Read Article Directory Louisiana: September 2016

Friday, September 30, 2016

Zopax

Zopax may be available in the countries listed below.

Ingredient matches for Zopax

Alprazolam

Alprazolam is reported as an ingredient of Zopax in the following countries:

South Africa

International Drug Name Search

Tetraciclinã

Tetraciclinã may be available in the countries listed below.

Ingredient matches for Tetraciclinã

Tetracycline

Tetracycline hydrochloride (a derivative of Tetracycline) is reported as an ingredient of Tetraciclinã in the following countries:

Romania

International Drug Name Search

valdecoxib

Generic Name: valdecoxib (val deh COCK sib)

Brand Names: Bextra

What is valdecoxib?

Valdecoxib (Bextra) was withdrawn from the U.S. market in 2005.

Valdecoxib is in a class of drugs called nonsteroidal anti-inflammatory drugs (NSAIDs). Valdecoxib works by reducing substances in the body that cause inflammation, pain, and fever.

Valdecoxib is used to reduce pain, inflammation, and stiffness caused by osteoarthritis and adult rheumatoid arthritis. Valdecoxib is also used to treat painful menstruation.

Valdecoxib may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about valdecoxib?

Valdecoxib (Bextra) was withdrawn from the U.S. market in 2005.

The manufacturer of valdecoxib (Bextra) has announced the voluntary withdrawal of the drug from the U.S. market. This withdrawal is due to safety concerns of an increased risk of cardiovascular events (including heart attack and stroke) in patients taking non-steroidal anti-inflammatory drugs (valdecoxib is a "COX-2" selective non-steroidal anti-inflammatory drug) and safety concerns of an increased risk of rare but serious skin reactions in patients taking valdecoxib.

Do not take valdecoxib without first talking to your doctor if you have experienced asthma, hives, or an allergic reaction after taking a sulfa-based medication such as sulfamethoxazole (Bactrim, Septra, Gantanol, and others) or sulfisoxazole (Gantrisin); aspirin; or another NSAID such as celecoxib (Celebrex), ibuprofen (Motrin, Advil, Nuprin, and others), naproxen (Aleve, Naprosyn, Anaprox), ketoprofen (Orudis KT, Orudis, Oruvail), diclofenac (Voltaren, Cataflam), diflunisal (Dolobid), etodolac (Lodine, Lodine XL), fenoprofen (Nalfon), flurbiprofen (Ansaid), indomethacin (Indocin), ketorolac (Toradol), meloxicam (Mobic), nabumetone (Relafen), oxaprozin (Daypro), piroxicam (Feldene), sulindac (Clinoril), or tolmetin (Tolectin). You may experience a similar reaction to valdecoxib. Notify your doctor immediately if you develop abdominal pain, tenderness, or discomfort; nausea; bloody vomit; bloody, black, or tarry stools; unexplained weight gain; swelling or water retention; fatigue or lethargy; a skin rash; itching; yellowing of the skin or eyes;"flu-like" symptoms; or unusual bruising or bleeding. These symptoms could be early signs of dangerous side effects. Serious skin reactions have occurred in patients taking valdecoxib. These reactions tend to occur within the first two weeks of treatment, but may occur at any time during treatment. Stop taking valdecoxib and contact your doctor immediately if you develop a skin rash; hives; itching; difficulty breathing; swelling of the lips, tongue or face; or other symptoms of an allergic reaction.

What should I discuss with my healthcare provider before taking valdecoxib?

Valdecoxib should not be used for the treatment of pain after coronary artery bypass surgery (CABG). The use of valdecoxib in such patients has led to an increased incidence of cardiovascular events, deep surgical infections and wound complications. Talk to your doctor before taking valdecoxib if you are being treated for pain associated with CABG.

Before taking valdecoxib, tell your doctor if you

smoke;

drink alcohol;

have an ulcer or bleeding in the stomach;

have liver disease;

have kidney disease;

have asthma;

have congestive heart failure;

have fluid retention;

have heart disease;

have high blood pressure;

have a coagulation (bleeding) disorder or are taking an anticoagulant (blood thinner) such as warfarin (Coumadin); or

are taking a steroid medicine such as prednisone (Deltasone and others), methylprednisolone (Medrol and others), prednisolone (Prelone, Pediapred, and others), and others.

You may not be able to take valdecoxib, or you may require a dosage adjustment or special monitoring during treatment if you have any of the conditions, or are taking any of the medicines, listed above.

Valdecoxib is in the FDA pregnancy category C. This means that it is not known whether it will be harmful to an unborn baby. Valdecoxib should not be taken late in pregnancy (the third trimester) because it may affect the formation of the baby's heart. Do not take valdecoxib without first talking to your doctor if you are pregnant or could become pregnant during treatment. It is not known whether valdecoxib passes into breast milk. Do not take valdecoxib without first talking to your doctor if you are breast-feeding a baby. If you are over the age of 65 years, you may be more likely to experience side effects from valdecoxib. You may require a lower dosage or special monitoring during your therapy.

How should I take valdecoxib?

Take valdecoxib exactly as directed by your doctor. If you do not understand these instructions, ask your pharmacist, nurse, or doctor to explain them to you.

Take each dose with a full glass of water.

Valdecoxib can be taken with or without food or milk. Follow your doctor's instructions.

Store valdecoxib at room temperature away from moisture and heat.

See also: Valdecoxib dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. If it is almost time for the next dose, skip the dose you missed and take only the next regularly scheduled dose as directed. Do not take a double dose of this medication unless otherwise directed by your doctor.

What happens if I overdose?

Seek emergency medical attention.

Symptoms of a valdecoxib overdose include drowsiness, nausea, vomiting, and stomach pain.

What should I avoid while taking valdecoxib?

There are no restrictions on food, beverages, or activity while taking valdecoxib unless otherwise directed by your doctor.

Valdecoxib side effects

Serious skin reactions have occurred in patients taking valdecoxib. These reactions tend to occur within the first two weeks of treatment, but may occur at any time during treatment. Stop taking valdecoxib and contact your doctor immediately if you develop a skin rash; hives; itching; difficulty breathing; swelling of the lips, tongue or face; or other symptoms of an allergic reaction. Notify your doctor immediately if you develop abdominal pain, tenderness, or discomfort; nausea; bloody vomit; bloody, black, or tarry stools; unexplained weight gain; swelling or water retention; fatigue or lethargy; a skin rash; itching; yellowing of the skin or eyes;"flu-like" symptoms; or unusual bruising or bleeding. These symptoms could be early signs of dangerous side effects.

Other, less serious side effects may be more likely to occur. Continue to take valdecoxib and talk to your doctor if you experience

diarrhea;

nausea or upset stomach; or

headache.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.

Valdecoxib Dosing Information

Usual Adult Dose for Osteoarthritis:

Valdecoxib was voluntarily withdrawn from the market in April, 2005 by the manufacturer following an FDA Public Health Advisory announcing that the overall risk versus benefit profile for valdecoxib is unfavorable, based on the following: reports of serious and potentially life-threatening skin reactions, including deaths, in patients taking Bextra. The risk of these reactions have occurred in patients with and without a prior history of sulfa allergy, and after both short- and long-term use. The lack of adequate data on the cardiovascular safety of long-term use of Bextra, along with the increased risk of adverse CV events in short-term coronary artery bypass surgery (CABG) trial that FDA believes may be relevant to chronic use, and lack of any demonstrated advantages for Bextra compared with other NSAIDs. The following dosage information applies to when the drug was available in the USA.

Initial dose: 10 mg once daily

Usual Adult Dose for Rheumatoid Arthritis:

Usual Adult Dose for Dysmenorrhea:

Usual Adult Dose for Pain:

What other drugs will affect valdecoxib?

Before taking valdecoxib, tell your doctor if you are taking any of the following drugs:

aspirin or another salicylate (form of aspirin) such as salsalate (Disalcid), choline salicylate-magnesium salicylate (Trilisate, Tricosal, others), and magnesium salicylate (Doan's, Bayer Select Backache Formula, others);

an over-the-counter cough, cold, allergy, or pain medicine that contains dextromethorphan, aspirin, ibuprofen, naproxen, or ketoprofen;

a diuretic (water pill) such as furosemide (Lasix), hydrochlorothiazide (HydroDiuril, others), chlorothiazide (Diuril, others), chlorthalidone (Hygroton, Thalitone), and others;

an angiotensin-converting-enzyme inhibitor (ACE inhibitor) such as benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil, Zestril), moexipril (Univasc), quinapril (Accupril), and others;

a steroid medicine such as prednisone (Deltasone and others), methylprednisolone (Medrol and others), prednisolone (Prelone, Pediapred, and others), and others;

an anticoagulant (blood thinner) such as warfarin (Coumadin);

diazepam (Valium);

phenytoin (Dilantin);

glyburide (DiaBeta, others);

an oral contraceptive (Micronor, Triphasil, Levlen, others);

omeprazole (Prilosec, Zegerid);

lithium (Eskalith, Lithobid, others); or

fluconazole (Diflucan) or ketoconazole (Nizoral).

You may not be able to take valdecoxib, or you may require a dosage adjustment or special monitoring during treatment if you are taking any of the medicines listed above.

