skin and soft tissue infections; septicemia; intra-abdominal infections such as peritonitis and intra-abdominal abscess (typically resulting from anaerobic organisms resident in the normal gastrointestinal tract); infections of the female pelvis and genital tract such as endometritis, nongonococcal tubo-ovarian abscess, pelvic cellulitis, and postsurgical vaginal cuff infection.

Streptococci: Serious respiratory tract infections; serious skin and soft tissue infections.

Staphylococci: Serious respiratory tract infections; serious skin and soft tissue infections.

Pneumococci: Serious respiratory tract infections.

Bacteriologic studies should be performed to determine the causative organisms and their susceptibility to clindamycin.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of clindamycin hydrochloride capsules, USP and other antibacterial drugs, clindamycin hydrochloride capsules, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy.

In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

PEDIATRIC USE

Pediatric Use When clindamycin hydrochloride is administered to the pediatric population (birth to 16 years), appropriate monitoring of organ system functions is desirable.

PREGNANCY

Pregnancy: Teratogenic effects Pregnancy Category B Reproduction studies performed in rats and mice using oral doses of clindamycin up to 600 mg/kg/day (3.2 and 1.6 times the highest recommended adult human dose based on mg/m2, respectively) or subcutaneous doses of clindamycin up to 250 mg/kg/day (1.3 and 0.7 times the highest recommended adult human dose based on mg/m2, respectively) revealed no evidence of teratogenicity.

There are, however, no adequate and well-controlled studies in pregnant women.

Because animal reproduction studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed.

NUSRING MOTHERS

Nursing Mothers Clindamycin has been reported to appear in breast milk in the range of 0.7 to 3.8 mcg/mL.

BOXED WARNING

WARNING Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including clindamycin hydrochloride and may range in severity from mild diarrhea to fatal colitis.

Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C.

difficile.

Because clindamycin hydrochloride therapy has been associated with severe colitis which may end fatally, it should be reserved for serious infections where less toxic antimicrobial agents are inappropriate, as described in the INDICATIONS AND USAGE section.

It should not be used in patients with nonbacterial infections such as most upper respiratory tract infections.

C.

difficile produces toxins A and B, which contribute to the development of CDAD.

Hypertoxin producing strains of C.

difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

CDAD must be considered in all patients who present with diarrhea following antibiotic use.

Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C.

difficile may need to be discontinued.

Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C.

difficile, and surgical evaluation should be instituted as clinically indicated.

INFORMATION FOR PATIENTS

Information for Patients Patients should be counseled that antibacterial drugs, including clindamycin hydrochloride capsules, should only be used to treat bacterial infections.

They do not treat viral infections (e.g., the common cold).

When clindamycin hydrochloride capsules are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.

Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by clindamycin hydrochloride capsules or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued.

Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic.

If this occurs, patients should contact their physician as soon as possible.

DOSAGE AND ADMINISTRATION

If significant diarrhea occurs during therapy, this antibiotic should be discontinued (see WARNING box).

Adults: Serious infections—150 to 300 mg every 6 hours.

More severe infections – 300 to 450 mg every 6 hours.

Pediatric Patients: Serious infections – 8 to 16 mg/kg/day (4 to 8 mg/lb/day) divided into three or four equal doses.

More severe infections – 16 to 20 mg/kg/day (8 to 10 mg/lb/day) divided into three or four equal doses.

To avoid the possibility of esophageal irritation, clindamycin hydrochloride capsules should be taken with a full glass of water.

Serious infections due to anaerobic bacteria are usually treated with clindamycin injection.

However, in clinically appropriate circumstances, the physician may elect to initiate treatment or continue treatment with clindamycin hydrochloride capsules.

In cases of β-hemolytic streptococcal infections, treatment should continue for at least 10 days.

clopidogrel 75 MG (as clopidogrel bisulfate 97.875 MG) Oral Tablet

WARNINGS

Thrombotic thrombocytopenic purpura (TTP) TTP has been reported rarely following use of PLAVIX, sometimes after a short exposure (<2 weeks).

