phenytoin Intravenous

FEN-i-toin

Injection route(Solution)

This drug must be administered slowly. In adults do not exceed 50 mg per minute intravenously. In neonates, the drug should be administered at a rate not exceeding 1 to 3 mg/kg/min .

Available Dosage Forms:

• Solution

Therapeutic Class: Anticonvulsant

Chemical Class: Hydantoin (class)

Uses For phenytoin

Phenytoin injection is used to control certain types of seizures (convulsions) in the treatment of epilepsy. It is also used to prevent and treat seizures that occur during brain surgery. phenytoin is an anticonvulsant that works in the brain tissue to stop seizures.

phenytoin is to be given only or under the direct supervision of a doctor.

Before Using phenytoin

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For phenytoin, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to phenytoin or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of phenytoin injection in children.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of phenytoin injection in the elderly. However, elderly patients are more likely to have age-related liver, kidney, or heart problems, which may require an adjustment in the dose for patients receiving phenytoin injection.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	D	Studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy in a life threatening situation or a serious disease, may outweigh the potential risk.

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving phenytoin, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using phenytoin with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Boceprevir


• Delavirdine


• Nifedipine


• Praziquantel


• Ranolazine


• Rilpivirine

Using phenytoin with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abiraterone


• Apazone


• Beclamide


• Bortezomib


• Cabazitaxel


• Crizotinib


• Dasatinib


• Dopamine


• Dronedarone


• Erlotinib


• Etravirine


• Everolimus


• Ezogabine


• Imatinib


• Infliximab


• Irinotecan


• Ixabepilone


• Ketorolac


• Lapatinib


• Lidocaine


• Linagliptin


• Lopinavir


• Maraviroc


• Naproxen


• Nilotinib


• Posaconazole


• Rivaroxaban


• Roflumilast


• Romidepsin


• St John's Wort


• Sunitinib


• Tacrolimus


• Temsirolimus


• Ticagrelor


• Tolvaptan


• Vandetanib


• Vemurafenib


• Voriconazole

Using phenytoin with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acetaminophen


• Acetazolamide


• Acyclovir


• Amiodarone


• Amitriptyline


• Amprenavir


• Aprepitant


• Atorvastatin


• Betamethasone


• Bexarotene


• Busulfan


• Capecitabine


• Carbamazepine


• Caspofungin


• Chloramphenicol


• Cimetidine


• Ciprofloxacin


• Cisplatin


• Clarithromycin


• Clobazam


• Clofazimine


• Clopidogrel


• Clozapine


• Colesevelam


• Cortisone


• Cyclosporine


• Desogestrel


• Dexamethasone


• Diazepam


• Dicumarol


• Dienogest


• Digitoxin


• Diltiazem


• Disopyramide


• Disulfiram


• Doxepin


• Doxorubicin Hydrochloride


• Drospirenone


• Estradiol Cypionate


• Estradiol Valerate


• Ethinyl Estradiol


• Ethosuximide


• Ethynodiol Diacetate


• Etonogestrel


• Felbamate


• Fentanyl


• Fluconazole


• Fludrocortisone


• Fluorouracil


• Fluoxetine


• Fluvoxamine


• Folic Acid


• Fosamprenavir


• Gefitinib


• Ginkgo


• Ibuprofen


• Imipramine


• Isoniazid


• Itraconazole


• Levodopa


• Levomethadyl


• Levonorgestrel


• Levothyroxine


• Medroxyprogesterone Acetate


• Meperidine


• Mestranol


• Methoxsalen


• Methsuximide


• Miconazole


• Midazolam


• Nafimidone


• Nelfinavir


• Nilutamide


• Nisoldipine


• Norelgestromin


• Norethindrone


• Norgestimate


• Norgestrel


• Oxcarbazepine


• Paclitaxel


• Pancuronium


• Paroxetine


• Phenprocoumon


• Piperine


• Prednisolone


• Prednisone


• Progabide


• Quetiapine


• Quinidine


• Quinine


• Remacemide


• Rifampin


• Rifapentine


• Risperidone


• Ritonavir


• Rufinamide


• Sabeluzole


• Sertraline


• Shankhapulshpi


• Simvastatin


• Sirolimus


• Sulfamethizole


• Sulfaphenazole


• Sulthiame


• Telithromycin


• Tenidap


• Theophylline


• Tiagabine


• Ticlopidine


• Ticrynafen


• Tirilazad


• Tizanidine


• Tolbutamide


• Topiramate


• Trazodone


• Triamcinolone


• Trimethoprim


• Tubocurarine


• Valproic Acid


• Vecuronium


• Verapamil


• Vigabatrin


• Viloxazine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using phenytoin with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use phenytoin, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other Medical Problems

The presence of other medical problems may affect the use of phenytoin. Make sure you tell your doctor if you have any other medical problems, especially:

• Diabetes or


• Heart failure or


• Heart rhythm problems or


• Hypotension (low blood pressure) or


• Lymphadenopathy (lymph node problems) or


• Porphyria (an enzyme problem)—Use with caution. May make these conditions worse.

• Heart block (e.g., Adams-Stokes syndrome, AV block, or sinoatrial block) or


• Sinus bradycardia (slow heartbeat)—Should not be used in patients with these conditions.

• Hypoalbuminemia (low albumin in the blood) or


• Kidney disease or


• Liver disease—Use with caution. The effects may be increased because of slower removal from the body.

Proper Use of phenytoin

A nurse or other trained health professional will give you or your child phenytoin in a hospital. phenytoin is given as a shot into one of your muscles or through a needle placed in one of your veins.

Your doctor will only give you or your child a few doses of phenytoin until your condition improves. You will be switched to an oral medicine that works the same way. If you have any concerns about this, talk to your doctor.

Precautions While Using phenytoin

It is very important that your doctor check your progress closely while you or your child are receiving phenytoin. This is to see if it is working properly and to allow for a change in the dose. Blood tests may be needed to check for any unwanted effects.

Using phenytoin while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away. Your doctor may want you to join a pregnancy registry for patients using a seizure medicine.

Do not receive phenytoin while you or your child are also taking delavirdine (Rescriptor®). Using these medicines together may cause unwanted effects.

phenytoin may cause some people to become dizzy, lightheaded, faint, or less alert than they are normally. Make sure you know how you react to phenytoin before you drive, use machines, or do anything else that could be dangerous if you are dizzy or are not alert and able to see well.

Do not stop using phenytoin without first checking with your doctor. Stopping the medicine suddenly may cause your seizures to return or to occur more often.

If you or your child develop a skin rash, hives, or any allergic reaction to phenytoin, tell your doctor or nurse as soon as possible.

