Fouch may be available in the countries listed below.
Clindamycin dihydrogen phosphate (a derivative of Clindamycin) is reported as an ingredient of Fouch in the following countries:
International Drug Name Search
Treating high blood pressure. It may be used alone or with other medicines. It may also be used for other conditions as determined by your doctor.
Tenex is an alpha agonist. It works by relaxing (dilating) blood vessels and decreasing heart rate, which lowers blood pressure.
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with Tenex. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
Some MEDICINES MAY INTERACT with Tenex. Tell your health care provider if you are taking any other medicines, especially any of the following:
This may not be a complete list of all interactions that may occur. Ask your health care provider if Tenex 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.
Use Tenex as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Ask your health care provider any questions you may have about how to use Tenex.
If you suddenly stop taking Tenex, you may experience WITHDRAWAL symptoms, including nervousness, agitation, headache, tremor, and rapid increase in blood pressure.
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:
Constipation; dizziness; drowsiness; dry mouth; tiredness.
Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); changes in heartbeat; inability to have sex; pounding in the chest.
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: Tenex side effects (in more detail)
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Accidental overdose of Tenex is an increasing cause of poisoning in children 3 years of age and younger. Symptoms may include difficult or slow breathing; drowsiness leading to unresponsiveness or coma; irritability; lightheadedness, especially upon standing; pinpoint pupils; slow heartbeat; vomiting; weakness.
Store Tenex between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Tenex out of the reach of children and away from pets.
This information is a summary only. It does not contain all information about Tenex. 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.
Ondansetron 4 mg/2 ml Solution for Injection
Each ampoule containing 2 ml solution contains 4 mg ondansetron (as ondansetron hydrochloride dihydrate). The strength of the solution is 2 mg/ml ondansetron.
For excipients, see 6.1.
Solution for injection
The aqueous solution is clear and colourless.
Ondansetron hydrochloride is indicated for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy, and for the prevention and treatment of post-operative nausea and vomiting (PONV).
Chemotherapy and radiotherapy:
Adults:
The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. The route of administration and dose of ondansetron hydrochloride should be flexible in the range of 8-32 mg a day and selected as shown below.
Emetogenic chemotherapy and radiotherapy:
Ondansetron hydrochloride can be given either by rectal, oral (tablets or syrup), intravenous or intramuscular administration.
For most patients receiving emetogenic chemotherapy or radiotherapy, ondansetron hydrochloride 8 mg should be administered as a slow intravenous or intramuscular injection immediately before treatment, followed by 8 mg orally twelve hourly.
To protect against delayed or prolonged emesis after the first 24 hours, oral or rectal treatment with ondansetron hydrochloride should be continued for up to 5 days after a course of treatment.
Highly emetogenic chemotherapy:
For patients receiving highly emetogenic chemotherapy, e.g. high-dose cisplatin, ondansetron hydrochloride can be given either by rectal, intravenous or intramuscular administration.
Ondansetron hydrochloride has been shown to be equally effective in the following dose schedules over the first 24 hours of chemotherapy:
- A single dose of 8 mg by slow intravenous or intramuscular injection immediately before chemotherapy
- A dose of 8 mg by slow intravenous or intramuscular injection immediately before chemotherapy, followed by two further intravenous or intramuscular doses of 8 mg two or four hours apart, or by a constant infusion of 1 mg/hour for up to 24 hours
- A single dose of 32 mg diluted in 50-100 ml of saline or other compatible infusion fluid (see Pharmaceutical Precautions) and infused over not less than 15 minutes immediately before chemotherapy
The selection of dose regimen should be determined by the severity of the emetogenic challenge.
The efficacy of ondansetron hydrochloride in highly emetogenic chemotherapy may be enhanced by the addition of a single intravenous dose of dexamethasone sodium phosphate, 20 mg administered prior to chemotherapy.
To protect against delayed or prolonged emesis after the first 24 hours, oral or rectal treatment with ondansetron hydrochloride should be continued for up to 5 days after a course of treatment.