TTP is a serious condition that can be fatal and requires urgent treatment including plasmapheresis (plasma exchange).

It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragmented RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever.

(See ADVERSE REACTIONS .)

DRUG INTERACTIONS

Drug Interactions Since clopidogrel is metabolized to its active metabolite by CYP2C19, use of drugs that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel and a reduction in clinical efficacy.

Concomitant use of drugs that inhibit CYP2C19 (e.g., omeprazole) should be discouraged.

Study of specific drug interactions yielded the following results: Aspirin Aspirin did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation.

Concomitant administration of 500 mg of aspirin twice a day for 1 day did not significantly increase the prolongation of bleeding time induced by PLAVIX.

PLAVIX potentiated the effect of aspirin on collagen-induced platelet aggregation.

PLAVIX and aspirin have been administered together for up to one year.

Heparin In a study in healthy volunteers, PLAVIX did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation.

Coadministration of heparin had no effect on inhibition of platelet aggregation induced by PLAVIX.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) In healthy volunteers receiving naproxen, concomitant administration of PLAVIX was associated with increased occult gastrointestinal blood loss.

NSAIDs and PLAVIX should be coadministered with caution.

Warfarin Because of the increased risk of bleeding, the concomitant administration of warfarin with PLAVIX should be undertaken with caution.

(See PRECAUTIONS: General .) Other Concomitant Therapy No clinically significant pharmacodynamic interactions were observed when PLAVIX was coadministered with atenolol, nifedipine, or both atenolol and nifedipine.

The pharmacodynamic activity of PLAVIX was also not significantly influenced by the coadministration of phenobarbital, cimetidine or estrogen.

The pharmacokinetics of digoxin or theophylline were not modified by the coadministration of PLAVIX (clopidogrel bisulfate).

At high concentrations in vitro, clopidogrel inhibits P450 (2C9).

Accordingly, PLAVIX may interfere with the metabolism of phenytoin, tamoxifen, tolbutamide, warfarin, torsemide, fluvastatin, and many non-steroidal anti-inflammatory agents, but there are no data with which to predict the magnitude of these interactions.

Caution should be used when any of these drugs is coadministered with PLAVIX.

In addition to the above specific interaction studies, patients entered into clinical trials with PLAVIX received a variety of concomitant medications including diuretics, beta-blocking agents, angiotensin converting enzyme inhibitors, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), thrombolytics, heparins (unfractionated and LMWH), GPIIb/IIIa antagonists, antiepileptic agents and hormone replacement therapy without evidence of clinically significant adverse interactions.

There are no data on the concomitant use of oral anticoagulants, non study oral anti-platelet drugs and chronic NSAIDs with clopidogrel.

OVERDOSAGE

Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent bleeding complications.

A single oral dose of clopidogrel at 1500 or 2000 mg/kg was lethal to mice and to rats and at 3000 mg/kg to baboons.

Symptoms of acute toxicity were vomiting (in baboons), prostration, difficult breathing, and gastrointestinal hemorrhage in all species.

Recommendations About Specific Treatment Based on biological plausibility, platelet transfusion may be appropriate to reverse the pharmacological effects of PLAVIX if quick reversal is required.

DESCRIPTION

PLAVIX (clopidogrel bisulfate) is an inhibitor of ADP-induced platelet aggregation acting by direct inhibition of adenosine diphosphate (ADP) binding to its receptor and of the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex.

Chemically it is methyl (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (1:1).

The empirical formula of clopidogrel bisulfate is C16H16ClNO2S•H2SO4 and its molecular weight is 419.9.

The structural formula is as follows: Clopidogrel bisulfate is a white to off-white powder.

It is practically insoluble in water at neutral pH but freely soluble at pH 1.

It also dissolves freely in methanol, dissolves sparingly in methylene chloride, and is practically insoluble in ethyl ether.

It has a specific optical rotation of about +56°.