Drugs other than those listed here may also interact with valdecoxib. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines including vitamins, minerals, and herbal products.

More valdecoxib resources

Valdecoxib Side Effects (in more detail)
Valdecoxib Dosage
Valdecoxib Use in Pregnancy & Breastfeeding
Valdecoxib Drug Interactions
Valdecoxib Support Group
10 Reviews for Valdecoxib - Add your own review/rating

valdecoxib Advanced Consumer (Micromedex) - Includes Dosage Information

Bextra Prescribing Information (FDA)

Bextra Consumer Overview

Compare valdecoxib with other medications

Osteoarthritis
Pain
Period Pain
Rheumatoid Arthritis

Where can I get more information?

Your pharmacist has additional information about valdecoxib written for health professionals that you may read.

What does my medication look like?

Valdecoxib (Bextra) was withdrawn from the U.S. market in 2005.

See also: valdecoxib side effects (in more detail)

Bikalutamid medac

Bikalutamid medac may be available in the countries listed below.

Ingredient matches for Bikalutamid medac

Bicalutamide

Bicalutamide is reported as an ingredient of Bikalutamid medac in the following countries:

Finland

Sweden

International Drug Name Search

Albendazole Oxide

Albendazole Oxide may be available in the countries listed below.

Ingredient matches for Albendazole Oxide

Albendazole

Albendazole Oxide (BAN) is known as Albendazole in the US.

International Drug Name Search

Glossary

BAN

British Approved Name

Click for further information on drug naming conventions and International Nonproprietary Names.

Thursday, September 29, 2016

Pennsaid

Pennsaid is a brand name of diclofenac topical, approved by the FDA in the following formulation(s):

PENNSAID (diclofenac sodium - solution; topical)

Manufacturer: MALLINCKRODT

Approval date: November 4, 2009

Strength(s): 1.5% ^[RLD]

Has a generic version of Pennsaid been approved?

No. There is currently no therapeutically equivalent version of Pennsaid available.

Note: Fraudulent online pharmacies may attempt to sell an illegal generic version of Pennsaid. These medications may be counterfeit and potentially unsafe. If you purchase medications online, be sure you are buying from a reputable and valid online pharmacy. Ask your health care provider for advice if you are unsure about the online purchase of any medication.

Related Patents

There are no current U.S. patents associated with Pennsaid.

Related Exclusivities

Exclusivity is exclusive marketing rights granted by the FDA upon approval of a drug and can run concurrently with a patent or not. Exclusivity is a statutory provision and is granted to an NDA applicant if statutory requirements are met.

Exclusivity expiration dates:
- November 4, 2012 - NEW DOSAGE FORM

Ingredient matches for Aciclobene Pulver

Acyclovir

Aciclovir sodium salt (a derivative of Aciclovir) is reported as an ingredient of Aciclobene Pulver in the following countries:

Austria

International Drug Name Search

Fragmin

dalteparin sodium

Dosage Form: injection
FULL PRESCRIBING INFORMATION

WARNING: SPINAL/EPIDURAL HEMATOMAS

Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:

Use of indwelling epidural catheters

Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants.

A history of traumatic or repeated epidural or spinal punctures

A history of spinal deformity or spinal surgery

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions (5.1) and Drug Interactions (7)].

Indications and Usage for Fragmin

Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction

Fragmin® Injection is indicated for the prophylaxis of ischemic complications in unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin therapy [see Clinical Studies (14.1)].

Prophylaxis of Deep Vein Thrombosis

Fragmin is also indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE):

In patients undergoing hip replacement surgery [see Clinical Studies (14.2)];

In patients undergoing abdominal surgery who are at risk for thromboembolic complications [see Clinical Studies (14.3)];

In medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness [see Clinical Studies (14.4)].

Extended Treatment of Symptomatic Venous Thromboembolism in Patients with Cancer

Fragmin is also indicated for the extended treatment of symptomatic venous thromboembolism (VTE) (proximal DVT and/or PE), to reduce the recurrence of VTE in patients with cancer In these patients, the Fragmin therapy begins with the initial VTE treatment and continues for six months [see Clinical Studies (14.5)].

Limitations of Use

Fragmin is not indicated for the acute treatment of VTE.

Fragmin Dosage and Administration

Fragmin is administered by subcutaneous injection. It must not be administered by intramuscular injection.

Fragmin Injection should not be mixed with other injections or infusions unless specific compatibility data are available that support such mixing.

Routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) are relatively insensitive measures of Fragmin activity and, therefore, unsuitable for monitoring the anticoagulant effect of Fragmin. [See Warnings and Precautions (5)].

Adult Dosage

Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction: In patients with unstable angina or non-Q-wave myocardial infarction, the recommended dose of Fragmin Injection is 120 IU/kg of body weight, but not more than 10,000 IU, subcutaneously every 12 hours with concurrent oral aspirin (75 to 165 mg once daily) therapy. Treatment should be continued until the patient is clinically stabilized. The usual duration of administration is 5 to 8 days. Concurrent aspirin therapy is recommended except when contraindicated.

Table 1 lists the volume of Fragmin, based on the 9.5 mL multiple-dose vial (10,000 IU/mL), to be administered for a range of patient weights.

Table 1
Volume of Fragmin to be Administered by Patient Weight, Based on 9.5 mL Vial (10,000 IU/mL)
Patient weight (lb)	< 110	110 to 131	132 to 153	154 to 175	176 to 197	≥ 198
Patient weight (kg)	< 50	50 to 59	60 to 69	70 to 79	80 to 89	≥ 90
Volume of Fragmin (mL)	0.55	0.65	0.75	0.90	1.0	1.0

Prophylaxis of Venous Thromboembolism Following Hip Replacement Surgery: Table 2 presents the dosing options for patients undergoing hip replacement surgery. The usual duration of administration is 5 to 10 days after surgery; up to 14 days of treatment with Fragmin have been well tolerated in clinical trials.

1 Or later, if hemostasis has not been achieved. 2 Up to 14 days of treatment was well tolerated in controlled clinical trials, where the usual duration of treatment was 5 to 10 days postoperatively. 3 Allow a minimum of 6 hours between this dose and the dose to be given on Postoperative Day 1. Adjust the timing of the dose on Postoperative Day 1 accordingly. 4 Allow approximately 24 hours between doses.
Table 2
Dosing Options for Patients Undergoing Hip Replacement Surgery
Timing of First Dose of Fragmin	Dose of Fragmin to be Given Subcutaneously
Timing of First Dose of Fragmin	10 to 14 Hours Before Surgery	Within 2 Hours Before Surgery	4 to 8 Hours After Surgery1	Postoperative Period2
Postoperative Start	---	---	2500 IU3	5000 IU once daily
Preoperative Start - Day of Surgery	---	2500 IU	2500 IU3	5000 IU once daily
Preoperative Start - Evening Before Surgery4	5000 IU	---	5000 IU	5000 IU once daily

Abdominal Surgery: In patients undergoing abdominal surgery with a risk of thromboembolic complications, the recommended dose of Fragmin is 2500 IU administered by subcutaneous injection once daily, starting 1 to 2 hours prior to surgery and repeated once daily postoperatively. The usual duration of administration is 5 to 10 days.

In patients undergoing abdominal surgery associated with a high risk of thromboembolic complications, such as malignant disorder, the recommended dose of Fragmin is 5000 IU subcutaneously the evening before surgery, then once daily postoperatively. The usual duration of administration is 5 to 10 days. Alternatively, in patients with malignancy, 2500 IU of Fragmin can be administered subcutaneously 1 to 2 hours before surgery followed by 2500 IU subcutaneously 12 hours later, and then 5000 IU once daily postoperatively. The usual duration of administration is 5 to 10 days.

Medical Patients During Acute Illness: In medical patients with severely restricted mobility during acute illness, the recommended dose of Fragmin is 5000 IU administered by subcutaneous injection once daily. In clinical trials, the usual duration of administration was 12 to 14 days.

Extended Treatment of Symptomatic Venous Thromboembolism in Patients with Cancer: In patients with cancer and symptomatic venous thromboembolism, the recommended dosing of Fragmin is as follows: for the first 30 days of treatment administer Fragmin 200 IU/kg total body weight subcutaneously once daily. The total daily dose should not exceed 18,000 IU. Table 3 lists the dose of Fragmin to be administered once daily during the first month for a range of patient weights.

Month 1

Table 3
Dose of Fragmin to be Administered Subcutaneously by Patient Weight during the First Month
Body Weight (lbs)	Body Weight (kg)	Fragmin Dose (IU) (prefilled syringe) once daily
≤ 124	≤ 56	10,000
125 to 150	57 to 68	12,500
151 to 181	69 to 82	15,000
182 to 216	83 to 98	18,000
≥ 217	≥ 99	18,000

Months 2 to 6

Administer Fragmin at a dose of approximately 150 IU/kg, subcutaneously once daily during Months 2 through 6. The total daily dose should not exceed 18,000 IU. Table 4 lists the dose of Fragmin to be administered once daily for a range of patient weights during months 2-6.