Children:
Ondansetron hydrochloride may be administered as a single intravenous dose of 5 mg/m2 immediately before chemotherapy, followed by 4 mg orally twelve hours later. 4 mg orally twice daily should be continued for up to 5 days after a course of treatment.
Elderly:
Ondansetron hydrochloride is well tolerated by patients over 65 years and no alteration of dosage, dosing frequency or route of administration are required.
Patients with renal impairment:
No alteration of daily dosage, frequency of dosing or route of administration are required.
Patients with hepatic impairment:
Clearance of ondansetron hydrochloride is significantly reduced and serum half-life significantly prolonged in subjects with moderate or severe impairment of hepatic function. In such patients a total daily dose of 8 mg should not be exceeded.
Post-operative nausea and vomiting (PONV):
Adults:
For the prevention of PONV ondansetron hydrochloride can be administered orally or by intravenous or intramuscular injection.
Ondansetron hydrochloride may be administered as a single dose of 4 mg given by intramuscular or slow intravenous injection at induction of anaesthesia.
For treatment of established PONV a single dose of 4 mg given by intramuscular or slow intravenous injection is recommended.
Children (aged 2 years and over):
For prevention of PONV in paediatric patients having surgery performed under general anaesthesia, ondansetron may be administered by slow intravenous injection at a dose of 0.1 mg/kg up to a maximum of 4 mg either prior to, at or after induction of anaesthesia.
For treatment of established PONV in paediatric patients, ondansetron may be administered by slow intravenous injection at a dose of 0.1 mg/kg up to a maximum of 4 mg.
There is limited data on the use of ondansetron hydrochloride in the prevention and treatment of PONV in children under 2 years of age.
Elderly:
There is limited experience in the use of ondansetron hydrochloride in the prevention and treatment of PONV in the elderly, however ondansetron hydrochloride is well tolerated in patients over 65 years receiving chemotherapy.
Patients with renal impairment:
No alteration of daily dosage, frequency of dosing or route of administration are required.
Patients with hepatic impairment:
Clearance of ondansetron hydrochloride is significantly reduced and serum half-life significantly prolonged in subjects with moderate or severe impairment of hepatic function. In such patients a total daily dose of 8 mg should not be exceeded.
Patients with poor sparteine / debrisoquine metabolism:
The elimination half-life of ondansetron is not altered in subjects classified as poor metabolisers of sparteine and debrisoquine. Consequently in such patients repeat dosing will give drug exposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing are required.
Hypersensitivity to any component of the preparation.
Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5HT3 receptor antagonists.
As ondansetron is known to increase large bowel transit time, patients with signs of subacute intestinal obstruction should be monitored following administration.
This medicinal product contains less than 1 mmol sodium (23 mg) per ampoule, i.e. essentially 'sodium-free'.
There is no evidence that ondansetron either induces or inhibits the metabolism of other drugs commonly co-administered with it. Specific studies have shown that there are no pharmacokinetic interactions when ondansetron is administered with alcohol, temazepan, furosemide, tramadol or propofol.
Ondansetron is metabolised by multiple hepatic cytochrome P-450 enzymes: CYP3A4, CYP2D6 and CYP1A2. Due to the multiplicity of metabolic enzymes capable of metabolising ondansetron, enzyme inhibition or reduced activity of one enzyme (e.g. CYP2D6 genetic deficiency) is normally compensated by other enzymes and should result in little or no significant change in overall ondansetron clearance or dose requirement.
Phenytoin, Carbamazepine and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e. phenytoin, carbamazepine, and rifampicin), the oral clearance of ondansetron was increased and ondansetron blood concentrations were decreased.
Tramadol: Data from small studies indicate that ondansetron may reduce the analgesic effect of tramadol.
The safety of ondansetron for use in human pregnancy has not been established.
Evaluation of experimental animal studies does not indicate direct or indirect harmful effects with respect to the development of the embryo, or foetus, the course of gestation and peri- and post-natal development. However, as animal studies are not always predictive of human response, the use of ondansetron in pregnancy is not recommended.