PLAVIX for oral administration is provided as either pink, round, biconvex, debossed, film-coated tablets containing 97.875 mg of clopidogrel bisulfate which is the molar equivalent of 75 mg of clopidogrel base or pink, oblong, debossed film-coated tablets containing 391.5 mg of clopidogrel bisulfate which is the molar equivalent of 300 mg of clopidogrel base.

Each tablet contains hydrogenated castor oil, hydroxypropylcellulose, mannitol, microcrystalline cellulose and polyethylene glycol 6000 as inactive ingredients.

The pink film coating contains ferric oxide, hypromellose 2910, lactose monohydrate, titanium dioxide and triacetin.

The tablets are polished with Carnauba wax.

Chemical Structure

CLINICAL STUDIES

The clinical evidence for the efficacy of PLAVIX is derived from four double-blind trials involving 81,090 patients: the CAPRIE study (Clopidogrel vs.

Aspirin in Patients at Risk of Ischemic Events), a comparison of PLAVIX to aspirin, and the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events), the COMMIT/CCS-2 (Clopidogrel and Metoprolol in Myocardial Infarction Trial / Second Chinese Cardiac Study) studies comparing PLAVIX to placebo, both given in combination with aspirin and other standard therapy and CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy – Thrombolysis in Myocardial Infarction).

Recent Myocardial Infarction (MI), Recent Stroke or Established Peripheral Arterial Disease The CAPRIE trial was a 19,185-patient, 304-center, international, randomized, double-blind, parallel-group study comparing PLAVIX (75 mg daily) to aspirin (325 mg daily).

The patients randomized had: 1) recent histories of myocardial infarction (within 35 days); 2) recent histories of ischemic stroke (within 6 months) with at least a week of residual neurological signs; or 3) objectively established peripheral arterial disease.

Patients received randomized treatment for an average of 1.6 years (maximum of 3 years).

The trial’s primary outcome was the time to first occurrence of new ischemic stroke (fatal or not), new myocardial infarction (fatal or not), or other vascular death.

Deaths not easily attributable to nonvascular causes were all classified as vascular.

Table 2: Outcome Events in the CAPRIE Primary Analysis Patients PLAVIX 9599 aspirin 9586 IS (fatal or not) 438 (4.6%) 461 (4.8%) MI (fatal or not) 275 (2.9%) 333 (3.5%) Other vascular death 226 (2.4%) 226 (2.4%) Total 939 (9.8%) 1020 (10.6%) As shown in the table, PLAVIX (clopidogrel bisulfate) was associated with a lower incidence of outcome events of every kind.

The overall risk reduction (9.8% vs.

10.6%) was 8.7%, P=0.045.

Similar results were obtained when all-cause mortality and all-cause strokes were counted instead of vascular mortality and ischemic strokes (risk reduction 6.9%).

In patients who survived an on-study stroke or myocardial infarction, the incidence of subsequent events was again lower in the PLAVIX group.

The curves showing the overall event rate are shown in Figure 1.

The event curves separated early and continued to diverge over the 3-year follow-up period.

Figure 1: Fatal or Non-Fatal Vascular Events in the CAPRIE Study Although the statistical significance favoring PLAVIX over aspirin was marginal (P=0.045), and represents the result of a single trial that has not been replicated, the comparator drug, aspirin, is itself effective (vs.

placebo) in reducing cardiovascular events in patients with recent myocardial infarction or stroke.

Thus, the difference between PLAVIX and placebo, although not measured directly, is substantial.

The CAPRIE trial included a population that was randomized on the basis of 3 entry criteria.

The efficacy of PLAVIX relative to aspirin was heterogeneous across these randomized subgroups (P=0.043).

It is not clear whether this difference is real or a chance occurrence.

Although the CAPRIE trial was not designed to evaluate the relative benefit of PLAVIX over aspirin in the individual patient subgroups, the benefit appeared to be strongest in patients who were enrolled because of peripheral vascular disease (especially those who also had a history of myocardial infarction) and weaker in stroke patients.

In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, PLAVIX was not numerically superior to aspirin.

In the meta-analyses of studies of aspirin vs.

placebo in patients similar to those in CAPRIE, aspirin was associated with a reduced incidence of thrombotic events.