Table 4
Dose of Fragmin to be Administered Subcutaneously by Patient Weight during Months 2-6
Body Weight (lbs)	Body Weight (kg)	Fragmin Dose (IU) (prefilled syringe) once daily
≤ 124	≤ 56	7,500
125 to 150	57 to 68	10,000
151 to 181	69 to 82	12,500
182 to 216	83 to 98	15,000
≥ 217	≥ 99	18,000

Safety and efficacy beyond six months have not been evaluated in patients with cancer and acute symptomatic VTE [see Warnings and Precaution (5) and Adverse Reactions (6.1)].

Dose reductions for thrombocytopenia in patients with cancer and acute symptomatic VTE

In patients receiving Fragmin who experience platelet counts between 50,000 and 100,000/mm3, reduce the daily dose of Fragmin by 2,500 IU until the platelet count recovers to ≥ 100,000/mm3. In patients receiving Fragmin who experience platelet counts < 50,000/mm3, discontinue Fragmin until the platelet count recovers above 50,000/mm3.

Dose reductions for renal insufficiency in extended treatment of acute symptomatic venous thromboembolism in patients with cancer

In patients with severely impaired renal function (CrCl < 30 mL/min), monitor anti-Xa levels to determine the appropriate Fragmin dose. Target anti-Xa range is 0.5-1.5 IU/mL. When monitoring anti-Xa in these patients, perform sampling 4-6 hrs after Fragmin dosing and only after the patient has received 3-4 doses.

Administration

Subcutaneous injection technique: Patients should be sitting or lying down and Fragmin administered by deep subcutaneous injection. Fragmin may be injected in a U-shape area around the navel, the upper outer side of the thigh or the upper outer quadrangle of the buttock. The injection site should be varied daily. When the area around the navel or the thigh is used, using the thumb and forefinger, you must lift up a fold of skin while giving the injection. The entire length of the needle should be inserted at a 45 to 90 degree angle.

Inspect Fragmin prefilled syringes and vials visually for particulate matter and discoloration prior to administration

After first penetration of the rubber stopper, store the multiple-dose vials at room temperature for up to 2 weeks. Discard any unused solution after 2 weeks.

Instructions for using the prefilled single-dose syringes preassembled with needle guard devices

Fixed dose syringes: To ensure delivery of the full dose, do not expel the air bubble from the prefilled syringe before injection. Hold the syringe assembly by the open sides of the device. Remove the needle shield. Insert the needle into the injection area as instructed above. Depress the plunger of the syringe while holding the finger flange until the entire dose has been given. The needle guard will not be activated unless the entire dose has been given. Remove needle from the patient. Let go of the plunger and allow syringe to move up inside the device until the entire needle is guarded. Discard the syringe assembly in approved containers.

Graduated syringes: Hold the syringe assembly by the open sides of the device. Remove the needle shield. With the needle pointing up, prepare the syringe by expelling the air bubble and then continuing to push the plunger to the desired dose or volume, discarding the extra solution in an appropriate manner. Insert the needle into the injection area as instructed above. Depress the plunger of the syringe while holding the finger flange until the entire dose remaining in the syringe has been given. The needle guard will not be activated unless the entire dose has been given. Remove needle from the patient. Let go of the plunger and allow syringe to move up inside the device until the entire needle is guarded. Discard the syringe assembly in approved containers.

Dosage Forms and Strengths

2,500 IU / 0.2 mL single-dose prefilled syringe

5,000 IU / 0.2 mL single-dose prefilled syringe

7,500 IU / 0.3 mL single-dose prefilled syringe

10,000 IU / 0.4 mL single-dose prefilled syringe

10,000 IU / 1 mL single-dose graduated syringe

12,500 IU / 0.5 mL single-dose prefilled syringe

15,000 IU / 0.6 mL single-dose prefilled syringe

18,000 IU / 0.72 mL single-dose prefilled syringe

95,000 IU / 3.8 mL multiple-dose vial

95,000 IU / 9.5 mL multiple-dose vial

Contraindications

Active major bleeding

History of heparin induced thrombocytopenia or heparin induced thrombocytopenia with thrombosis.

Hypersensitivity to dalteparin sodium (e.g., pruritis, rash, anaphylactic reactions) [see Adverse Reactions (6.2)]

In patients undergoing Epidural/Neuraxial anesthesia, do not administer Fragmin [See Boxed Warning];
- As a treatment for unstable angina and non_q wave MI
- For prolonged VTE prophylaxis.

Hypersensitivity to heparin or pork products

Warnings and Precautions

Increased Risk of Hemorrhage

Spinal or epidural hematomas can occur with the associated use of low molecular weight heparins or heparinoids and neuraxial (spinal/epidural) anesthesia or spinal puncture. The risk of these events is higher with the use of post-operative indwelling epidural catheters, with the concomitant use of additional drugs affecting hemostasis such as NSAIDs, with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal surgery or spinal deformity , [see Boxed Warning and Adverse Reactions (6.2) and Drug Interactions (7)].

Use Fragmin with extreme caution in patients who have an increased risk of hemorrhage, such as those with severe uncontrolled hypertension, bacterial endocarditis, congenital or acquired bleeding disorders, active ulceration and angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal or ophthalmological surgery. Fragmin may enhance the risk of bleeding in patients with thrombocytopenia or platelet defects; severe liver or kidney insufficiency, hypertensive or diabetic retinopathy, and recent gastrointestinal bleeding. Bleeding can occur at any site during therapy with Fragmin.

Thrombocytopenia

Heparin-induced thrombocytopenia can occur with the administration of Fragmin. The incidence of this complication is unknown at present. In clinical practice, cases of thrombocytopenia with thrombosis, amputation and death have been observed.[See Contraindications (4)] Closely monitor thrombocytopenia of any degree.

In Fragmin clinical trials supporting non-cancer indications, platelet counts of < 50,000/mm3 occurred in < 1% of patients.

In the clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated for up to 6 months in the Fragmin treatment arm, platelet counts of < 100,000/mm3 occurred in 13.6% of patients, including 6.5% who also had platelet counts less than 50,000/mm3. In the same clinical trial, thrombocytopenia was reported as an adverse event in 10.9% of patients in the Fragmin arm and 8.1% of patients in the OAC arm. Fragmin dose was decreased or interrupted in patients whose platelet counts fell below 100,000/mm3.

Benzyl Alcohol

Each multiple-dose vial of Fragmin contains benzyl alcohol as a preservative. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants. Because benzyl alcohol may cross the placenta, use caution when administering Fragmin preserved with benzyl alcohol to pregnant women. If anticoagulation with Fragmin is needed during pregnancy, use preservative-free formulations, where possible. [See Use in Specific Populations (8.1)].

Laboratory Tests

Periodic routine complete blood counts, including platelet count, blood chemistry, and stool occult blood tests are recommended during the course of treatment with Fragmin. When administered at recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) are relatively insensitive measures of Fragmin activity and, therefore, unsuitable for monitoring the anticoagulant effect of Fragmin. Anti-Factor Xa may be used to monitor the anticoagulant effect of Fragmin, such as in patients with severe renal impairment or if abnormal coagulation parameters or bleeding occurs during Fragmin therapy.

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not accurately reflect the rates observed in practice.

Hemorrhage

The incidence of hemorrhagic complications during treatment with Fragmin Injection has been low. The most commonly reported side effect is hematoma at the injection site. The risk for bleeding varies with the indication and may increase with higher doses.

Unstable Angina and Non-Q-Wave Myocardial Infarction

Table 5 summarizes major bleeding reactions that occurred with Fragmin, heparin, and placebo in clinical trials of unstable angina and non-Q-wave myocardial infarction.

1 Treatment was administered for 5 to 8 days. 2 Heparin intravenous infusion for at least 48 hours, APTT 1.5 to 2 times control, then 12,500 U subcutaneously every 12 hours for 5 to 8 days. 3 Aspirin (75 to 165 mg per day) and beta blocker therapies were administered concurrently. 4 Bleeding reactions were considered major if: 1) accompanied by a decrease in hemoglobin of ≥ 2 g/dL in connection with clinical symptoms; 2) a transfusion was required; 3) bleeding led to interruption of treatment or death; or 4) intracranial bleeding.
Table 5
Major Bleeding Reactions in Unstable Angina and Non-Q-Wave Myocardial Infarction
Indication	Dosing Regimen
Unstable Angina and Non-Q-Wave MI	Fragmin 120 IU/kg/12 hr subcutaneous1 n (%)	Heparin2 intravenous and subcutaneous2 n (%)	Placebo every 12 hr subcutaneous n (%)
Major Bleeding Reactions3,4	15/1497 (1.0)	7/731 (1.0)	4/760 (0.5)

Hip Replacement Surgery

Table 6 summarizes: 1) all major bleeding reactions and, 2) other bleeding reactions possibly or probably related to treatment with Fragmin (preoperative dosing regimen), warfarin sodium, or heparin in two hip replacement surgery clinical trials.