Tests have shown that ondansetron passes into the milk of lactating animals. It is therefore recommended that mothers receiving ondansetron hydrochloride should not breast-feed their babies.
In psychomotor testing ondansetron does not impair performance nor cause sedation.
Ondansetron is known to increase large bowel transit time and may cause constipation in some patients. The following side effects can occur: headache, a sensation of flushing or warmth, hiccups and occasional asymptomatic increases in liver function tests. There have been rare reports of immediate hypersensitivity reactions sometimes severe including anaphylaxis. Rare cases of transient visual disturbances (e.g. blurred vision) and dizziness have been reported during rapid intravenous administration of ondansetron. There have been rare reports suggestive of involuntary movement disorders such as extrapyramidal reactions e.g. oculogyric crisis/dystonic reactions without definitive evidence of persistent clinical sequelae and seizures have been rarely observed although no known pharmacological mechanism can account for ondansetron causing these effects. Chest pain with or without ST segment depression, cardiac arrhythmias, hypotension and bradycardia have been rarely reported.
Occasionally, hypersensitivity reactions around the injection site (e.g. rash, urticaria, itching) may occur, sometimes extending along the drug administration vein.
Little is known at present about overdosage with ondansetron, however, a limited number of patients received overdoses. Manifestations that have been reported include visual disturbances, severe constipation, hypotension and a vasovagal episode with transient second degree AV block. In all instances, the events resolved completely. There is no specific antidote for ondansetron, therefore in all cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate.
Pharmacotherapeutic group: Antiemetics and Antinauseants – Serotonin (5HT3) antagonists, ATC code: A04A A01.
Ondansetron is a potent, highly selective 5HT3 receptor-antagonist. Its precise mode of action in the control of nausea and vomiting is not known. Chemotherapeutic agents and radiotherapy may cause release of 5HT in the small intestine initiating a vomiting reflex by activating vagal afferents via 5HT3 receptors. Ondansetron blocks the initiation of this reflex. Activation of vagal afferents may also cause a release of 5HT in the area postrema, located on the floor of the fourth ventricle, and this may also promote emesis through a central mechanism.
Thus, the effect of ondansetron in the management of the nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy is probably due to antagonism of 5HT3 receptors on neurons located both in the peripheral and central nervous system. The mechanisms of action in post-operative nausea and vomiting are not known but there may be common pathways with cytotoxic induced nausea and vomiting.
Ondansetron does not alter plasma prolactin concentrations.
The role of ondansetron in opiate-induced emesis is not yet established.
Following oral administration, ondansetron is passively and completely absorbed from the gastrointestinal tract and undergoes first pass metabolism. Peak plasma concentrations of about 30 ng/ml are attained approximately 1.5 hours after an 8 mg dose. For doses above 8 mg the increase in ondansetron systemic exposure with dose is greater than proportional; this may reflect some reduction in first pass metabolism at higher oral doses. Bioavailability, following oral administration, is slightly enhanced by the presence of food but unaffected by antacids. Studies in healthy elderly volunteers have shown slight, but clinically insignificant, age-related increases in both oral bioavailability (65%) and half-life (5 hours) of ondansetron. Gender differences were shown in the disposition of ondansetron, with females having a greater rate and extent of absorption following an oral dose and reduced systemic clearance and volume of distribution (adjusted for weight).
The disposition of ondansetron following oral, intramuscular (IM) and intravenous (IV) dosing is similar with a terminal half-life of about 3 hours and steady state volume of distribution of about 140 litres. Equivalent systemic exposure is achieved after IM and IV administration of ondansetron.
A 4 mg intravenous infusion of ondansetron given over 5 minutes results in peak plasma concentrations of about 65 ng/ml. Following intramuscular administration of ondansetron, peak plasma concentrations of about 25 ng/ml are attained within 10 minutes of injection.