Tell your doctor right away if you or your child develop a fever; rash; swollen, painful, or tender lymph glands in the neck, armpit, or groin; unusual bleeding or bruising; or yellow eyes or skin after receiving phenytoin. These may be symptoms of a serious and life-threatening condition called Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).

phenytoin may cause purple glove syndrome. Tell your doctor right away if you or your child have skin discoloration, pain, or swelling at the injection site after receiving phenytoin.

phenytoin may affect blood sugar levels. If you or your child notice a change in the results of your blood or urine sugar tests or if you have any questions, check with your doctor.

If you or your child develop any unusual or strange thoughts and behavior while receiving phenytoin injection, be sure to discuss it with your doctor. Some changes that have occurred in people receiving phenytoin are like those seen in people who drink too much alcohol. Other changes might be confusion, worsening of depression, hallucinations (seeing, hearing, or feeling things that are not there), suicidal thoughts, and unusual excitement, nervousness, or irritability.

Birth control pills may not work while you are using phenytoin. To keep from getting pregnant, use another form of birth control along with your birth control pills. Other forms include a condom, a diaphragm, or a contraceptive foam or jelly.

Avoid drinking alcohol while you are receiving phenytoin.

Before you have any medical tests, tell the medical doctor in charge that you or your child are taking phenytoin. The results of some tests may be affected by phenytoin.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

phenytoin Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

More common

• Chest pain or discomfort


• cold, clammy, or pale skin


• decreased coordination


• difficulty with sleeping


• disorientation


• dizziness


• drowsiness to profound coma


• fainting


• fast, slow, or irregular heartbeat


• hallucination


• headache


• lightheadedness


• measles-like skin rash


• mood or other mental changes


• nausea


• nervousness


• pain in the shoulders, back, neck, or jaw


• shakiness and unsteady walk


• shortness of breath


• slow heart rate


• slurred speech


• sweating


• swelling of the feet and lower legs


• troubled breathing


• uncontrolled eye movements


• unsteadiness, trembling, or other problems with muscle control or coordination


• unusual tiredness or weakness

Rare

• Bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site


• blistering, crusting, irritation, itching, peeling, or reddening of the skin


• cracked, dry, or scaly skin


• inability to move the eyes


• increased blinking or spasms of the eyelid


• shakiness in the legs, arms, hands, or feet


• sticking out of the tongue


• trouble with breathing, speaking, or swallowing


• twitching, uncontrolled movements of the tongue, lips, face, neck, trunk, arms, or legs


• unusual facial expressions

Incidence not known

• Abdominal or stomach pain


• bleeding gums


• blisters, hives, or itching


• bloating of the abdomen or stomach


• blood in the urine or stools


• bloody, black, or tarry stools


• blurred vision


• break in the skin, especially associated with blue-black discoloration, swelling, or drainage of fluid


• burning, numbness, tingling, or painful sensations


• chills


• cough or hoarseness


• dark urine


• diarrhea


• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position


• fainting spells


• fever with or without chills


• general feeling of discomfort or illness


• general feeling of tiredness or weakness


• hair loss


• high fever


• irritation in the mouth


• joint or muscle pain


• light-colored stools


• loss of appetite


• loss of heat from the body


• lower back or side pain


• muscle or joint pain


• painful or difficult urination


• pale skin


• pinpoint red spots on the skin


• red skin lesions, often with a purple center


• red, irritated eyes


• red, swollen skin


• redness and swelling of the gums


• skin rash


• sore throat


• soreness of the muscles


• sores, ulcers, or white spots on the lips or in the mouth


• sweating


• swollen glands


• swollen, painful, or tender lymph glands in the neck, armpit, or groin


• unexplained bleeding or bruising


• unsteadiness or awkwardness


• unusual bleeding or bruising


• weakness in the arms, hands, legs, or feet


• weight loss


• yellow eyes or skin

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose

• Change in consciousness


• changes in patterns and rhythms of speech


• loss of consciousness


• pounding in the ears


• unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Sleeplessness


• unable to sleep

Incidence not known

• Difficulty having a bowel movement (stool)


• enlarged lips


• increased hair growth on the forehead, back, arms, and legs


• pain of the penis on erection

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: phenytoin Intravenous side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More phenytoin Intravenous resources

• Phenytoin Intravenous Side Effects (in more detail)
• Phenytoin Intravenous Use in Pregnancy & Breastfeeding
• Drug Images
• Phenytoin Intravenous Drug Interactions
• Phenytoin Intravenous Support Group
• 46 Reviews for Phenytoin Intravenous - Add your own review/rating

Compare phenytoin Intravenous with other medications

• Anxiety
• Arrhythmia
• Epilepsy
• Neurosurgery
• Peripheral Neuropathy
• Rheumatoid Arthritis
• Seizures
• Status Epilepticus
• Trigeminal Neuralgia

Neosalus Foam

Pronunciation: Not applicable
Generic Name: Hydrating
Brand Name: Examples include Hylatopic and Neosalus

Neosalus Foam is used for:

Treating or preventing dry, itchy skin or minor skin irritations caused by various skin conditions, including atopic dermatitis and allergic contact dermatitis. Some brands of Neosalus Foam may also be used to treat radiation dermatitis.

Neosalus Foam is an emollient, protectant, and skin barrier combination. It works by moisturizing the skin and reducing skin irritation.

Do NOT use Neosalus Foam if:

• you are allergic to any ingredient in Neosalus Foam

Contact your doctor or health care provider right away if any of these apply to you.

Before using Neosalus Foam:

Some medical conditions may interact with Neosalus Foam. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if the affected area has open sores or severe irritation

Some MEDICINES MAY INTERACT with Neosalus Foam. However, no specific interactions with Neosalus Foam are known at this time.

Ask your health care provider if Neosalus Foam may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Neosalus Foam:

Use Neosalus Foam as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• The container may need to be primed before the first use of Neosalus Foam. Check with your pharmacist to see if your container must be primed. If so, follow the instructions provided or ask your pharmacist how to prime the container.


• Wash your hands before and after using Neosalus Foam unless your hands are a part of the treated area.


• Shake well before each use.


• To dispense the foam from the container, follow the instructions provided with Neosalus Foam. If you are unsure how to dispense the foam, check with your pharmacist.


• Wash and completely dry the affected area with a mild or soapless cleanser. Apply enough of Neosalus Foam to completely cover the affected area and gently rub it in until it is evenly distributed and completely absorbed.


• Do not wrap or bandage the treated area unless directed to do so by your doctor.


• Wipe any excess foam off of the container after use.


• Additional skin moisturizers may be used if necessary. Contact your doctor if you have any questions.


• If you miss a dose of Neosalus Foam, use it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

Ask your health care provider any questions you may have about how to use Neosalus Foam.

Important safety information:

• Neosalus Foam is for external use only. Do not get Neosalus Foam in your eyes, nose, or mouth. If you get Neosalus Foam in any of these areas, rinse them right away with cool tap water.


• If you use topical products too often, your condition may become worse.