There was a suggestion of heterogeneity in these studies too, with the effect strongest in patients with a history of myocardial infarction, weaker in patients with a history of stroke, and not discernible in patients with a history of peripheral vascular disease.

With respect to the inferred comparison of PLAVIX to placebo, there is no indication of heterogeneity.

Figure Acute Coronary Syndrome The CURE study included 12,562 patients with acute coronary syndrome without ST segment elevation (unstable angina or non-Q-wave myocardial infarction) and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischemia.

Patients were required to have either ECG changes compatible with new ischemia (without ST segment elevation) or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal.

The patient population was largely Caucasian (82%) and included 38% women, and 52% patients ≥65 years of age.

Patients were randomized to receive PLAVIX (300 mg loading dose followed by 75 mg/day) or placebo, and were treated for up to one year.

Patients also received aspirin (75–325 mg once daily) and other standard therapies such as heparin.

The use of GPIIb/IIIa inhibitors was not permitted for three days prior to randomization.

The number of patients experiencing the primary outcome (CV death, MI, or stroke) was 582 (9.30%) in the PLAVIX-treated group and 719 (11.41%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10%–28%; p=0.00009) for the PLAVIX-treated group (see Table 3).

At the end of 12 months, the number of patients experiencing the co-primary outcome (CV death, MI, stroke or refractory ischemia) was 1035 (16.54%) in the PLAVIX-treated group and 1187 (18.83%) in the placebo-treated group, a 14% relative risk reduction (95% CI of 6%–21%, p=0.0005) for the PLAVIX-treated group (see Table 3).

In the PLAVIX-treated group, each component of the two primary endpoints (CV death, MI, stroke, refractory ischemia) occurred less frequently than in the placebo-treated group.

Table 3: Outcome Events in the CURE Primary Analysis Outcome PLAVIX (+ aspirin)Other standard therapies were used as appropriate.

Placebo (+ aspirin) Relative Risk Reduction (%) (95% CI) (n=6259) (n=6303) Primary outcome 582 (9.3%) 719 (11.4%) 20% (Cardiovascular death, MI, Stroke) (10.3, 27.9) P=0.00009 Co-primary outcome 1035 (16.5%) 1187 (18.8%) 14% (Cardiovascular death, MI, Stroke, Refractory Ischemia) (6.2, 20.6) P=0.00052 All Individual Outcome Events: CV death 318 (5.1%) 345 (5.5%) 7% (-7.7, 20.6) MI 324 (5.2%) 419 (6.6%) 23% (11.0, 33.4) Stroke 75 (1.2%) 87 (1.4%) 14% (-17.7, 36.6) Refractory ischemia 544 (8.7%) 587 (9.3%) 7% (-4.0, 18.0) The benefits of PLAVIX (clopidogrel bisulfate) were maintained throughout the course of the trial (up to 12 months).

Figure 2: Cardiovascular Death, Myocardial Infarction, and Stroke in the CURE Study In CURE, the use of PLAVIX was associated with a lower incidence of CV death, MI or stroke in patient populations with different characteristics, as shown in Figure 3.

The benefits associated with PLAVIX were independent of the use of other acute and long-term cardiovascular therapies, including heparin/LMWH (low molecular weight heparin), IV glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, lipid-lowering drugs, beta-blockers, and ACE-inhibitors.

The efficacy of PLAVIX was observed independently of the dose of aspirin (75–325 mg once daily).

The use of oral anticoagulants, non-study anti-platelet drugs and chronic NSAIDs was not allowed in CURE.

Figure 3: Hazard Ratio for Patient Baseline Characteristics and On-Study Concomitant Medications/Interventions for the CURE Study The use of PLAVIX in CURE was associated with a decrease in the use of thrombolytic therapy (71 patients [1.1%] in the PLAVIX group, 126 patients [2.0%] in the placebo group; relative risk reduction of 43%, P=0.0001), and GPIIb/IIIa inhibitors (369 patients [5.9%] in the PLAVIX group, 454 patients [7.2%] in the placebo group, relative risk reduction of 18%, P=0.003).