Following administration of ondansetron suppository, plasma ondansetron concentrations become detectable between 15 and 60 minutes after dosing. Concentrations rise in an essentially linear fashion, until peak concentrations of 20-30 ng/ml are attained, typically 6 hours after dosing. Plasma concentrations then fall, but at a slower rate than observed following oral dosing due to continued absorption of ondansetron. The absolute bioavailability of ondansetron from the suppository is approximately 60% and is not affected by gender. The half-life of the elimination phase following suppository administration is determined by the rate of ondansetron absorption, not systemic clearance and is approximately 6 hours. Females show a small, clinically insignificant, increase in half-life in comparison with males.
Ondansetron is not highly protein bound (70-76%). Ondansetron is cleared from the systemic circulation predominantly by hepatic metabolism through multiple enzymatic pathways. Less than 5% of the absorbed dose is excreted unchanged in the urine. The absence of the enzyme CYP2D6 (the debrisoquine polymorphism) has no effect on ondansetron's pharmacokinetics. The pharmacokinetic properties of ondansetron are unchanged on repeat dosing.
In a study of 21 paediatric patients aged between 3 and 12 years undergoing elective surgery with general anaesthesia, the absolute values for both the clearance and volume of distribution of ondansetron following a single intravenous dose of 2 mg (3-7 years old) or 4 mg (8-12 years old) were reduced. The magnitude of the change was age-related, with clearance falling from about 300 ml/min at 12 years of age to 100 ml/min at 3 years. Volume of distribution fell from about 75 litres at 12 years to 17 litres at 3 years. Use of weight-based dosing (0.1 mg/kg up to 4 mg maximum) compensates for these changes and is effective in normalising systemic exposure in paediatric patients.
In patients with renal impairment (creatinine clearance 15-60 ml/min), both systemic clearance and volume of distribution are reduced following IV administration of ondansetron, resulting in a slight, but clinically insignificantly, increase in elimination half-life (5.4 h). A study in patients with severe renal impairment who required regular haemodialysis (studied between dialyses) showed ondansetron's pharmacokinetics to be essentially unchanged following IV administration.
Specific studies in the elderly or patients with renal impairment have been limited to IV and oral administration. However, it is anticipated that the half-life of ondansetron after rectal administration in these populations will be similar to that seen in healthy volunteers, since the rate of elimination of ondansetron following rectal administration is not determined by systemic clearance.
Following oral, intravenous or intramuscular dosing in patients with severe hepatic impairment, ondansetron's systemic clearance is markedly reduced with prolonged elimination half-lives (15-32 h) and oral bioavailability approaching 100% due to reduced pre-systemic metabolism. The pharmacokinetics of ondansetron following administration as a suppository have not been evaluated in patients with hepatic impairment.
No additional data of relevance.
Sodium chloride
Citric acid monohydrate
Sodium citrate
Water for injections
Ondansetron 4 mg/2 ml Solution for Injection should not be administered in the same syringe or infusion as any other medication.
12 months (unopened). 24 hours (dilutions stored at 2-8°C).
Do not store above 30°C. Keep ampoules in the outer carton.
Dilutions of Ondansetron 4 mg/2 ml Solution for Injection in compatible intravenous infusion fluids are stable under normal room lighting conditions or daylight for at least 24 hours, thus no protection from light is necessary while infusion takes place.
Ondansetron 4 mg/2 ml Solution for Injection, is contained in 2 ml Type I colourless ampoules with a green marking for the One-Point-Cut.
There are packs of 1, 2, 5, 6, 10, 25, 50 and 5x 50 ampoules.
Compatibility with intravenous fluids:
Ondansetron 4 mg/2 ml Solution for Injection should only be admixed with those infusion solutions, which are recommended:
- Sodium chloride intravenous infusion 0.9 %
- Glucose intravenous infusion 5 %
- Mannitol intravenous infusion 10 %
- Ringer's intravenous infusion
- Potassium chloride 0.3 % and sodium chloride 0.9 % intravenous infusion
- Potassium chloride 0.3 % and glucose 5 % intravenous infusion
In keeping with good pharmaceutical practice, dilutions of Ondansetron 4 mg/2 ml Solution for Injection in intravenous fluids should be prepared at the time of infusion or stored at 2-8°C for no more than 24 hours before the start of administration.