• Do not apply Neosalus Foam within 4 hours before a radiation session.


• Neosalus Foam may cause you to become sunburned more easily. Avoid the sun, sunlamps, or tanning booths until you know how you react to Neosalus Foam. Use a sunscreen or wear protective clothing if you must be outside for more than a short time.


• Talk with your doctor before you use any other medicines or cleansers on your skin.


• If the symptoms do not improve, if they get worse, or if they clear up and then come back again, contact your doctor.


• Neosalus Foam may be flammable. Do not store near fire or an open flame. Avoid fire, open flame, or smoking during and immediately after use.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Neosalus Foam while you are pregnant. It is not known if Neosalus Foam is found in breast milk after topical use. If you are or will be breast-feeding while you use Neosalus Foam, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Neosalus Foam:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Mild burning, itching, dryness, redness, or scaling at the application site.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); severe, persistent, or worsening itching, burning, redness, scaling, stinging, or irritation at the application site.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Neosalus side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Neosalus Foam:

Store Neosalus Foam at room temperature, between 59 and 77 degrees F (15 and 25 degrees C). Store away from heat and direct sunlight. Do not freeze. Do not expose to heat or store at temperatures above 120 degrees F (49 degrees C). Do not puncture, break, or burn the canister, even if it appears to be empty. Keep Neosalus Foam out of the reach of children and away from pets.

General information:

• If you have any questions about Neosalus Foam, please talk with your doctor, pharmacist, or other health care provider.


• Neosalus Foam is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Neosalus Foam. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Neosalus resources

• Neosalus Side Effects (in more detail)
• Neosalus Use in Pregnancy & Breastfeeding
• Neosalus Support Group
• 0 Reviews for Neosalus - Add your own review/rating

Compare Neosalus with other medications

• Dry Skin

Prefest

estradiol and norgestimate

Dosage Form: tablets
Prefest® (estradiol/norgestimate) tablets

Rx only

Iss. 9/2010

11001719

PHYSICIAN’S PACKAGE INSERT

WARNING

Estrogens and progestins should not be used for the prevention of cardiovascular disease. (See WARNINGS, Cardiovascular disorders.)

The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated equine estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo (See CLINICAL PHARMACOLOGY, CLINICAL STUDIES).

The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative to placebo. It is unknown whether this finding applies to younger postmenopausal women or to women taking estrogen alone therapy. (See CLINICAL PHARMACOLOGY, CLINICAL STUDIES.)

Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

DESCRIPTION:

The Prefest regimen provides for a single oral tablet to be taken once daily. The peach tablet containing 1 mg estradiol is taken on days one through three of therapy; the white tablet containing 1 mg estradiol and 0.09 mg norgestimate is taken on days four through six of therapy. This pattern is then repeated continuously to produce the constant estrogen/intermittent progestogen regimen of Prefest.

The estrogenic component of Prefest is estradiol, USP. It is a white, crystalline solid, chemically described as estra-1,3,5(10)-triene-3,17β-diol. The structural formula is as follows:

 

C18H24O2                            Molecular Weight: 272.39

The progestational component of Prefest is micronized norgestimate, a white powder which is chemically described as 18,19-dinor-17-pregn-4-en-20-yn-3-one, 17-(acetyloxy)-13-ethyl-,oxime,(17α)-(+)-. The structural formula is as follows:

 

C23H31NO3                              Molecular Weight: 369.50

Each tablet for oral administration contains 1 mg estradiol alone or 1 mg estradiol and 0.09 mg of norgestimate. The inactive ingredients are as follows:

The estradiol tablet contains anhydrous lactose, croscarmellose sodium, FD&C yellow no. 6 aluminum lake, magnesium stearate and microcrystalline cellulose.

The estradiol and norgestimate tablet contains anhydrous lactose, croscarmellose sodium, magnesium stearate and microcrystalline cellulose.

CLINICAL PHARMACOLOGY:

Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.

The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.

Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

Norgestimate is a derivative of 19-nortestosterone and binds to androgen and progestogen receptors, similar to that of the natural hormone progesterone; it does not bind to estrogen receptors. Progestins counter the estrogenic effects by decreasing the number of nuclear estradiol receptors and suppressing epithelial DNA synthesis in endometrial tissue.

Pharmacokinetics:

Absorption:

Estradiol reaches its peak serum concentration (Cmax) at approximately 7 hours in postmenopausal women receiving Prefest (Table 1). Norgestimate is completely metabolized; its primary active metabolite, 17-deacetylnorgestimate, reaches Cmax at approximately 2 hours after dose (Table 1). Upon co-administration of Prefest with a high fat meal, the Cmax values for estrone and estrone sulfate were increased by 14% and 24%, respectively, and the Cmax for 17-deacetylnorgestimate was decreased by 16%. The AUC values for these analytes were not significantly affected by food.

Distribution:

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. 17-deacetylnorgestimate, the primary active metabolite of norgestimate, does not bind to SHBG, but to other serum proteins. The percent protein binding of 17-deacetylnorgestimate is approximately 99%.

Metabolism:

Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. Norgestimate is extensively metabolized by first-pass mechanisms in the gastrointestinal tract and/or liver. Norgestimate’s primary active metabolite is 17-deacetylnorgestimate.

Excretion:

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Norgestimate metabolites are eliminated in the urine and feces. The half-life (t1/2) of estradiol and 17-deacetylnorgestimate in postmenopausal women receiving Prefest is approximately 16 and 37 hours, respectively.

Drug Interactions:

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.

Results of a subset population (n=24) from a clinical study conducted in 36 healthy postmenopausal women indicated that the steady state serum estradiol levels during the estradiol plus norgestimate phase of the regimen may be lower by 12-18% as compared with estradiol administered alone. The serum estrone levels may decrease by 4% and the serum estrone sulfate levels may increase by 17% during the estradiol plus norgestimate phase as compared with estradiol administered alone. The clinical relevance of these observations is unknown.

Special Populations:

Race and Body Weight:

The effects of race and body weight on the pharmacokinetics of estradiol, norgestimate, and their metabolites were evaluated in 164 healthy postmenopausal women (100 Caucasians, 61 Hispanics, 2 Blacks, and 1 Asian). No significant pharmacokinetic difference was observed between the Caucasian and the Hispanic postmenopausal women. No significant difference due to body weight was observed in women in the 60 to 80 kg weight range. Women with body weight higher than 80 kg, however, had approximately 40% lower peak serum levels of 17-deacetylnorgestimate, 30% lower AUC values for 17-deacetylnorgestimate and 30% lower Cmax values for norgestrel. The clinical relevance of these observations is unknown.

No pharmacokinetic studies were conducted in other special populations.