1 Warfarin sodium dosage was adjusted to maintain a prothrombin time index of 1.4 to 1.5, corresponding to an International Normalized Ratio (INR) of approximately 2.5. 2 Includes three treated patients who did not undergo a surgical procedure. 3 A bleeding event was considered major if: 1) hemorrhage caused a significant clinical event, 2) it was associated with a hemoglobin decrease of ≥ 2 g/dL or transfusion of 2 or more units of blood products, 3) it resulted in reoperation due to bleeding, or 4) it involved retroperitoneal or intracranial hemorrhage. 4 Includes two treated patients who did not undergo a surgical procedure. 5 Occurred at a rate of at least 2% in the group treated with Fragmin 5000 IU once daily.
Table 6
Bleeding Reactions Following Hip Replacement Surgery
Indication	Fragmin vs Warfarin Sodium		Fragmin vs Heparin
Indication	Dosing Regimen		Dosing Regimen
Hip Replacement Surgery	Fragmin2 5000 IU once daily subcutaneous n (%)	Warfarin Sodium1 oral n (%)	Fragmin4 5000 IU once daily subcutaneous n (%)	Heparin 5000 U three times a day subcutaneous n (%)
Major Bleeding Reactions3	7/274 (2.6)	1/279 (0.4)	0	3/69 (4.3)
Other Bleeding Reactions5 Hematuria	8/274 (2.9)	5/279 (1.8)	0	0
Wound Hematoma	6/274 (2.2)	0	0	0
Injection Site Hematoma	3/274 (1.1)	NA	2/69 (2.9)	7/69 (10.1)

Six of the patients treated with Fragmin experienced seven major bleeding reactions. Two of the reactions were wound hematoma (one requiring reoperation), three were bleeding from the operative site, one was intraoperative bleeding due to vessel damage, and one was gastrointestinal bleeding. None of the patients experienced retroperitoneal or intracranial hemorrhage or died of bleeding complications.

In the third hip replacement surgery clinical trial, the incidence of major bleeding reactions was similar in all three treatment groups: 3.6% (18/496) for patients who started Fragmin before surgery; 2.5% (12/487) for patients who started Fragmin after surgery; and 3.1% (15/489) for patients treated with warfarin sodium.

Abdominal Surgery

Table 7 summarizes bleeding reactions that occurred in clinical trials which studied Fragmin 2500 and 5000 IU administered once daily to abdominal surgery patients.

Table 7
Bleeding Reactions Following Abdominal Surgery
Indication	Fragmin vs Placebo		Fragmin vs Fragmin
Indication	Dosing Regimen		Dosing Regimen
Abdominal Surgery	Fragmin 2500 IU once daily subcutaneous n (%)	Placebo once daily subcutaneous n (%)	Fragmin 2500 IU once daily subcutaneous n (%)	Fragmin 5000 IU once daily subcutaneous n (%)
Postoperative Transfusions	14/182 (7.7)	13/182 (7.1)	89/1025 (8.7)	125/1033 (12.1)
Wound Hematoma	2/79 (2.5)	2/77 (2.6)	1/1030 (0.1)	4/1039 (0.4)
Reoperation Due to Bleeding	1/79 (1.3)	1/78 (1.3)	2/1030 (0.2)	13/1038 (1.3)
Injection Site Hematoma	8/172 (4.7)	2/174 (1.1)	36/1026 (3.5)	57/1035 (5.5)
Indication	Fragmin vs Heparin
Indication	Dosing Regimen
Abdominal Surgery	Fragmin 2500 IU once daily subcutaneous n (%)	Heparin 5000 U twice daily subcutaneous n (%)	Fragmin 5000 IU once daily subcutaneous n (%)	Heparin 5000 U twice daily subcutaneous n (%)
Postoperative Transfusions	26/459 (5.7)	36/454 (7.9)	81/508 (15.9)	63/498 (12.7)
Wound Hematoma	16/467 (3.4)	18/467 (3.9)	12/508 (2.4)	6/498 (1.2)
Reoperation Due to Bleeding	2/392 (0.5)	3/392 (0.8)	4/508 (0.8)	2/498 (0.4)
Injection Site Hematoma	1/466 (0.2)	5/464 (1.1)	36/506 (7.1)	47/493 (9.5)

In a trial comparing Fragmin 5000 IU once daily to Fragmin 2500 IU once daily in patients undergoing surgery for malignancy, the incidence of bleeding reactions was 4.6% and 3.6%, respectively (n.s.). In a trial comparing Fragmin 5000 IU once daily to heparin 5000 U twice daily, in the malignancy subgroup the incidence of bleeding reactions was 3.2% and 2.7%, respectively for Fragmin and Heparin (n.s.).

Medical Patients with Severely Restricted Mobility During Acute Illness

Table 8 summarizes major bleeding reactions that occurred in a clinical trial of medical patients with severely restricted mobility during acute illness.

1 A bleeding event was considered major if: 1) it was accompanied by a decrease in hemoglobin of ≥ 2 g/dL in connection with clinical symptoms; 2) intraocular, spinal/epidural, intracranial, or retroperitoneal bleeding; 3) required transfusion of ≥ 2 units of blood products; 4) required significant medical or surgical intervention; or 5) led to death.
Table 8
Bleeding Reactions in Medical Patients with Severely Restricted Mobility During Acute Illness
Indication	Dosing Regimen
Medical Patients with Severely Restricted Mobility	Fragmin 5000 IU once daily subcutaneous n (%)	Placebo once daily subcutaneous n (%)
Major Bleeding Reactions1 at Day 14	8/1848 (0.4)	0/1833 (0)
Major Bleeding Reactions1 at Day 21	9/1848 (0.5)	3/1833 (0.2)

Three of the major bleeding reactions that occurred by Day 21 were fatal, all due to gastrointestinal hemorrhage (two patients in the group treated with Fragmin and one in the group receiving placebo).

Patients with Cancer and Acute Symptomatic Venous Thromboembolism

Table 9 summarizes the number of patients with bleeding reactions that occurred in the clinical trial of patients with cancer and acute symptomatic venous thromboembolism. A bleeding event was considered major if it: 1) was accompanied by a decrease in hemoglobin of ≥ 2 g/dL in connection with clinical symptoms; 2) occurred at a critical site (intraocular, spinal/epidural, intracranial, retroperitoneal, or pericardial bleeding); 3) required transfusion of ≥ 2 units of blood products; or 4) led to death. Minor bleeding was classified as clinically overt bleeding that did not meet criteria for major bleeding.

At the end of the six-month study, a total of 46 (13.6%) patients in the Fragmin arm and 62 (18.5%) patients in the OAC arm experienced any bleeding event. One bleeding event (hemoptysis in a patient in the Fragmin arm at Day 71) was fatal.

1 Patients with multiple bleeding episodes within any time interval were counted only once in that interval. However, patients with multiple bleeding episodes that occurred at different time intervals were counted once in each interval in which the event occurred.
Table 9
Bleeding Reactions (Major and Any) (As treated population)1
Study period	Fragmin 200 IU/kg (max. 18,000 IU) subcutaneous once daily x 1 month, then 150 IU/kg (max. 18,000 IU) subcutaneous once daily x 5 months			OAC Fragmin 200 IU/kg (max 18,000 IU) subcutaneous once daily x 5-7 days and OAC for 6 months (target INR 2-3)
Study period	Number at risk	Patients with Major Bleeding n (%)	Patients with Any Bleeding n (%)	Number at risk	Patients with Major Bleeding n (%)	Patients with Any Bleeding n (%)
Total during study	338	19 (5.6)	46 (13.6)	335	12 (3.6)	62 (18.5)
Week 1	338	4 (1.2)	15 (4.4)	335	4 (1.2)	12 (3.6)
Weeks 2-4	332	9 (2.7)	17 (5.1)	321	1 (0.3)	12 (3.7)
Weeks 5-28	297	9 (3.0)	26 (8.8)	267	8 (3.0)	40 (15.0)

Thrombocytopenia

[See Warnings and Precautions (5.2)]

Elevations of Serum Transaminases

In Fragmin clinical trials supporting non-cancer indications, where hepatic transaminases were measured, asymptomatic increases in transaminase levels (SGOT/AST and SGPT/ALT) greater than three times the upper limit of normal of the laboratory reference range were seen in 4.7% and 4.2%, respectively, of patients during treatment with Fragmin.

In the Fragmin clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated with Fragmin for up to 6 months, asymptomatic increases in transaminase levels, AST and ALT, greater than three times the upper limit of normal of the laboratory reference range were reported in 8.9% and 9.5% of patients, respectively. The frequencies of Grades 3 and 4 increases in AST and ALT, as classified by the National Cancer Institute, Common Toxicity Criteria (NCI-CTC) Scoring System, were 3% and 3.8%, respectively. Grades 2, 3 & 4 combined have been reported in 12% and 14% of patients, respectively.

Other

Allergic Reactions: Allergic reactions (i.e., pruritus, rash, fever, injection site reaction, bullous eruption) have occurred. Cases of anaphylactoid reactions have been reported.

Local Reactions: Pain at the injection site, the only non-bleeding event determined to be possibly or probably related to treatment with Fragmin and reported at a rate of at least 2% in the group treated with Fragmin, was reported in 4.5% of patients treated with Fragmin 5000 IU once daily vs 11.8% of patients treated with heparin 5000 U twice daily in the abdominal surgery trials. In the hip replacement trials, pain at injection site was reported in 12% of patients treated with Fragmin 5000 IU once daily vs 13% of patients treated with heparin 5000 U three times a day.