Compatibility studies have been undertaken in polyvinyl chloride infusion bags and polyvinyl chloride administration sets. It is considered that adequate stability would also be conferred by the use of polyethylene infusion bags or type I glass bottles.
Dilutions of Ondansetron 4 mg/2 ml Solution for Injection in sodium chloride 0.9 % or in glucose 5 % have been demonstrated to be stable in polypropylene syringes. It is considered that Ondansetron 4 mg/2 ml Solution for Injection diluted with other compatible infusion fluids would be stable in polypropylene syringes.
Compatibility with other drugs:
Ondansetron 4 mg/2 ml Solution for Injection may be administered by intravenous infusion at 1 mg/hour, e.g. from an infusion bag or syringe pump. The following drugs may be administered via the Y-site of the Ondansetron 4 mg/2 ml Solution for Injection giving set for ondansetron concentrations of 16 to 160 micrograms/ml (e.g. 8 mg/500 ml and 8 mg/50 ml, respectively):
Cisplatin:
Concentrations up to 0.48 mg/ml (e.g. 240 mg in 500 ml) administered over one to eight hours.
5 -Fluorouracil:
Concentrations up to 0.8 mg/ml (e.g. 2.4 g in 3 litres or 400 mg in 500 ml) administered at a rate of at least 20 ml per hour (500 ml per 24 hours). Higher concentrations of 5-fluorouracil may cause precipitation of ondansetron. The 5-flourouracil infusions may contain up to 0.045% (w/v) magnesium chloride in addition to other excipients shown to be compatible.
Carboplatin:
Concentrations in the range 0.18 mg/ml to 9.9 mg/ml (e.g. 90 mg in 500 ml to 990 mg in 100 ml), administered over ten minutes to one hour.
Etoposide:
Concentrations in the range 0.14 mg/ml to 0.25 mg/ml (e.g. 72 mg in 500 ml to 250 mg in 1 litre) administered over thirty minutes to one hour.
Ceftazidime:
Doses in the range 250 mg to 2000 mg, reconstituted with water for injections as recommended by the manufacturer (e.g. 2.5 ml for 250 mg and 10 ml for 2 g ceftazidime), and given as an intravenous bolus injection over approximately five minutes.
Cyclophosphamide:
Doses in the range 100 mg to 1 g, reconstituted with water for injections, 5 ml per 100 mg cyclophosphamide, as recommended by the manufacturer and given as an intravenous bolus injection over approximately five minutes.
Doxorubicin:
Doses in the range 10-100 mg reconstituted with water for injections, 5 ml per 10 mg doxorubicin, as recommended by the manufacturer and given as an intravenous bolus injection over approximately 5 minutes.
Dexamethasone:
Dexamethasone sodium phosphate 20 mg may be administered as a slow intravenous injection over 2-5 minutes via the Y-site of an infusion set delivering 8 or 32 mg of ondansetron diluted in 50-100 ml of a compatible infusion fluid over approximately 15 minutes. Compatibility between dexamethasone sodium phosphate and ondansetron has been demonstrated supporting administration of these drugs through the same giving set resulting in concentrations in line of 32 microgram – 2.5 mg/ml for dexamethasone sodium phosphate and 8 microgram – 1 mg/ml for ondansetron.
Hospira Enterprises B.V.
Taurusavenue 19-21
2132LS Hoofddorp
The Netherlands
PL 23061/0013
May 4th, 2006
May 29th, 2006
Generic Name: horse chestnut (HORSE CHEST nut)
Brand Names: Venastat
The use of horse chestnut in cultural and traditional settings may differ from concepts accepted by current Western medicine. When considering the use of herbal supplements, consultation with a primary health care professional is advisable. Additionally, consultation with a practitioner trained in the uses of herbal/health supplements may be beneficial, and coordination of treatment among all health care providers involved may be advantageous.