Table 1. Mean Pharmacokinetic Parameters of E2, E1, E1S and 17d-NGM*  Following Single and Multiple Dosing of Prefest

* E2 = Estradiol, E1 = Estrone, E1S = Estrone Sulfate, 17d-NGM = 17 -deacetylnorgestimate. Baseline uncorrected data are reported for E2, E1 and E1S. † Cmax= peak serum concentration, tmax = time to reach peak serum concentration, AUC (0-24 h) = area under serum concentration vs. time curve from 0 to 24 hours after dose, t½ = half life. ‡ NA = Not available or not applicable.
Analyte	Parameter†	Units	First Dose E2	First Dose E2/NGM	Multiple Dose E2	Multiple Dose E2/NGM
E2	C max	pg/mL	27.4	39.3	49.7	46.2
	tmax	h	7	7	7	7
	AUC (0-24 h)	pg. h/mL	424	681	864	779
E1	Cmax	pg/mL	210	285	341	325
	t max	h	6	6	341	6
	AUC (0-24 h)	pg. h/mL	2774	4153	5429	4957
E1S	Cmax	ng/mL	11.1	13.9	14.9	14.5
	tmax	h	5	4	6	5
	AUC (0-24 h)	ng. h/mL	135	180	198	198
17d-NGM	Cmax	pg/mL	NA‡	515	NA	643
	tmax	h	NA	2	NA	2
	AUC (0-24 h)	pg. h/mL	NA	2146	NA	5322
	t½	h	NA	37	NA	NA

CLINICAL STUDIES:

Effects on Vasomotor Symptoms:

The effect of the estrogen component of Prefest on vasomotor symptoms was confirmed in a 12-week placebo-controlled trial of 168 healthy postmenopausal women between 28 and 66 years of age (87% Caucasian) with moderate to severe vasomotor symptoms (MSVS). The addition of norgestimate to estrogen (i.e., the Prefest regimen) was studied in two 12-month trials in 1212 healthy postmenopausal women between 40 and 65 years of age (85% Caucasian) for endometrial protection. Results from a subset population (n=119) of these 12-month trials (women with MSVS) are shown in Table 2.

Table 2. Change in the Mean Number of Moderate-to-Severe Vasomotor Symptoms (Subset of Subjects with 7 or More Moderate-to-Severe Hot Flushes per Day)

	1 mg E2		Prefest
	N	Mean	N	Mean
Baseline	29	11.0	26	10.9
Week 4	29	3.3	26	2.6
Week 8	29	1.1	23	0.9
Week 12	29	1.1	23	0.7

The effects of the addition of norgestimate on steady state estrogen levels and the clinical relevance thereof have been discussed in CLINICAL PHARMACOLOGY (see Drug Interactions).

Effects on Vulvar and Vaginal Atrophy:

The effect of the estrogen component of Prefest on vulvar and vaginal atrophy was confirmed in a 12-week placebo-controlled trial of healthy postmenopausal women with moderate to severe vasomotor symptoms (MSVS). The addition of norgestimate to estrogen (i.e., the Prefest regimen) was studied in a 12-month trial in 143 healthy postmenopausal women between 42 and 65 years of age (92% Caucasian) for endometrial protection. Results from a subset population (n=69) with paired tests for maturation index of the vaginal mucosa are shown in Table 3.

Table 3. Summary of Maturation Index Results in Subjects with Paired Tests Following 7 Months Treatment with Prefest or Estradiol

	Pretreatment Mean	Month 7 Mean	Mean Change
1 mg Estradiol (N=37)
Parabasal Cells (%)	25.1	2.7	-22.4
Intermediate Cells (%)	69.2	76.4	7.2
Superficial Cells (%)	5.7	20.9	15.3
Prefest (N=32)
Parabasal Cells (%)	31.9	0.0	-31.9
Intermediate Cells (%)	64.2	80.9	16.7
Superficial Cells (%)	3.9	19.1	15.2

Effects on the Endometrium:

The effect of Prefest on the endometrium was evaluated in two 12-month trials. The combined results are shown in Table 4.

 

Table 4. Incidence of Endometrial Hyperplasia After 12 Months of Treatment (Intent to Treat Population)

	Continuous 1 mg estradiol	Prefest
Total No. Subjects	265	242
Total No. Evaluable Biopsies	256 (97%)	227 (94%)
Normal endometrium	182 (71%)	227 (100%)
Simple hyperplasia	64 (25%)	0 (0%)
Complex hyperplasia	2 (0.8%)	0 (0%)
Hyperplasia with cytological atypia	8 (3%)	0 (0%)

In another 12-month controlled clinical trial for endometrial protection an additional 190 postmenopausal women were treated with Prefest. No subject had a diagnosis of endometrial hyperplasia after treatment.

Effects on Uterine Bleeding or Spotting:

The effects of Prefest on uterine bleeding or spotting, as recorded on daily diary cards, were evaluated in two 12-month trials. Combined results are shown in Figure 1.

 

Figure 1: Subjects with Cumulative Amenorrhea Over Time (Percentage of Women With No Bleeding or Spotting at a Given Month Through Month 12), Intent to treat Population

Effects on Lipids:

The effect of Prefest on lipids was evaluated in a 12-month metabolic trial of healthy postmenopausal women. Results are shown in Table 5.

Table 5. Effects on Lipoproteins at Month 12

	1 mg E2		Prefest
	N	Change	N	Change
Total Cholesterol	36	1.2	31	-1.9
HDL	36	12.0	31	9.7
LDL	31	1.7	30	1.2
Triglycerides	36	29.0	31	9.4

Women's Health Initiative Studies

The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of oral 0.625 mg conjugated estrogens (CE) per day alone or the use of oral 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.

The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 6 below:

Table 6. RELATIVE AND ABSOLUTE RISK SEEN IN THE CE/MPA SUBSTUDY OF WHI* 

* adapted from JAMA, 2002; 288:321-333 † a subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes ‡ nominal confidence intervals unadjusted for multiple looks and multiple comparisons § includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer ¶ not included in Global Index
Event†	Relative Risk CE/MPA vs placebo at 5.2 Years	Placebo n = 8102	CE/MPA n = 8506
	(95% CI‡)	Absolute Risk per 10,000 Person-years
CHD events        Non-fatal MI       CHD death	1.29 (1.02-1.63) 1.32 (1.02-1.72) 1.18 (0.70-1.97)	30 23 6	37 30 7
Invasive breast cancer§	1.26 (1.00-1.59)	30	38
Stroke	1.41 (1.07-1.85)	21	29
Pulmonary embolism	2.13 (1.39-3.25)	8	16
Colorectal cancer	0.63 (0.43-0.92)	16	10
Endometrial cancer	0.83 (0.47-1.47)	6	5
Hip fracture	0.66 (0.45-0.98)	15	10
Death due to causes other than the events above	0.92 (0.74-1.14)	40	37
Global Index†	1.15 (1.03-1.28)	151	170
Deep vein thrombosis¶	2.07 (1.49-2.87)	13	26
Vertebral fractures¶	0.66 (0.44-0.98)	15	9
Other osteoporotic fractures¶	0.77 (0.69-0.86)	170	131

For those outcomes included in the “global index,” the absolute excess risks per 10,000 women-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)

Women's Health Initiative Memory Study

The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and WARNINGS, Dementia.)