The use of PLAVIX in CURE did not impact the number of patients treated with CABG or PCI (with or without stenting), (2253 patients [36.0%] in the PLAVIX group, 2324 patients [36.9%] in the placebo group; relative risk reduction of 4.0%, P=0.1658).

In patients with ST-segment elevation acute myocardial infarction, safety and efficacy of clopidogrel have been evaluated in two randomized, placebo-controlled, double-blind studies, COMMIT- a large outcome study conducted in China – and CLARITY- a supportive study of a surrogate endpoint conducted internationally.

The randomized, double-blind, placebo-controlled, 2×2 factorial design COMMIT trial included 45,852 patients presenting within 24 hours of the onset of the symptoms of suspected myocardial infarction with supporting ECG abnormalities (i.e., ST elevation, ST depression or left bundle-branch block).

Patients were randomized to receive PLAVIX (75 mg/day) or placebo, in combination with aspirin (162 mg/day), for 28 days or until hospital discharge whichever came first.

The co-primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death.

The patient population included 28% women, 58% patients ≥60 years (26% patients ≥70 years) and 55% patients who received thrombolytics, 68% received ace-inhibitors, and only 3% had percutaneous coronary intervention (PCI).

As shown in Table 4 and Figures 4 and 5 below, PLAVIX significantly reduced the relative risk of death from any cause by 7% (p = 0.029), and the relative risk of the combination of re-infarction, stroke or death by 9% (p = 0.002).

Table 4: Outcome Events in the COMMIT Analysis Event PLAVIX (+ aspirin) (N=22961) Placebo (+ aspirin) (N=22891) Odds ratio (95% CI) p-value Composite endpoint: Death, MI, or Stroke 2121 (9.2%) 2310 (10.1%) 0.91 (0.86, 0.97) 0.002 Death 1726 (7.5%) 1845 (8.1%) 0.93 (0.87, 0.99) 0.029 Non-fatal MINon-fatal MI and non-fatal stroke exclude patients who died (of any cause).

270 (1.2%) 330 (1.4%) 0.81 (0.69, 0.95) 0.011 Non-fatal Stroke 127 (0.6%) 142 (0.6%) 0.89 (0.70, 1.13) 0.33 Figure 4: Cumulative Event Rates for Death in the COMMIT Study Figure 5: Cumulative Event Rates for the Combined Endpoint Re-Infarction, Stroke or Death in the COMMIT Study The effect of PLAVIX did not differ significantly in various pre-specified subgroups as shown in Figure 6.

Additionally, the effect was similar in non-prespecified subgroups including those based on infarct location, Killip class or prior MI history (see Figure 7).

Such subgroup analyses should be interpreted very cautiously.

Figure 6: Effects of Adding PLAVIX to Aspirin on the Combined Primary Endpoint across Baseline and Concomitant Medication Subgroups for the COMMIT Study Figure 7: Effects of Adding PLAVIX to Aspirin in the Non-Prespecified Subgroups in the COMMIT Study The randomized, double-blind, placebo-controlled CLARITY trial included 3,491 patients, 5% U.S., presenting within 12 hours of the onset of a ST elevation myocardial infarction and planned for thrombolytic therapy.

Patients were randomized to receive PLAVIX (300-mg loading dose, followed by 75 mg/day) or placebo until angiography, discharge, or Day 8.

Patients also received aspirin (150 to 325 mg as a loading dose, followed by 75 to 162 mg/day), a fibrinolytic agent and, when appropriate, heparin for 48 hours.

The patients were followed for 30 days.

The primary endpoint was the occurrence of the composite of an occluded infarct-related artery (defined as TIMI Flow Grade 0 or 1) on the predischarge angiogram, or death or recurrent myocardial infarction by the time of the start of coronary angiography.

The patient population was mostly Caucasian (89.5%) and included 19.7% women and 29.2% patients ≥65 years.

A total of 99.7% of patients received fibrinolytics (fibrin specific: 68.7%, non-fibrin specific: 31.1%), 89.5% heparin, 78.7% beta-blockers, 54.7% ACE inhibitors and 63% statins.