Horse chestnut is also known as Aesculus hippocastanum, Cellu-Var, Variclear, Reparil, Varicare, Varicosin, VeinAway, Venastat, and others.
Horse chestnut has been used topically to cosmetically improve the appearance of varicose veins. It has also been promoted for relief of swelling or inflammation of joints, tendons, and muscles and hemorrhoids. Horse chestnut has been used orally to improve symptoms of fatigue, and pain, nighttime cramping, itching and swelling in the legs.
Horse chestnut has not been evaluated by the FDA for safety, effectiveness, or purity. All potential risks and/or advantages of horse chestnut may not be known. Additionally, there are no regulated manufacturing standards in place for these compounds. There have been instances where herbal/health supplements have been sold which were contaminated with toxic metals or other drugs. Herbal/health supplements should be purchased from a reliable source to minimize the risk of contamination.
Horse chestnut may also have uses other than those listed in this product guide.
Horse chestnut has not been evaluated by the FDA for safety, effectiveness, or purity. All potential risks and/or advantages of horse chestnut may not be known. Additionally, there are no regulated manufacturing standards in place for these compounds. There have been instances where herbal/health supplements have been sold which were contaminated with toxic metals or other drugs. Herbal/health supplements should be purchased from a reliable source to minimize the risk of contamination.
a history of blood clots;
colitis or other stomach or intestine related illnesses;
diabetes;
vitamin K deficiency;
a bleeding or blood clotting disorder;
are taking a blood thinner such as warfarin (Coumadin);
heart disease;
low blood pressure;
poor blood circulation;
Horse chestnut may not be safe for use if you have any of the conditions listed above.
Before using horse chestnut, talk to your doctor, pharmacist, or health care professional if you have allergies (especially to plants, foods, medicines, dyes, or preservatives), have any medical condition, or if you take other medicines or other herbal/health supplements. Horse chestnut may not be recommended in some situations.
The use of horse chestnut in cultural and traditional settings may differ from concepts accepted by current Western medicine. When considering the use of herbal supplements, consultation with a primary health care professional is advisable. Additionally, consultation with a practitioner trained in the uses of herbal/health supplements may be beneficial, and coordination of treatment among all health care providers involved may be advantageous.
If you choose to use horse chestnut, use it as directed on the package or as directed by your doctor, pharmacist, or other healthcare provider.
Horse chestnut cream and gel is intended for external use only. Do not take it my mouth. Wash your hands before and after application of the topical product. Apply a thin layer of the medication to the affected area and rub it gently into the skin. Do not apply the product to the eyes, nose, mucous membranes, or broken skin.
Standardized extracts, tinctures, and solid formulations of herbal/health supplements may provide a more reliable dose of the product.
Store horse chestnut as directed on the package. In general, horse chestnut should be protected from light, heat, and moisture.
Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra horse chestnut to make up the missed dose.
an allergic reaction (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives);
bleeding (gums, nose, skin, stool, urine);
decreased amounts of urine;
joint or muscle pain;
skin rash; or
unusual bruising.
Other less serious side effects have also been reported. Talk to your doctor or pharmacist if you experience
stomach upset or heartburn; or
burning or stinging where cream or gel is applied.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
aspirin;
a nonsteroidal anti-inflammatory drug (NSAID) such as ibuprofen (Advil, Motrin, others), naproxen (Aleve, Anaprox, Naprosyn, others), ketoprofen (Orudis, Orudis KT), diclofenac (Cataflam, Voltaren), nabumetone (Relafen), etodolac (Lodine), indomethacin (Indocin), piroxicam (Feldene), oxaprozin (Daypro), and others;
clopidogrel (Plavix);
cilostazol (Pletal);
dipyridamole (Persantine, Aggrenox);
warfarin (Coumadin);
heparin, dalteparin (Fragmin), danaparoid (Orgaran), enoxaparin (Lovenox), or tinzaparin (Innohep);
feverfew;
danshen;
garlic; or
ginger.