INDICATIONS AND USAGE:

Prefest is indicated in women who have a uterus for the:

1. Treatment of moderate to severe vasomotor symptoms associated with the menopause.


2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribed solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.


3. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and nonestrogen medications should be carefully considered.

The mainstays for decreasing the risk of postmenopausal osteoporosis are weight bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400-800 IU/day may also be required to ensure adequate daily intake in postmenopausal women.

CONTRAINDICATIONS:

Prefest should not be used in women with any of the following conditions:

1. Undiagnosed abnormal genital bleeding.


2. Known, suspected, or history of cancer of the breast.


3. Known or suspected estrogen-dependent neoplasia.


4. Active deep vein thrombosis, pulmonary embolism or history of these conditions.


5. Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction).


6. Liver dysfunction or disease.


7. Prefest should not be used in patients with known hypersensitivity to its ingredients.


8. Known or suspected pregnancy. There is no indication for Prefest in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy (See PRECAUTIONS).

 

WARNINGS:

See BOXED WARNINGS.

1. Cardiovascular disorders:

Estrogen and estrogen/progestin therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogens should be discontinued immediately.

Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.

a. Coronary heart disease and stroke.

In the Women’s Health Initiative (WHI) study, an increase in the number of myocardial infarctions and strokes has been observed in women receiving CE compared to placebo. These observations are preliminary. (See CLINICAL PHARMACOLOGY, CLINICAL STUDIES.)

In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs 30 per 10,000 women-years). The increase in risk was observed in year one and persisted.

In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 women-years). The increase in risk was observed after the first year and persisted.

In postmenopausal women with documented heart disease (n=2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with (CE/MPA 0.625 mg/2.5 mg per day) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in HERS, HERS II, and overall.

Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.

b. Venous thromboembolism (VTE).

In the Women’s Health Initiative (WHI) study, an increase in VTE has been observed in women receiving CE compared to placebo. These observations are preliminary. (See CLINICAL PHARMACOLOGY, CLINICAL STUDIES.)

In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the CE/MPA group compared to 16 per 10,000 women-years in the placebo group. The increase in VTE risk was observed during the first year and persisted.

If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

2. Malignant neoplasms:

a. Endometrial cancer.

The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than one year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five to ten years or more and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

b. Breast cancer.

The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women’s Health Initiative (WHI) substudy of CE/MPA (see CLINICAL PHARMACOLOGY, CLINICAL STUDIES). The results from observational studies are generally consistent with those of the WHI clinical trial and report no significant variation in the risk of breast cancer among different estrogens or progestins, doses, or routes of administration.

The CE/MPA substudy of WHI reported an increased risk of breast cancer in women who took CE/MPA for a mean follow-up of 5.6 years. Observational studies have also reported an increased risk for estrogen/progestin combination therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. In the WHI trial and from observational studies, the excess risk increased with duration of use. From observational studies, the risk appeared to return to baseline in about five years after stopping treatment. In addition, observational studies suggest that the risk of breast cancer was greater, and become apparent earlier, with estrogen/progestin combination therapy as compared to estrogen alone therapy.

In the CE/MPA substudy, 26% of the women reported prior use of estrogen alone and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01-1.54), and the overall absolute risk was 41 vs. 33 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09 and the absolute risk was 40 vs. 36 cases per 10,000 women-years for CE/MPA compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups.

The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patients age, risk factors, and prior mammogram results.

Ceftriaxone 1g Powder for solution for injection

1. Name Of The Medicinal Product

Ceftriaxone 1g Powder for solution for injection

2. Qualitative And Quantitative Composition

Each vial contains ceftriaxone sodium equivalent to 1g of ceftriaxone.

Each gram of ceftriaxone contains approximately82 mg (3.6mmol) of sodium.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder for solution for injection (Powder for injection).

White to pale yellow crystalline powder.

4. Clinical Particulars

4.1 Therapeutic Indications

Ceftriaxone sodium is a broad-spectrum bactericidal cephalosporin antibiotic. Ceftriaxone is active in vitro against a wide range of Gram-positive and Gram-negative organisms, which include β-lactamase producing strains.

Ceftriaxone is indicated in the treatment of the following infections either before the infecting organism has been identified or when known to be caused by bacteria of established

Skin and soft tissue infections

Infections in neutropenic patients

Gonorrhoea

Peri-operative prophylaxis of infections associated with surgery

Treatment may be started before the results of susceptibility tests are known.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology And Method Of Administration

Ceftriaxone may be administered by deep intramuscular injection, or as a slow intravenous injection, after reconstitution of the solution according to the directions given below. The dosage and mode of administration should be determined by the severity of the infection, susceptibility of the causative organism and the patient's condition. Under most circumstances a once-daily dose or, in the specified indications, one dose will give satisfactory therapeutic results.

Diluents containing calcium, (e.g. Ringer's solution or Hartmann's solution), should not be used to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same IV administration line. Therefore, ceftriaxone and calcium-containing solutions must not be mixed or administered simultaneously (see sections 4.3, 4.4 and 6.2).

Intramuscular injection: 1g ceftriaxone should be dissolved in 3.5ml of 1% Lidocaine Injection BP. The solution should be administered by deep intramuscular injection. Doses greater than 1g should be divided and injected at more than one site.

Intravenous injection: 1g ceftriaxone should be dissolved in 10ml of Water for Injections PhEur. The injection should be administered over at least 2-4 minutes, directly into the vein or via the tubing of an intravenous infusion.

Adults and children 12 years and over:

Standard therapeutic dosage: 1g once daily.

Severe infections: 2-4 g daily, normally as a once daily dose.

The duration of therapy varies according to the course of the disease. As with antibiotic therapy in general, administration of ceftriaxone should be continued for a minimum of 48 to 72 hours after the patient has become afebrile or evidence of bacterial eradication has been obtained.

Acute, uncomplicated gonorrhoea: One dose of 250mg intramuscularly should be administered. Simultaneous administration of probenecid is not indicated.

Peri-operative prophylaxis: Usually one dose of 1g given by intramuscular or slow intravenous injection. In colorectal surgery, 2g should be given intramuscularly (in divided doses at different injection sites), by slow intravenous injection or by slow intravenous infusion, in conjunction with a suitable agent against anaerobic bacteria.

Elderly: These dosages do not require modification in elderly patients provided that renal and hepatic function are satisfactory (see below).