Post-Marketing Experience

The following adverse reactions have been identified during postapproval use of Fragmin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Since first international market introduction in 1985, there have been more than 15 reports of epidural or spinal hematoma formation with concurrent use of dalteparin sodium and spinal/epidural anesthesia or spinal puncture. The majority of patients had postoperative indwelling epidural catheters placed for analgesia or received additional drugs affecting hemostasis. In some cases the hematoma resulted in long-term or permanent paralysis (partial or complete). [see Boxed Warning]

Skin necrosis has occurred. There have been cases of alopecia reported that improved on drug discontinuation.

Drug Interactions

Use Fragmin with care in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents because of increased risk of bleeding [see Warning and Precautions (5)].

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies of Fragmin use in pregnant women. In reproductive and developmental toxicity studies, pregnant rats and rabbits received dalteparin sodium at intravenous doses up to 2400 IU/kg (14,160 IU/m2) (rats) and 4800 IU/kg (40,800 IU/m2) (rabbits). These exposures were 2 to 4 times (rats) and 4 times (rabbits) the human dose of 100 IU/kg dalteparin based on the body surface area. No evidence of impaired fertility or harm to the fetuses occurred in these studies. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Cases of "Gasping Syndrome" have occurred in premature infants when large amounts of benzyl alcohol have been administered (99-404 mg/kg/day). The 9.5 mL and the 3.8 mL multiple-dose vials of Fragmin contain 14 mg/mL of benzyl alcohol [see Warnings and Precautions (5.3)].

Nursing Mothers

Based on limited published data dalteparin is minimally excreted in human milk. One study of 15 lactating women receiving prophylactic doses of dalteparin, in the immediate postpartum period, detected small amounts of anti-Xa activity (range < 0.005 to 0.037 IU/ml) in breast milk that were equivalent to a milk/plasma ratio of < 0.025-0.224. Oral absorption of LMWH is extremely low, but the clinical implications, if any, of this small amount of anticoagulant activity on a nursing infant are unknown. Caution should be exercised when Fragmin is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of the total number of patients in clinical studies of Fragmin, 5516 patients were 65 years of age or older and 2237 were 75 or older. No overall differences in effectiveness were observed between these subjects and younger subjects. Some studies suggest that the risk of bleeding increases with age. Postmarketing surveillance and literature reports have not revealed additional differences in the safety of Fragmin between elderly and younger patients. Give careful attention to dosing intervals and concomitant medications (especially antiplatelet medications) in geriatric patients, particularly in those with low body weight (< 45 kg) and those predisposed to decreased renal function [see Warnings and Precautions (5) and Clinical Pharmacology (12)].

Overdosage

An excessive dosage of Fragmin Injection may lead to hemorrhagic complications. These may generally be stopped by slow intravenous injection of protamine sulfate (1% solution), at a dose of 1 mg protamine for every 100 anti-Xa IU of Fragmin given. If the APTT measured 2 to 4 hours after the first infusion remains prolonged, a second infusion of 0.5 mg protamine sulfate per 100 anti-Xa IU of Fragmin may be administered. Even with these additional doses of protamine, the APTT may remain more prolonged than would usually be found following administration of unfractionated heparin. In all cases, the anti-Factor Xa activity is never completely neutralized (maximum about 60 to 75%).

Take particular care to avoid overdosage with protamine sulfate. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions, often resembling anaphylaxis, have been reported with protamine sulfate, give protamine sulfate only when resuscitation techniques and treatment for anaphylactic shock are readily available. For additional information, consult the labeling of Protamine Sulfate Injection, USP, products.

Fragmin Description

Fragmin Injection (dalteparin sodium injection) is a sterile, low molecular weight heparin. It is available in single-dose, prefilled syringes preassembled with a needle guard device, and multiple-dose vials. With reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard, each syringe contains either 2500, 5000, 7500, 10,000, 12,500, 15,000 or 18,000 anti-Factor Xa international units (IU), equivalent to 16, 32, 48, 64, 80, 96 or 115.2 mg dalteparin sodium, respectively. Each multiple-dose vial contains either 10,000 or 25,000 anti-Factor Xa IU per 1 mL (equivalent to 64 or 160 mg dalteparin sodium, respectively), for a total of 95,000 anti-Factor Xa IU per vial.

Each prefilled syringe also contains Water for Injection and sodium chloride, when required, to maintain physiologic ionic strength. The prefilled syringes are preservative-free. Each multiple-dose vial also contains Water for Injection and 14 mg of benzyl alcohol per mL as a preservative. The pH of both formulations is 5.0 to 7.5. [See Dosage and Administration (2) and How Supplied (16)]

Dalteparin sodium is produced through controlled nitrous acid depolymerization of sodium heparin from porcine intestinal mucosa followed by a chromatographic purification process. It is composed of strongly acidic sulfated polysaccharide chains (oligosaccharide, containing 2,5-anhydro-D-mannitol residues as end groups) with an average molecular weight of 5000 and about 90% of the material within the range 2000-9000. The molecular weight distribution is:

    < 3000 daltons    3.0-15%

    3000 to 8000 daltons    65.0-78.0%

    > 8000 daltons    14.0-26.0%

STRUCTURAL FORMULA

Fragmin - Clinical Pharmacol

Geneprami

Geneprami may be available in the countries listed below.

Ingredient matches for Geneprami

Metoclopramide

Metoclopramide hydrochloride (a derivative of Metoclopramide) is reported as an ingredient of Geneprami in the following countries:

Greece

International Drug Name Search

Pentacel

Dosage Form: injection
FULL PRESCRIBING INFORMATION

1. INDICATIONS AND USAGE

Pentacel® is a vaccine indicated for active immunization against diphtheria, tetanus, pertussis, poliomyelitis and invasive disease due to Haemophilus influenzae type b. Pentacel vaccine is approved for use as a four dose series in children 6 weeks through 4 years of age (prior to fifth birthday).

2. DOSAGE AND ADMINISTRATION

. Immunization Series

Pentacel vaccine is to be administered as a 4 dose series at 2, 4, 6 and 15-18 months of age. The first dose may be given as early as 6 weeks of age. Four doses of Pentacel vaccine constitute a primary immunization course against pertussis. Three doses of Pentacel vaccine constitute a primary immunization course against diphtheria, tetanus, H influenzae type b invasive disease, and poliomyelitis; the fourth dose is a booster for diphtheria, tetanus, H influenzae type b invasive disease, and poliomyelitis immunizations. [See 14 Clinical Studies (14.1, 14.2, 14.3, 14.4, 14.5).]

Mixed Sequences of Pentacel Vaccine and DTaP Vaccine

While Pentacel and DAPTACEL (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed [DTaP], Sanofi Pasteur Limited) vaccines contain the same pertussis antigens, manufactured by the same process, Pentacel vaccine contains twice the amount of detoxified pertussis toxin (PT) and four times the amount of filamentous hemagglutinin (FHA) as DAPTACEL vaccine. Pentacel vaccine may be used to complete the first 4 doses of the 5-dose DTaP series in infants and children who have received 1 or more doses of DAPTACEL vaccine and are also scheduled to receive the other antigens of Pentacel vaccine. Children who have completed a 4-dose series with Pentacel vaccine should receive a fifth dose of DTaP vaccine using DAPTACEL at 4-6 years of age. However, data are not available on the safety and immunogenicity of mixed sequences of Pentacel vaccine and DAPTACEL vaccine for successive doses of the DTaP series.

Data are not available on the safety and immunogenicity of using mixed sequences of Pentacel vaccine and DTaP vaccine from different manufacturers.

Mixed Sequences of Pentacel Vaccine and IPV Vaccine

Pentacel vaccine may be used in infants and children who have received 1 or more doses of another licensed IPV vaccine and are scheduled to receive the antigens of Pentacel vaccine. However, data are not available on the safety and immunogenicity of Pentacel vaccine in such infants and children.

The Advisory Committee on Immunization Practices (ACIP) recommends that the final dose in the 4-dose IPV series be administered at age ≥4 years. (1) When Pentacel vaccine is administered at ages 2, 4, 6, and 15-18 months, an additional booster dose of IPV vaccine should be administered at age 4-6 years, resulting in a 5-dose IPV series. (1)

Mixed Sequences of Pentacel Vaccine and Haemophilus b Conjugate Vaccine

Pentacel vaccine may be used to complete the vaccination series in infants and children previously vaccinated with one or more doses of Haemophilus b Conjugate Vaccine (either separately administered or as part of another combination vaccine), who are also scheduled to receive the other antigens of Pentacel vaccine. However, data are not available on the safety and immunogenicity of Pentacel vaccine in such infants and children. If different brands of Haemophilus b Conjugate Vaccines are administered to complete the series, three primary immunizing doses are needed, followed by a booster dose.

. Administration

Just before use, thoroughly but gently shake the vial of DTaP-IPV component, withdraw the entire liquid content and inject into the vial of the lyophilized ActHIB vaccine component. Shake the vial now containing Pentacel vaccine thoroughly until a cloudy, uniform, white to off-white (yellow tinge) suspension results. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. If these conditions exist, Pentacel vaccine should not be administered.

Withdraw and administer a 0.5 mL dose of Pentacel vaccine intramuscularly. Pentacel vaccine should be used immediately after reconstitution. Refer to Figures 1, 2, 3, 4 and 5.