You may not be able to take horse chestnut, 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 horse chestnut. Talk to your doctor, pharmacist, or health care professional before taking any prescription or over-the-counter medicines or other herbal/health supplements.
See also: horse chestnut side effects (in more detail)
Chemical name: (2-mercaptoethyl) trimethylammonium iodide O,O-diethyl phosphorothioate
Echothiophate iodide for ophthalmic solution occurs as a white, crystalline, water-soluble, hygroscopic solid having a slight mercaptan-like odor. When freeze-dried in the presence of potassium acetate, the mixture appears as a white amorphous deposit on the walls of the bottle.
Each package contains materials for dispensing 5 mL of eyedrops: (1) bottle containing sterile echothiophate iodide for ophthalmic solution in one of four potencies [1.5 mg (0.03%), 3 mg (0.06%), 6.25 mg (0.125%), or 12.5 mg (0.25%)] as indicated on the label, with 40 mg potassium acetate in each case. Sodium hydroxide or acetic acid may have been incorporated to adjust pH during manufacturing. (2) a 5 mL bottle of sterile diluent containing chlorobutanol (chloral derivative), 0.55%; mannitol, 1.2%; boric acid, 0.06%; and sodium phosphate, 0.026%. (3) sterilized dropper.
Echothiophate iodide for ophthalmic solution is a long-acting cholinesterase inhibitor for topical use which enhances the effect of endogenously liberated acetylcholine in iris, ciliary muscle, and other parasympathetically innervated structures of the eye. It thereby causes miosis, increase in facility of outflow of aqueous humor, fall in intraocular pressure, and potentiation of accommodation.
Echothiophate iodide for ophthalmic solution will depress both plasma and erythrocyte cholinesterase levels in most patients after a few weeks of eyedrop therapy.
Chronic open-angle glaucoma. Subacute or chronic angle-closure glaucoma after iridectomy or where surgery is refused or contraindicated. Certain non-uveitic secondary types of glaucoma, especially glaucoma following cataract surgery.
Concomitant esotropias with a significant accommodative component.
1. Succinylcholine should be administered only with great caution, if at all, prior to or during general anesthesia to patients receiving anticholinesterase medication because of possible respiratory or cardiovascular collapse.
2. Caution should be observed in treating glaucoma with echothiophate iodide for ophthalmic solution in patients who are at the same time undergoing treatment with systemic anticholinesterase medications for myasthenia gravis, because of possible adverse additive effects.
(See “PRECAUTIONS, Drug Interactions” for further information.)
1. Gonioscopy is recommended prior to initiation of therapy. Routine examination to detect lens opacity should accompany clinical use of echothiophate iodide for ophthalmic solution.
2. Where there is a quiescent uveitis or a history of this condition, anticholinesterase therapy should be avoided or used cautiously because of the intense and persistent miosis and ciliary muscle contraction that may occur.
3. While systemic effects are infrequent, proper use of the drug requires digital compression of the nasolacrimal ducts for a minute or two following instillation to minimize drainage into the nasal chamber with its extensive absorption area. To prevent possible skin absorption, hands should be washed following instillation.
4. Temporary or permanent discontinuance of medication is necessary if cardiac irregularities occur.
5. Anticholinesterase drugs should be used with extreme caution, if at all, in patients with marked vagotonia, bronchial asthma, spastic gastrointestinal disturbances, peptic ulcer, pronounced bradycardia and hypotension, recent myocardial infarction, epilepsy, parkinsonism, and other disorders that may respond adversely to vagotonic effects.
6. Anticholinesterase drugs should be employed prior to ophthalmic surgery only as a considered risk because of the possible occurrence of hyphema.
7. Echothiophate iodide for ophthalmic solution should be used with great caution, if at all, where there is a prior history of retinal detachment.
8. Temporary discontinuance of medication is necessary if salivation, urinary incontinence, diarrhea, profuse sweating, muscle weakness, or respiratory difficulties occur.