In the neonate, the intravenous dose should be given over 60 minutes to reduce the displacement of bilirubin from albumin, thereby reducing the potential risk of bilirubin encephalopathy (see Special warning and precautions for use).

Children under 12 years

Standard therapeutic dosage: 20-50mg/kg body-weight once daily.

Up to 80mg/kg body-weight daily may be given in severe infections, except in premature neonates where a daily dosage of 50mg/kg should not be exceeded. For children with body weights of 50kg or more, the usual dosage should be used. Doses of 50mg/kg or over should be given by slow intravenous infusion over at least 30 minutes. Doses greater than 80mg/kg body weight should be avoided because of the increased risk of biliary precipitates.

Renal and hepatic impairment: In patients with impaired renal function, there is no need to reduce the dosage of ceftriaxone provided liver function is intact. Only in cases of pre-terminal renal failure (creatinine clearance <10ml per minute) should the daily dosage be limited to 2g or less.

In patients with liver damage there is no need for the dosage to be reduced provided renal function is intact.

In severe renal impairment accompanied by hepatic insufficiency, the plasma concentration of ceftriaxone should be determined at regular intervals and dosage adjusted.

In patients undergoing dialysis, no additional supplementary dosage is required following the dialysis. Plasma concentrations should be monitored, however, to determine whether dosage adjustments are necessary, since the elimination rate in these patients may be reduced.

4.3 Contraindications

Known or suspected allergy to cephalosporins.

Previous immediate and/or severe hypersensitivity reaction to a penicillin or to any other type of beta

Ceftriaxone constituted with Lidocaine Injection BP must never be used:

- by the intravenous route

- in infants under 30 months

- in subjects with a previous history of hypersensitivity to Lidocaine Injection BP

- in patients who have an unpaced heart block

- in patients with severe heart failure.

Ceftriaxone should not be given to:

• premature newborns up to a corrected age of 41 weeks (weeks of gestation + weeks of life); or

• full-term newborns (up to 28 days of age)

o with jaundice, or who are hypoalbuminaemic or acidotic because these are conditions in which bilirubin binding is likely to be impaired

o if they require (or are expected to require) IV calcium treatment, or calcium-containing infusions because of the risk of precipitation of ceftriaxone-calcium (see sections 4.4, 4.8 and 6.2).

4.4 Special Warnings And Precautions For Use

The stated dosage should not be exceeded.

Before therapy with ceftriaxone is instituted, careful inquiry should be made to determine whether the patient has had any previous hypersensitivity reactions to ceftriaxone, cephalosporins, penicillins, or other beta

In severe renal impairment accompanied by hepatic insufficiency, dosage reduction is required as outlined under Posology and method of administration.

In vivo and in vitro studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin. Clinical data obtained in neonates have confirmed this finding. Ceftriaxone should therefore not be used in jaundiced newborns or in babies who are hypoalbuminaemic, acidotic or born prematurely, in whom bilirubin binding is likely to be impaired.

Cases of fatal reactions with calcium-ceftriaxone precipitates in lungs and kidneys in premature and full-term newborns aged less than 1 month have been described. At least one of them had received ceftriaxone and calcium at different times and through different intravenous lines. In the available scientific data, there are no reports of confirmed intravascular precipitations in patients, other than newborns, treated with ceftriaxone and calcium-containing solutions or any other calcium-containing products. In vitro studies demonstrated that newborns have an increased risk of precipitation of ceftriaxone-calcium compared to other age groups. In patients of any age ceftriaxone must not be mixed or administered simultaneously with any calcium-containing IV solutions, even via different infusion lines or at different infusion sites. However, in patients older than 28 days of age ceftriaxone and calcium-containing solutions may be administered sequentially one after another if infusion lines at different sites are used or if the infusion lines are replaced or thoroughly flushed between infusions with physiological salt-solution to avoid precipitation. In patients requiring continuous infusion with calcium-containing TPN solutions, healthcare professionals may wish to consider the use of alternative antibacterial treatments which do not carry a similar risk of precipitation. If use of ceftriaxone is considered necessary in patients requiring continuous nutrition, TPN solutions and ceftriaxone can be administered simultaneously, albeit via different infusion lines at different sites. Alternatively, infusion of TPN solution could be stopped for the period of ceftriaxone infusion, considering the advice to flush infusion lines between solutions. (see sections 4.3, 4.8, 5.2 and 6.2).

Ceftriaxone may precipitate in the gall bladder and then be detectable as shadows on ultrasound (see section 4.8). This can happen in patients of any age, but is more likely in infants and small children who are usually given a larger dose of ceftriaxone on a body weight basis. In children, doses greater than 80mg/kg body weight should be avoided because of the increased risk of biliary precipitates. There is no clear evidence of gallstones or of acute cholecystitis developing in children or infants treated with ceftriaxone. As the condition appears to be transient and reversible upon discontinuation, therapeutic procedures are normally not indicated.

Cephalosporins as a class tend to be absorbed onto the surface of the red cell membranes and react with antibodies directed against the drug to produce a positive Coombs' test and occasionally a rather mild haemolytic anaemia. In this respect, there may be some cross-reactivity with penicillins.

Regular blood counts (haemoglobin, erythrocyte, leucocyte and platelet counts and screening for prolongation of prothrombin time) should be carried out during treatment.

Cases of pancreatitis, possibly of biliary obstruction aetiology, have been rarely reported in patients treated with ceftriaxone. Most patients presented with risk factors for biliary stasis and biliary sludge, e.g. preceding major therapy, severe illness and total parenteral nutrition. A trigger or cofactor role of ceftriaxone-related biliary precipitation can not be ruled out.

Superinfections with yeasts, fungi or other resistant organisms may occur. A rare side-effect is pseudomembranous colitis which has resulted from infection with Clostridium difficile during treatment with ceftriaxone. Therefore it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of antibacterial agents.

Each gram of ceftriaxone sodium contains approximately 3.6mmol sodium.

This should be taken into account for patients on a controlled sodium diet.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Aminoglycoside antibiotics and diuretics: No impairment of renal function has been observed in man after simultaneous administration of ceftriaxone with diuretics. No interference with the action or increase in nephrotoxicity of aminoglycosides has been observed during simultaneous administration with ceftriaxone.

Alcohol: The ceftriaxone molecule does not contain the N-methylthio-tetrazole substituent, which has been associated with a disulfiram-like effect, when alcohol is taken during therapy with certain cephalosporins.

Antibiotics: In an in vitro study, antagonistic effects have been observed with the combination of chloramphenicol and ceftriaxone.

Anticoagulants: As ceftriaxone has an N-methylthiotriazine side-chain, it might have the potential to cause hypoprothrombinaemia.Refer to section 4.8, Undesirable effects.

Interference with Laboratory Tests:

In patients treated with ceftriaxone, the Coombs' test may rarely become false-positive and can interfere with blood cross-matching.