The number of patients who reached the primary endpoint was 262 (15.0%) in the PLAVIX-treated group and 377 (21.7%) in the placebo group, but most of the events related to the surrogate endpoint of vessel patency.

Table 5: Event Rates for the Primary Composite Endpoint in the CLARITY Study Clopidogrel 1752 Placebo 1739 OR 95% CI *The total number of patients with a component event (occluded IRA, death, or recurrent MI) is greater than the number of patients with a composite event because some patients had more than a single type of component event.

Number (%) of patients reporting the composite endpoint 262 (15.0%) 377 (21.7%) 0.64 0.53, 0.76 Occluded IRA N (subjects undergoing angiography) 1640 1634 n (%) patients reporting endpoint 192 (11.7%) 301 (18.4%) 0.59 0.48, 0.72 Death n (%) patients reporting endpoint 45 (2.6%) 38 (2.2%) 1.18 0.76, 1.83 Recurrent MI n (%) patients reporting endpoint 44 (2.5%) 62 (3.6%) 0.69 0.47, 1.02 Figure Figure Figure Figure Figure Figure

HOW SUPPLIED

PLAVIX (clopidogrel bisulfate) 75-mg tablets are available as pink, round, biconvex, film-coated tablets debossed with “75” on one side and “1171” on the other.

Tablets are provided as follows: NDC 67046-099-30 blister of 30 Storage Store at 25° C (77° F); excursions permitted to 15°–30° C (59°–86° F) [See USP Controlled Room Temperature].

GERIATRIC USE

Geriatric Use Of the total number of subjects in the CAPRIE, CURE and CLARITY controlled clinical studies, approximately 50% of patients treated with PLAVIX were 65 years of age and older, and 15% were 75 years and older.

In COMMIT, approximately 58% of the patients treated with PLAVIX were 60 years and older, 26% of whom were 70 years and older.

The observed risk of thrombotic events with clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Figures 3 and 6 for the CURE and COMMIT trials, respectively (see CLINICAL STUDIES ).

The observed risk of bleeding events with clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Tables 6 and 7 for the CURE and COMMIT trials, respectively (see ADVERSE REACTIONS ).

MECHANISM OF ACTION

Mechanism of Action and Pharmacodynamic Properties Clopidogrel is a prodrug, one of whose metabolites is an inhibitor of platelet aggregation.

A variety of drugs that inhibit platelet function have been shown to decrease morbid events in people with established cardiovascular atherosclerotic disease as evidenced by stroke or transient ischemic attacks, myocardial infarction, unstable angina or the need for vascular bypass or angioplasty.

This indicates that platelets participate in the initiation and/or evolution of these events and that inhibiting platelet function can reduce the event rate.

Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation.

The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation.

This action is irreversible.

Consequently, platelets exposed to clopidogrel’s active metabolite are affected for the remainder of their lifespan (about 7 to 10 days).

Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.

Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or subject to inhibition by other drugs, not all patients will have adequate platelet inhibition.

Dose dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of PLAVIX.

Repeated doses of 75 mg PLAVIX per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7.

At steady state, the average inhibition level observed with a dose of 75 mg PLAVIX per day was between 40% and 60%.

Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.

INDICATIONS AND USAGE

PLAVIX (clopidogrel bisulfate) is indicated for the reduction of atherothrombotic events as follows: Recent MI, Recent Stroke or Established Peripheral Arterial Disease For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, PLAVIX has been shown to reduce the rate of a combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.

Acute Coronary Syndrome -For patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave MI) including patients who are to be managed medically and those who are to be managed with percutaneous coronary intervention (with or without stent) or CABG, PLAVIX has been shown to decrease the rate of a combined endpoint of cardiovascular death, MI, or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia.

-For patients with ST-segment elevation acute myocardial infarction, PLAVIX has been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction or stroke.

This benefit is not known to pertain to patients who receive primary angioplasty.

PEDIATRIC USE

Pediatric Use Safety and effectiveness in the pediatric population have not been established.