Pentacel Vaccine: Instructions For Reconstitution of ActHIB Vaccine Component With DTaP-IPV Component

In infants younger than 1 year, the anterolateral aspect of the thigh provides the largest muscle and is the preferred site of injection. In older children, the deltoid muscle is usually large enough for injection. The vaccine should not be injected into the gluteal area or areas where there may be a major nerve trunk.

Do not administer this product intravenously or subcutaneously.

Pentacel vaccine should not be mixed in the same syringe with other parenteral products.

3. DOSAGE FORMS AND STRENGTHS

Pentacel vaccine is a suspension for injection (0.5-mL dose) supplied as a liquid vaccine component that is combined through reconstitution with a lyophilized vaccine component, both in single dose vials. [See Dosage and Administration (2.2) and How Supplied/Storage and Handling (16).]

4. CONTRAINDICATIONS

. Hypersensitivity

A severe allergic reaction (eg, anaphylaxis) after a previous dose of Pentacel vaccine or any other diphtheria toxoid, tetanus toxoid, or pertussis-containing vaccine, inactivated poliovirus vaccine or H influenzae type b vaccine, or any ingredient of this vaccine is a contraindication to administration of Pentacel vaccine. [See Description (11).]

. Encephalopathy

Encephalopathy (eg, coma, decreased level of consciousness, prolonged seizures) within 7 days of a previous dose of a pertussis containing vaccine that is not attributable to another identifiable cause is a contraindication to administration of any pertussis-containing vaccine, including Pentacel vaccine.

. Progressive Neurologic Disorder

Progressive neurologic disorder, including infantile spasms, uncontrolled epilepsy, or progressive encephalopathy is a contraindication to administration of any pertussis-containing vaccine including Pentacel vaccine. Pertussis vaccine should not be administered to individuals with such conditions until a treatment regimen has been established and the condition has stabilized.

5. WARNINGS AND PRECAUTIONS

. Management of Acute Allergic Reactions

Epinephrine hydrochloride solution (1:1,000) and other appropriate agents and equipment must be available for immediate use in case an anaphylactic or acute hypersensitivity reaction occurs.

. Adverse Reactions Following Prior Pertussis Vaccination

If any of the following events occur within the specified period after administration of a pertussis vaccine, the decision to administer Pentacel vaccine should be based on careful consideration of potential benefits and possible risks.

Temperature of ≥40.5°C (≥105°F) within 48 hours, not attributable to another identifiable cause.

Collapse or shock-like state (hypotonic-hyporesponsive episode (HHE)) within 48 hours.

Persistent, inconsolable crying lasting ≥3 hours within 48 hours.

Seizures with or without fever within 3 days.

. Guillain-Barré Syndrome and Brachial Neuritis

A review by the Institute of Medicine (IOM) found evidence for a causal relation between tetanus toxoid and both brachial neuritis and Guillain-Barré syndrome. (2) If Guillain-Barré syndrome occurred within 6 weeks of receipt of prior vaccine containing tetanus toxoid, the decision to give Pentacel vaccine or any vaccine containing tetanus toxoid should be based on careful consideration of the potential benefits and possible risks.

. Infants and Children with a History of Previous Seizures

For infants or children with a history of previous seizures, an appropriate antipyretic may be administered (in the dosage recommended in its prescribing information) at the time of vaccination with a vaccine containing acellular pertussis antigens (including Pentacel vaccine) and for the following 24 hours, to reduce the possibility of post-vaccination fever.

. Limitations of Vaccine Effectiveness

Vaccination with Pentacel vaccine may not protect all individuals.

. Altered Immunocompetence

If Pentacel vaccine is administered to immunocompromised persons, including persons receiving immunosuppressive therapy, the expected immune response may not be obtained. [See Drug Interactions (7.2).]

6. ADVERSE REACTIONS

. Data from Clinical Studies

Rates of adverse reactions varied by dose number. The most frequent (>50% of participants) systemic reactions following any dose were fussiness/irritability and inconsolable crying. The most frequent (>30% of participants) injection site reactions following any dose were tenderness and increased circumference of the injected arm.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to vaccine use and for approximating rates of those events.

The safety of Pentacel vaccine was evaluated in four clinical studies in which a total of 5,980 participants received at least one dose of Pentacel vaccine. In three of the studies, conducted in the US, a total of 4,198 participants were enrolled to receive four consecutive doses of Pentacel vaccine. In the fourth study, conducted in Canada, 1,782 participants previously vaccinated with three doses of Pentacel vaccine received a fourth dose. The vaccination schedules of Pentacel vaccine, Control vaccines, and concomitantly administered vaccines used in these studies are provided in Table 1.

Across the four studies, 50.8% of participants were female. Among participants in the three US studies, 64.5% were Caucasian, 9.2% were Black, 12.9% were Hispanic, 3.9% were Asian, and 9.5% were of other racial/ethnic groups. In the two controlled studies, the racial/ethnic distribution of participants who received Pentacel and Control vaccines was similar. In the Canadian fourth dose study, 86.0% of participants were Caucasian, 1.9% were Black, 0.8% were Hispanic, 4.3% were Asian, 2.0% were East Indian, 0.5% were Native Indian, and 4.5% were of other racial/ethnic groups.

Table 1: Clinical Safety Studies of Pentacel Vaccine: Vaccination Schedules
Study	Pentacel	Control Vaccines	Concomitantly Administered Vaccines
HCPDT: non-US licensed DTaP vaccine that is identical to the DTaP component of Pentacel vaccine. POLIOVAX: US licensed Poliovirus Vaccine Inactivated, Sanofi Pasteur Limited. IPOL: US licensed Poliovirus Vaccine Inactivated, Sanofi Pasteur SA.
* PCV7 manufactured by Wyeth Laboratories. † PCV7 was introduced after the study was initiated, and thus, administered concomitantly with Pentacel vaccine in a subset of participants. ‡ The first dose of hepatitis B vaccine (manufacturer not specified) was administered prior to study initiation, from birth to 21 days of age. Subsequent doses were with hepatitis B vaccine manufactured by Merck and Co. § MMR and varicella vaccines were both manufactured by Merck and Co. ¶ Study participants previously had received three doses of Pentacel vaccine by 8 months of age.
494-01	2, 4, 6 and 15 months	HCPDT + POLIOVAX + ActHIB at 2, 4, 6, and 15 months	7-valent pneumococcal conjugate vaccine* (PCV7) at 2, 4, and 6 months in a subset of participants† Hepatitis B vaccine at 2 and 6 months‡
P3T06	2, 4, 6, and 15-16 months	DAPTACEL + IPOL + ActHIB at 2, 4, and 6 months; and DAPTACEL + ActHIB at 15-16 months	PCV7* at 2, 4, and 6 months Hepatitis B vaccine at 2 and 6 months‡
494-03	2, 4, 6, and 15-16 months	None	PCV7* at 2, 4, and 6 months in all participants; and at 15 months in a random subset of participants Hepatitis B vaccine at 2 and 6 months (if a dose was previously administered)‡ or at 2, 4, and 6 months (if no previous dose) Measles, mumps, rubella vaccine§ (MMR) and varicella§ vaccine at 12 or 15 months in random subsets of participants
5A9908	15-18 months¶	None	None

Solicited Adverse Reactions

The incidence and severity of selected solicited injection site and systemic adverse reactions that occurred within 3 days following each dose of Pentacel or Control vaccines in Study P3T06 is shown in Table 2. Information on these reactions was recorded daily by parents or guardians on diary cards. In Table 2, injection site reactions are reported for the Pentacel vaccine and DAPTACEL vaccine injection sites.