Ceftriaxone, like other antibiotics, may result in false-positive tests for galactosaemia. Likewise, non-enzymatic methods such as copper reduction methods (Benedict's, Fehling's or Clinitest) for glucose determination in urine may give false-positive results. For this reason, urine-glucose determination during therapy with ceftriaxone should be done enzymatically.

4.6 Pregnancy And Lactation

Pregnancy: It is known that ceftriaxone crosses the placental barrier. Ceftriaxone has not been associated with adverse events on foetal development in laboratory animals but its safety in human pregnancy has not been established. Therefore it should not be used in pregnancy unless absolutely indicated.

Lactation: Ceftriaxone is excreted in the milk in small amounts and is usually compatible with breast feeding, but careful monitoring of the infant is recommended. Only minimal amounts of ceftriaxone are excreted in breast milk. However, caution is advised in nursing mothers

4.7 Effects On Ability To Drive And Use Machines

Ceftriaxone has been associated with dizziness, which may affect the ability to drive or operate machinery.

4.8 Undesirable Effects

Ceftriaxone has been generally well tolerated. Adverse reactions are usually mild and transient.

Gastrointestinal

Common (

Rare (

Superinfections with yeasts or other resistant organisms may occur. A rare side-effect is pseudomembranous colitis which has resulted from infection with Clostridium difficile during treatment with ceftriaxone. Therefore it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of antibacterial agents.

Hypersensitivity

Uncommon (

Rare (

Very rare (< 0.01%): Isolated cases of severe cutaneous adverse reactions (erythema multiforme, Stevens Johnson Syndrome and Lyell's Syndrome/toxic epidermal necrolysis) have been reported.

Blood and lymphatic system disorders

Rare (

Central Nervous system

Rare (

Respiratory, renal and urinary

Rare (

Rarely, severe, and in some cases fatal, adverse reactions have been reported in preterm and full term newborns (aged <28 days) who had been treated with intravenous ceftriaxone and calcium. Precipitations of ceftriaxone-calcium salt have been observed in lung and kidneys post-mortem. The high risk of precipitation in newborns is due to their low blood volume and the longer half life of ceftriaxone compared with adults (see sections 4.3, 4.4 and 5.2).

Very rare (< 0.01%): reversible symptomatic urinary precipitates of calcium ceftriaxone have occurred after ceftriaxone administration. Patients who are very young, immobilised or who are dehydrated are at increased risk. There have been a few reports of anuria and renal impairment following this reaction.

Genital

Rare (

Hepatobiliary system

Rare (

Shadows which have been mistaken for gallstones, but which are precipitates of calcium ceftriaxone, have been detected by sonograms. These abnormalities are commonly observed after an adult daily dose of two grams per day or more, or its equivalent in children; these abnormalities were particularly observed in children with an incidence of above 30% in isolated reports. At doses of two grams a day or above these biliary precipitates may occasionally cause symptoms. Should patients develop symptoms, non-surgical management is recommended and discontinuation of ceftriaxone should be considered. The evidence suggests biliary precipitates usually disappear once ceftriaxone has been stopped. The risk of biliary precipitates may be increased by treatment duration greater than 14 days, renal failure, dehydration or total parenteral nutrition.

Pancreas

Very rare (< 0.01%): There have been isolated reports of pancreatitis although a causal relationship to ceftriaxone has not been established.

Local effects

Rare (

4.9 Overdose

In the case of overdosage, drug concentrations would not be reduced by haemodialysis or peritoneal dialysis. There is no specific antidote. Treatment should be symptomatic.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

General Properties

ATC classification: JO1D A13

Mode of action

Ceftriaxone has bactericidal activity resulting from the inhibition of bacterial cell wall synthesis ultimately leading to cell death. Ceftriaxone is stable to a broad range of bacterial β-lactamases.

Mechanism of resistance

Ceftriaxone is stable to a wide range of both Gram-positive and Gram-negative beta-lactamases, including those which are able to hydrolyse advanced generation penicillin derivatives and other cephalosporins. Resistance to ceftriaxone is encoded mainly by the production of some beta-lactam hydrolysing enzymes (including carbapenemases and some ESBLs) especially in Gram-negative organisms. For Gram-positive organisms such as S. aureus and S. pneumoniae, acquired resistance is mainly encoded by cell wall target site alterations. Outside of the advanced generation parenteral cephalosporins, cross-resistance to other drug classes is generally not encountered.

Breakpoints

Current MIC breakpoints used to interpret ceftriaxone susceptibility data are shown below. Values quoted comprise mg/L (MIC testing).

European Committee on Antimicrobial Susceptibility Testing (EUCAST) Clinical MIC Breakpoints (V1.1, 31/03/2006)

	Susceptible/Resistant
Enterobacteriaceae2	1/2
Pseudomonas	--
Acinetobacter	--
Staphylococcus 3	Note3
Enterococcus	--
Streptococcus A, B, C, G	0.5/0.54
Streptococcus pneumoniae	0.5/24
Haemophilus influenzae Moraxella Catarrhalis	0.12/0.124
Neisseria gonorrhoea	0.12/0.124
Neisseria Meningitidis	0.12/0.124
Gram-negative, anaerobes	--
Non-species related breakpoints1 S< />R	1/2

1. Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species that have not been given a species-specific breakpoint and not for those species where susceptibility testing is not recommended (marked with -- or IE in the table).

2. The cephalosporin breakpoints for Enterobacteriaceae will detect resistance mediated by most ESBLs and other clinically important beta-lactamases in Enterobacteriaceae. However, some ESBL-producing strains may appear susceptible or intermediate with these breakpoints. Laboratories may want to use a test which specifically screens for the presence of ESBL.

3. Susceptibility of staphylococci to cephalosporins is inferred from the methicillin susceptibility (except ceftazidime which should not be used for staphylococcal infections).

4. Strains with MIC values above the S/I breakpoint are very rare or not yet reported. The identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed isolates with MIC above the current resistant breakpoint (in italics) they should be reported resistant.

-- = Susceptibility testing not recommended as the species is a poor target for therapy with the drug.

IE = There is insufficient evidence that the species in question is a good target for therapy with the drug.

RD = rationale document listing data used by EUCAST for determining breakpoints.