PREGNANCY

Pregnancy Pregnancy Category B Reproduction studies performed in rats and rabbits at doses up to 500 and 300 mg/kg/day (respectively, 65 and 78 times the recommended daily human dose on a mg/m2 basis), revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel.

There are, however, no adequate and well-controlled studies in pregnant women.

Because animal reproduction studies are not always predictive of a human response, PLAVIX should be used during pregnancy only if clearly needed.

NUSRING MOTHERS

Nursing Mothers Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk.

It is not known whether this drug 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, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the nursing woman.

INFORMATION FOR PATIENTS

Information for Patients Patients should be told that it may take them longer than usual to stop bleeding, that they may bruise and/or bleed more easily when they take PLAVIX or PLAVIX combined with aspirin, and that they should report any unusual bleeding to their physician.

Patients should inform physicians and dentists that they are taking PLAVIX and/or any other product known to affect bleeding before any surgery is scheduled and before any new drug is taken.

DOSAGE AND ADMINISTRATION

Recent MI, Recent Stroke, or Established Peripheral Arterial Disease The recommended daily dose of PLAVIX is 75 mg once daily.

Acute Coronary Syndrome For patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave MI), PLAVIX should be initiated with a single 300-mg loading dose and then continued at 75 mg once daily.

Aspirin (75 mg–325 mg once daily) should be initiated and continued in combination with PLAVIX.

In CURE, most patients with Acute Coronary Syndrome also received heparin acutely (see CLINICAL STUDIES ).

For patients with ST-segment elevation acute myocardial infarction, the recommended dose of PLAVIX is 75 mg once daily, administered in combination with aspirin, with or without thrombolytics.

PLAVIX may be initiated with or without a loading dose (300 mg was used in CLARITY; see CLINICAL STUDIES ).

Pharmacogenetics CYP2C19 poor metabolizer status is associated with diminished response to clopidogrel.

The optimal dose regimen for poor metabolizers has yet to be determined.

(See CLINICAL PHARMACOLOGY: Pharmacogenetics .) No dosage adjustment is necessary for elderly patients or patients with renal disease.

(See CLINICAL PHARMACOLOGY: Special Populations.)

Gelato Anesthetic 0.2 MG/MG Oral Gel

Generic Name: BENZOCAINE
Brand Name: Gelato Topical Anesthetic
  • Substance Name(s):
  • BENZOCAINE

WARNINGS

Warnings: Allergy Alert: Do not use on patients with a history of allergies to local anesthetics such as benzocaine or other “caine” anesthetics.

Do not use for more than 7 days unless directed by a dentist or doctor.

If sore mouth symptoms do not improve in 7 days; irritation, pain or redness persists or worsens; or if swelling, rash or fever develops, see your dentist or doctor promptly.

When using this product: avoid contact with eyes.

If contact occurs, flush with water.

Stop use and consult a healthcare practitioner if the following symptoms appear: weakness, confusion, headache, difficulty breathing, and/or pale, grey or blue colored skin, as these may be signs of methemoglobinemia, a rare disorder, which may appear up to 2 hours after use.

Do not exceed recommended dosage.

If more than used for pain is accidentally swallowed, get medical help or contact a Poison Control Center immediately.

If pregnant or breast feeding, ask a health professional before use.

INDICATIONS AND USAGE

Use: For oral mucosal use only, as directed by dentist.

For the temporary relief of pain due to minor dental procedures.

INACTIVE INGREDIENTS

Inactive Ingredients: Flavoring, PEG 3350, PEG 400, sodium saccharin.

May contain yellow #5 (tartrazine), yellow #6, red #3, red #40, blue #1, green #3 as a color additive.

PURPOSE

Purpose: Oral Anesthetic

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children.

DOSAGE AND ADMINISTRATION

Do not exceed recommended dosage.

If more than used for pain is accidentally swallowed, get medical help or contact a Poison Control Center immediately.

ACTIVE INGREDIENTS

Active Ingredients (in each gram): Benzocaine 200mg