Table 2: Number (Percentage) of Children with Selected Solicited Adverse Reactions by Severity Occurring within 0-3 days of Pentacel Vaccine or Control Vaccines in Study P3T06
* Any: Mild, Moderate or Severe; Mild: subject whimpers when site is touched; Moderate: subject cries when site is touched; Severe: subject cries when leg or arm is moved. † Fever is based upon actual temperatures recorded with no adjustments to the measurement route. ‡ Following Doses 1-3 combined, the proportion of temperature measurements that were taken by axillary, rectal or other routes, or not recorded were 46.0%, 53.0%, 1.0%, and 0% respectively, for Pentacel vaccine and 44.8%, 54.0%, 1.0%, and 0.1%, respectively, for DAPTACEL + IPOL + ActHIB vaccines. Following Dose 4, the proportion of temperature measurements that were taken by axillary, rectal or other routes, or not recorded were 62.7%, 34.4%, 2.4% and 0.5%, respectively, for Pentacel vaccine, and 61.1%, 36.6%, 1.7% and 0.5%, respectively, for DAPTACEL + ActHIB vaccines. § Moderate: interferes with or limits usual daily activity; Severe: disabling, not interested in usual daily activity.
Injection Site Reactions	Pentacel Vaccine				DAPTACEL Vaccine
Injection Site Reactions	Dose 1 N = 465-467 %	Dose 2 N = 451 %	Dose 3 N = 438-440 %	Dose 4 N = 387-396 %	Dose 1 N = 1,400-1,404 %	Dose 2 N = 1,358-1,359 %	Dose 3 N = 1,311-1,312 %	Dose 4 N = 376-380 %
Redness
>5 mm	7.1	8.4	8.7	17.3	6.2	7.1	9.6	16.4
>25 mm	2.8	1.8	1.8	9.2	1.0	0.6	1.9	7.9
>50 mm	0.6	0.2	0.0	2.3	0.4	0.1	0.0	2.4
Swelling
>5 mm	7.5	7.3	5.0	9.7	4.0	4.0	6.5	10.3
>25 mm	3.0	2.0	1.6	3.8	1.6	0.7	1.1	4.0
>50 mm	0.9	0.0	0.0	0.8	0.4	0.1	0.1	1.3
Tenderness*
Any	47.5	39.2	42.7	56.1	48.8	38.2	40.9	51.1
Moderate or Severe	19.6	10.6	11.6	16.7	20.7	12.2	12.3	15.8
Severe	5.4	1.6	1.4	3.3	4.1	2.3	1.7	2.4
Increase in Arm Circumference
>5 mm				33.6				30.6
>20 mm	–	–	–	4.7	–	–	–	6.9
>40 mm				0.5				0.8
Systemic Reactions	Pentacel Vaccine				DAPTACEL + IPOL + ActHIB Vaccines			DAPTACEL + ActHIB Vaccines
Systemic Reactions	Dose 1 N = 466-467 %	Dose 2 N = 451-452 %	Dose 3 N = 435-440 %	Dose 4 N = 389-398 %	Dose 1 N = 1,390-1,406 %	Dose 2 N = 1,346-1,360 %	Dose 3 N = 1,301-1,312 %	Dose 4 N = 379-381 %
Fever†‡
≥38.0°C	5.8	10.9	16.3	13.4	9.3	16.1	15.8	8.7
>38.5°C	1.3	2.4	4.4	5.1	1.6	4.3	5.1	3.2
>39.5°C	0.4	0.0	0.7	0.3	0.1	0.4	0.3	0.8
Decreased Activity/Lethargy§
Any	45.8	32.7	32.5	24.1	51.1	37.4	33.2	24.1
Moderate or Severe	22.9	12.4	12.7	9.8	24.3	15.8	12.7	9.2
Severe	2.1	0.7	0.2	2.5	1.2	1.4	0.6	0.3
Inconsolable Crying
Any	59.3	49.8	47.3	35.9	58.5	51.4	47.9	36.2
≥1 hour	19.7	10.6	13.6	11.8	16.4	16.0	12.2	10.5
>3 hours	1.9	0.9	1.1	2.3	2.2	3.4	1.4	1.8
Fussiness/Irritability
Any	76.9	71.2	68.0	53.5	75.8	70.7	67.1	53.8
≥1 hour	34.5	27.0	26.4	23.6	33.3	30.5	26.2	19.4
>3 hours	4.3	4.0	5.0	5.3	5.6	5.5	4.3	4.5

Hypotonic Hyporesponsive Episodes

In Study P3T06, the diary cards included questions pertaining to HHEs. In Studies 494-01, 494-03, and 5A9908, a question about the occurrence of fainting or change in mental status was asked during post-vaccination phone calls. Across these 4 studies, no HHEs, as defined in a report of a US Public Health Service workshop (3) were reported among participants who received Pentacel vaccine (N = 5,979), separately administered HCPDT + POLIOVAX + ActHIB vaccines (N = 1,032) or separately administered DAPTACEL + IPOL + ActHIB vaccines (N = 1,455). Hypotonia not fulfilling HHE criteria within 7 days following vaccination was reported in 4 participants after the administration of Pentacel vaccine (1 on the same day as the 1st dose; 3 on the same day as the 3rd dose) and in 1 participant after the administration of DAPTACEL + IPOL + ActHIB vaccines (4 days following the 1st dose).

Seizures

Across Studies 494-01, 494-03, 5A9908 and P3T06, a total of 8 participants experienced a seizure within 7 days following either Pentacel vaccine (4 participants; N = 4,197 for at least one of Doses 1-3; N = 5,033 for Dose 4), separately administered HCPDT + POLIOVAX + ActHIB vaccines (3 participants; N = 1,032 for at least one of Doses 1-3, N = 739 for Dose 4), separately administered DAPTACEL + IPOL + ActHIB vaccines (1 participant; N = 1,455 for at least one of Doses 1-3), or separately administered DAPTACEL + ActHIB vaccines (0 participants; N = 418 for Dose 4). Among the four participants who experienced a seizure within 7 days following Pentacel vaccine, one participant in Study 494-01 had an afebrile seizure 6 days after the first dose, one participant in Study 494-01 had a possible seizure the same day as the third dose, and two participants in Study 5A9908 had a febrile seizure 2 and 4 days, respectively, after the fourth dose. Among the four participants who experienced a seizure within 7 days following Control vaccines, one participant had an afebrile seizure the same day as the first dose of DAPTACEL + IPOL + ActHIB vaccines, one participant had an afebrile seizure the same day as the second dose of HCPDT + POLIOVAX + ActHIB vaccines, and two participants had a febrile seizure 6 and 7 days, respectively, after the fourth dose of HCPDT + POLIOVAX + ActHIB vaccines.

Serious Adverse Events

In Study P3T06, within 30 days following any of Doses 1-3 of Pentacel or Control vaccines, 19 of 484 (3.9%) participants who received Pentacel vaccine and 50 of 1,455 (3.4%) participants who received DAPTACEL + IPOL + ActHIB vaccines experienced a serious adverse event. Within 30 days following Dose 4 of Pentacel or Control vaccines, 5 of 431 (1.2%) participants who received Pentacel vaccine and 4 of 418 (1.0%) participants who received DAPTACEL + ActHIB vaccines experienced a serious adverse event. In Study 494-01, within 30 days following any of Doses 1-3 of Pentacel or Control vaccines, 23 of 2,506 (0.9%) participants who received Pentacel vaccine and 11 of 1,032 (1.1%) participants who received HCPDT + POLIOVAX + ActHIB vaccines experienced a serious adverse event. Within 30 days following Dose 4 of Pentacel or Control vaccines, 6 of 1,862 (0.3%) participants who received Pentacel vaccine and 2 of 739 (0.3%) participants who received HCPDT + POLIOVAX + ActHIB vaccines experienced a serious adverse event.

Across Studies 494-01, 494-03 and P3T06, within 30 days following any of Doses 1-3 of Pentacel or Control vaccines, overall, the most frequently reported serious adverse events were bronchiolitis, dehydration, pneumonia and gastroenteritis. Across Studies 494-01, 494-03, 5A9908 and P3T06, within 30 days following Dose 4 of Pentacel or Control vaccines, overall, the most frequently reported serious adverse events were dehydration, gastroenteritis, asthma, and pneumonia.

Across Studies 494-01, 494-03, 5A9908 and P3T06, two cases of encephalopathy were reported, both in participants who had received Pentacel vaccine (N = 5,979). One case occurred 30 days post-vaccination and was secondary to cardiac arrest following cardiac surgery. One infant who had onset of neurologic symptoms 8 days post-vaccination was subsequently found to have structural cerebral abnormalities and was diagnosed with congenital encephalopathy.

A total of 5 deaths occurred during Studies 494-01, 494-03, 5A9908 and P3T06: 4 in children who had received Pentacel vaccine (N = 5,979) and one in a participant who had received DAPTACEL + IPOL + ActHIB vaccines (N = 1,455). There were no deaths reported in children who received HCPDT + POLIOVAX + ActHIB vaccines (N = 1,032). Causes of death among children who received Pentacel vaccine were asphyxia due to suffocation, head trauma, Sudden Infant Death syndrome, and neuroblastoma (8, 23, 52 and 256 days post-vaccination, respectively). One participant with ependymoma died secondary to aspiration 222 days following DAPTACEL + IPOL + ActHIB vaccines.

. Data from Post-Marketing Experience

The following additional adverse events have been spontaneously reported during the post-marketing use of Pentacel vaccine worldwide, since 1997. Between 1997 and 2007, Pentacel vaccine was primarily used in Canada. Because these events are reported voluntarily from a population of uncertain size, it may not be possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure.

The following adverse events were included based on one or more of the following factors: severity, frequency of reporting, or strength of evidence for a causal relationship to Pentacel vaccine.

Cardiac disorders

Cyanosis

Gastrointestinal disorders

Vomiting, diarrhea

General disorders and administration site conditions

Injection site reactions (including inflammation, mass, abscess and sterile abscess), extensive swelling of the injected limb (including swelling that involved adjacent joints), vaccination failure/therapeutic response decreased (invasive H influenzae type b disease)

Immune system disorders

Hypersensitivity (such as rash and urticaria)

Infections and infestations

Meningitis, rhinitis, viral infection

Metabolism and nutrition disorders

Decreased appetite

Nervous system disorders

Somnolence, HHE, depressed level of consciousness

Psychiatric disorders

Screaming

Respiratory, thoracic and mediastinal disorders

Apnea, cough

Skin and subcutaneous tissue disorders

Erythema, skin discoloration

Vascular disorders

Pallor

7. DRUG INTERACTIONS

. Concomitant Administration with Other Vaccines

In clinical trials, Pentacel vaccine was administered concomitantly with one or more of the following US licensed vaccines: hepatitis B vaccine, 7-valent pneumococcal conjugate vaccine, MMR and varicella vaccines. [See Adverse Reactions (6) and Clinical Studies (14).] When Pentacel vaccine is given at the same time as another injectable vaccine(s), the vaccine(s) should be administered with different syringes and at different injection sites.