Susceptibility

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Ceftriaxone susceptibility among Gram-positive and Gram-negative bacterial species in Europe from January 1999-December 2001:

Commonly susceptible species (i.e. resistance < 10% in all EU Member States)

Gram-Positive aerobes : MSa coagulase negative Staphylococcus spp. (including S. epidermis )* MSbStaphylococcus aureus* Group B (Streptococcus agalactiae ) Streptococcus bovis Streptococcus pneumoniae* Group A Streptococcus (Streptococcus pyogenes)* Streptococcus viridans* Gram-Negative aerobes : Citrobacter spp. (including C.freundii ) Escherichia coli* Haemophilus influenzae (including beta-lactamase positive isolates)c* Haemophilus para-influenzae* Klebsiella spp. (including K. pneumoniae and K. oxytoca )* Moraxella catarrhalis* Morganella morganii* Neisseria gonorrhoea (including penicillin-resistant isolates)* Neisseria meningitidis* Proteus spp. (including P. mirabilis and P. vulgaris )* Salmonella spp. (including S. typhimurium ) Serratia spp. (including Serratia marsescens )* Shigella spp. Anaerobes: Clostridium spp.*

Species for which acquired resistance may be a problem (i.e. resistance

Gram-Negative aerobes: Pseudomonas aeruginosa + Enterobacter spp. (including E. aerogenes and E. cloacae )*+ Acinetobacter spp. (including A. baumanii and A. calcoaceticus )*+ Anaerobes: Bacteroides spp.* Peptostreptococcus spp.*

Inherently resistant organisms

Gram-Positive aerobes: MRd coagulase negative Staphylococcus spp. (including S. epidermidis ) MReStaphylococcus aureus Enterococcus spp. Gram-Negative aerobes: Listeria monocytogenes Mycoplasma spp. Stenotrophomonas maltophilia Ureaplasma urealyticum Others: Chlamydia spp.

^aMethicillin-susceptible Coagulase-Negative Staphylococcus

^bMethicillin-susceptible Staphylococcus aureus

^cNon-susceptible range (no resistant breakpoints defined)

^dMethicillin-resistant Coagulase-Negative Staphylococcus

^eMethicillin-resistant Staphylococcus aureus

* Species for which the efficacy of ceftriaxone has been demonstrated both in vitro and in vivo

+ Species for which high rates of resistance have been observed in one or more regions within the EU

5.2 Pharmacokinetic Properties

The pharmacokinetics of ceftriaxone are largely determined by its concentration-dependent binding to plasma albumin. The plasma free (unbound) fraction of the drug in man is approximately 5% over most of the therapeutic concentration range, increasing to 15% at concentrations of 300mg/l. Owing to the lower albumin content, the proportion of free ceftriaxone in interstitial fluid is correspondingly higher than in plasma.

Plasma concentrations: Mean peak concentrations after bolus intravenous injection are about 120mg/l following a 500mg dose and about 200mg/l following a 1g dose; mean levels of 250mg/l are achieved after infusion of 2g over 30 minutes. Intramuscular injection of 500mg ceftriaxone in 1% Lidocaine Injection BP produces mean peak plasma concentrations of 40-70 mg/l within one hour. Bioavailability after intramuscular injection is 100%.

Excretion: Ceftriaxone is eliminated mainly as unchanged drug, approximately 60% of the dose being excreted in the urine (almost exclusively by glomerular filtration) and the remainder via the biliary and intestinal tracts. The total plasma clearance is 10-22 ml/min. The renal clearance is 5-12 ml/min. A notable feature of ceftriaxone is its relatively long plasma elimination half-life of approximately eight hours which makes single or once daily dosage of the drug appropriate for most patients. The half-life is not significantly affected by the dose, the route of administration or by repeated administration.

Pharmacokinetics in special clinical situations: In the first week of life, 80% of the dose is excreted in the urine; over the first month, this falls to levels similar to those in the adult. In infants aged less than 8 days the average elimination half-life is usually two to three times longer than that of young adults.

In elderly persons aged over 75 years, the average elimination half-life is usually two to three times longer that in the young adult group. As with all cephalosporins, a decrease in renal function in the elderly may lead to an increase in half-life. Evidence gathered to date with ceftriaxone however, suggests that no modification of the dosage regimen is needed.

In patients with renal or hepatic dysfunction, the pharmacokinetics of ceftriaxone are only minimally altered and the elimination half-life is only slightly increased. If kidney function alone is impaired, biliary elimination of ceftriaxone is increased; if liver function alone is impaired, renal elimination is increased.

Cerebrospinal fluid: Ceftriaxone crosses non-inflamed and inflamed meninges, attaining concentrations 4-17% of the simultaneous plasma concentration.

5.3 Preclinical Safety Data

There are no preclinical safety data of relevance to the prescriber that are additional to those included in other sections.

6. Pharmaceutical Particulars

6.1 List Of Excipients

None

6.2 Incompatibilities

Solutions containing ceftriaxone should not be mixed with or added to solutions containing other agents except 1% Lidocaine Injection BP (for intramuscular injection only). In particular, diluents containing calcium, (e.g. Ringer's solution, Hartmann's solution) should not be used to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Ceftriaxone must not be mixed or administered simultaneously with calcium containing solutions (see section 4.2, 4.3, 4.4 and 4.8). Based on literature reports, ceftriaxone is not compatible with amsacrine, vancomycin, fluconazole, aminoglycosides, pentamidine and labetalol.

6.3 Shelf Life

Unopened – Three years.

For reconstituted solution, chemical and physical in-use stability has been demonstrated for 24 hours at 25^oC and for four days at 2-8°C. From a microbiological point of view, once opened, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless reconstitution has taken place in controlled and validated aseptic conditions

6.4 Special Precautions For Storage

Unopened: Do not store above 25°C. Keep the vials in the outer carton.

After reconstitution: Store at 2-8^oC, see section 6.3 for complete storage instructions.

6.5 Nature And Contents Of Container

Ceftriaxone is supplied in Type III 10ml clear glass vials, closed with a Type I rubber stopper uncoated/coated in Omniflex and sealed with an aluminium cap.

The vials are packed in boxes of 1, 5, 10, 25 or 50 vials. Not all pack sizes are marketed.

6.6 Special Precautions For Disposal And Other Handling

Reconstitution table Water for Injection (Intravenous Injection):

Vial size	Volume of Diluent to be added	Approx available volume	Approx displacement volume
1g	10ml	10.5ml	0.5ml

Reconstitution table 1% Lidocaine Injection BP (Intramuscular Injection):

Vial size	Volume of Diluent to be added	Approx available volume	Approx displacement volume
1g	3.5ml	4.05ml	0.55ml

Ceftriaxone should not be mixed in the same syringe with any drug other than 1% Lidocaine Injection BP (for intramuscular injection only).

The reconstituted solution should be clear. Do not use if particles are present.

Ceftriaxone sodium when dissolved in Water for Injections Ph Eur forms a pale yellow to amber solution. Variations in the intensity of colour of the freshly prepared solutions do not indicate a change in potency or safety.

For single use only. Discard any unused contents.

7. Marketing Authorisation Holder

Wockhardt UK Ltd

Ash Road North

Wrexham

LL13 9UF

UK

8. Marketing Authorisation Number(S)

PL 29831/0034

PA 1339/4/1

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation:

16 October 2007 (UK) 19 December 2007 (Ireland)

10. Date Of Revision Of The Text

November 2009