. Immunosuppressive Treatments

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to Pentacel vaccine. [See Warnings and Precautions (5.6).]

. Drug/Laboratory Test Interactions

Antigenuria has been detected in some instances following receipt of ActHIB vaccine. Urine antigen detection may not have definite diagnostic value in suspected H influenzae type b disease within one week following receipt of Pentacel vaccine. (4)

8. USE IN SPECIFIC POPULATIONS

. Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with Pentacel vaccine. It is also not known whether Pentacel vaccine can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity.

. Pediatric Use

The safety and effectiveness of Pentacel vaccine was established in the age group 6 weeks through 18 months on the basis of clinical studies. [See Adverse Reactions (6.1) and Clinical Studies (14).] The safety and effectiveness of Pentacel vaccine in the age group 19 months through 4 years is supported by evidence in children 6 weeks through 18 months. The safety and effectiveness of Pentacel vaccine in infants less than 6 weeks of age and in children 5 to 16 years of age have not been established.

11. DESCRIPTION

Pentacel vaccine consists of a Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and Inactivated Poliovirus (DTaP-IPV) component and an ActHIB® vaccine component combined through reconstitution for intramuscular injection. ActHIB vaccine (Haemophilus b Conjugate Vaccine [Tetanus Toxoid Conjugate]), consists of H influenzae type b capsular polysaccharide (polyribosyl-ribitol-phosphate [PRP]) covalently bound to tetanus toxoid (PRP-T). The DTaP-IPV component is supplied as a sterile liquid used to reconstitute the lyophilized ActHIB vaccine component to form Pentacel vaccine. Pentacel vaccine is a uniform, cloudy, white to off-white (yellow tinge) suspension.

Each 0.5 mL dose contains 15 Lf diphtheria toxoid, 5 Lf tetanus toxoid, acellular pertussis antigens [20 mcg detoxified pertussis toxin (PT), 20 mcg filamentous hemagglutinin (FHA), 3 mcg pertactin (PRN), 5 mcg fimbriae types 2 and 3 (FIM)], inactivated polioviruses [40 D-antigen units (DU) Type 1 (Mahoney), 8 DU Type 2 (MEF-1), 32 DU Type 3 (Saukett)] and 10 mcg PRP of H influenzae type b covalently bound to 24 mcg of tetanus toxoid (PRP-T).

Other ingredients per 0.5 mL dose include 1.5 mg aluminum phosphate (0.33 mg aluminum) as the adjuvant, polysorbate 80 (approximately 10 ppm by calculation), ≤5 mcg residual formaldehyde, <50 ng residual glutaraldehyde, ≤50 ng residual bovine serum albumin, 3.3 mg (0.6% v/v) 2-phenoxyethanol (not as a preservative), <4 pg of neomycin and <4 pg polymyxin B sulfate.

Corynebacterium diphtheriae is grown in modified Mueller's growth medium. (5) After purification by ammonium sulfate fractionation, the diphtheria toxin is detoxified with formaldehyde and diafiltered.

Clostridium tetani is grown in modified Mueller-Miller casamino acid medium without beef heart infusion. (6) Tetanus toxin is detoxified with formaldehyde and purified by ammonium sulfate fractionation and diafiltration. Diphtheria and tetanus toxoids are individually adsorbed onto aluminum phosphate.

The acellular pertussis vaccine antigens are produced from Bordetella pertussis cultures grown in Stainer-Scholte medium (7) modified by the addition of casamino acids and dimethyl-beta-cyclodextrin. PT, FHA and PRN are isolated separately from the supernatant culture medium. FIM are extracted and copurified from the bacterial cells. The pertussis antigens are purified by sequential filtration, salt-precipitation, ultrafiltration and chromatography. PT is detoxified with glutaraldehyde. FHA is treated with formaldehyde and the residual aldehydes are removed by ultrafiltration. The individual antigens are adsorbed separately onto aluminum phosphate.

Poliovirus Type 1, Type 2 and Type 3 are each grown in separate cultures of MRC-5 cells, a line of normal human diploid cells, by the microcarrier method. (8) (9) The cells are grown in CMRL (Connaught Medical Research Laboratories) 1969 medium, supplemented with calf serum. For viral growth, the culture medium is replaced by Medium 199, without calf serum. After clarification and filtration, the viral suspensions are concentrated by ultrafiltration, and purified by liquid chromatography steps. The monovalent viral suspensions are inactivated with formaldehyde. Monovalent concentrates of each inactivated poliovirus are combined to produce a trivalent poliovirus concentrate.

The adsorbed diphtheria, tetanus and acellular pertussis antigens are combined with aluminum phosphate (as adjuvant), 2-phenoxyethanol (not as a preservative) and water for injection, into an intermediate concentrate. The trivalent poliovirus concentrate is added and the DTaP-IPV component is diluted to its final concentration. The DTaP-IPV component does not contain a preservative.

Both diphtheria and tetanus toxoids induce at least 2 neutralizing units per mL in the guinea pig potency test. The potency of the acellular pertussis antigens is evaluated by the antibody response of immunized mice to detoxified PT, FHA, PRN and FIM as measured by enzyme-linked immunosorbent assay (ELISA). The immunogenicity of the inactivated polioviruses is evaluated by the antibody response in monkeys measured by virus neutralization.

PRP, a high molecular weight polymer, is prepared from the Haemophilus influenzae type b strain 1482 grown in a semi-synthetic medium. (10) The tetanus toxoid for conjugation to PRP is prepared by ammonium sulfate purification, and formalin inactivation of the toxin from cultures of Clostridium tetani (Harvard strain) grown in a modified Mueller and Miller medium. (11) The toxoid is filter sterilized prior to the conjugation process. The ActHIB vaccine component does not contain a preservative. Potency of the ActHIB vaccine component is specified on each lot by limits on the content of PRP polysaccharide and protein per dose and the proportion of polysaccharide and protein that is characterized as high molecular weight conjugate.

The vial stoppers for the DTaP-IPV and ActHIB vaccine components of Pentacel vaccine do not contain natural latex rubber.

12. CLINICAL PHARMACOLOGY

. Mechanism of Action

Diphtheria

Diphtheria is an acute toxin-mediated disease caused by toxigenic strains of C diphtheriae. Protection against disease is due to the development of neutralizing antibodies to diphtheria toxin. A serum diphtheria antitoxin level of 0.01 IU/mL is the lowest level giving some degree of protection. Antitoxin levels of at least 0.1 IU/mL are generally regarded as protective. (12) Levels of 1.0 IU/mL have been associated with long-term protection. (13)

Tetanus

Tetanus is an acute disease caused by an extremely potent neurotoxin produced by C tetani. Protection against disease is due to the development of neutralizing antibodies to tetanus toxin. A serum tetanus antitoxin level of at least 0.01 IU/mL, measured by neutralization assay is considered the minimum protective level. (12) (14) A tetanus antitoxoid level ≥0.1 IU/mL as measured by the ELISA used in clinical studies of Pentacel vaccine is considered protective.

Pertussis

Pertussis (whooping cough) is a respiratory disease caused by B pertussis. This Gram-negative coccobacillus produces a variety of biologically active components, though their role in either the pathogenesis of, or immunity to, pertussis has not been clearly defined.

Poliomyelitis

Polioviruses, of which there are three serotypes (Types 1, 2, and 3) are enteroviruses. The presence of poliovirus type-specific neutralizing antibodies has been correlated with protection against poliomyelitis. (15)

Invasive Disease Due to H influenzae Type b

H influenzae type b can cause invasive disease such as meningitis and sepsis. Anti-PRP antibody has been shown to correlate with protection against invasive disease due to H influenzae type b.

Based on data from passive antibody studies (16) and an efficacy study with H influenzae type b polysaccharide vaccine in Finland, (17) a post-vaccination anti-PRP level of 0.15 mcg/mL has been accepted as a minimal protective level. Data from an efficacy study with H influenzae type

Friday, September 30, 2016

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1. INDICATIONS AND USAGE

2. DOSAGE AND ADMINISTRATION

. Immunization Series

. Administration

3. DOSAGE FORMS AND STRENGTHS

4. CONTRAINDICATIONS

. Hypersensitivity

. Encephalopathy

. Progressive Neurologic Disorder

5. WARNINGS AND PRECAUTIONS

. Management of Acute Allergic Reactions

. Adverse Reactions Following Prior Pertussis Vaccination

. Guillain-Barré Syndrome and Brachial Neuritis

. Infants and Children with a History of Previous Seizures

. Limitations of Vaccine Effectiveness

. Altered Immunocompetence

6. ADVERSE REACTIONS

. Data from Clinical Studies

. Data from Post-Marketing Experience

7. DRUG INTERACTIONS

. Concomitant Administration with Other Vaccines

. Immunosuppressive Treatments

. Drug/Laboratory Test Interactions

8. USE IN SPECIFIC POPULATIONS

. Pregnancy