9. Patients receiving echothiophate iodide for ophthalmic solution who are exposed to carbamate- or organophosphate-type insecticides and pesticides (professional gardeners, farmers, workers in plants manufacturing or formulating such products, etc.) should be warned of the additive systemic effects possible from absorption of the pesticide through the respiratory tract or skin. During periods of exposure to such pesticides, the wearing of respiratory masks, and frequent washing and clothing changes may be advisable.
Echothiophate iodide for ophthalmic solution potentiates other cholinesterase inhibitors such as succinylcholine or organophosphate and carbamate insecticides. Patients undergoing systemic anticholinesterase treatment should be warned of the possible additive effects of echothiophate iodide for ophthalmic solution.
No data is available regarding carcinogenesis, mutagenesis, and impairment of fertility.
Animal reproduction studies have not been conducted with echothiophate iodide for ophthalmic solution. It is also not known whether echothiophate iodide for ophthalmic solution can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Echothiophate iodide for ophthalmic solution should be given to a pregnant woman only if clearly needed.
Because of the potential for serious adverse reactions in nursing infants from echothiophate iodide for ophthalmic solution, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness in pediatric patients have been established.
No overall differences in safety or effectiveness have been observed between elderly and younger patients.
1. Although the relationship, if any, of retinal detachment to the administration of echothiophate iodide for ophthalmic solution has not been established, retinal detachment has been reported in a few cases during the use of echothiophate iodide for ophthalmic solution in adult patients without a previous history of this disorder.
2. Stinging, burning, lacrimation, lid muscle twitching, conjunctival and ciliary redness, browache, induced myopia with visual blurring may occur.
3. Activation of latent iritis or uveitis may occur.
4. Iris cysts may form, and if treatment is continued, may enlarge and obscure vision. This occurrence is more frequent in children. The cysts usually shrink upon discontinuance of the medication, reduction in strength of the drops or frequency of instillation. Rarely, they may rupture or break free into the aqueous. Regular examinations are advisable when the drug is being prescribed for the treatment of accommodative esotropia.
5. Prolonged use may cause conjunctival thickening, obstruction of nasolacrimal canals.
6. Lens opacities occurring in patients under treatment for glaucoma with echothiophate iodide for ophthalmic solution have been reported and similar changes have been produced experimentally in normal monkeys. Routine examinations should accompany clinical use of the drug.
7. Paradoxical increase in intraocular pressure may follow anticholinesterase instillation. This may be alleviated by prescribing a sympathomimetic mydriatic such as phenylephrine.
2. Tear off aluminum seals, and remove and discard rubber plugs from both drug and diluent containers.
3. Pour diluent into drug container.
4. Remove dropper assembly from its sterile wrapping. Holding dropper assembly by the screw cap and, WITHOUT COMPRESSING RUBBER BULB, insert into drug container and screw down tightly.
5. Shake for several seconds to ensure mixing.
6. Do not cover nor obliterate instructions to patient regarding storage of eyedrops.
Selection of Therapy – The medication prescribed should be that which will control the intraocular pressure around-the-clock with the least risk of side effects or adverse reactions. “Tonometric glaucoma” (ocular hypertension without other evidence of the disease) is frequently not treated with any medication, and echothiophate iodide for ophthalmic solution is certainly not recommended for this condition. In early chronic simple glaucoma with field loss or disc changes, pilocarpine is generally used for initial therapy and can be recommended so long as control is thereby maintained over the 24 hours of the day.
When this is not the case, echothiophate iodide for ophthalmic solution 0.03% may be effective and probably has no greater potential for side effects. If this dosage is inadequate, epinephrine and a carbonic anhydrase inhibitor may be added to the regimen. When still more effective medication is required, the higher strengths of echothiophate iodide for ophthalmic solution may be prescribed with the recognition that the control of the intraocular pressure should have priority regardless of potential side effects. In secondary glaucoma following cataract surgery, the higher strengths of the drug are frequently needed and are ordinarily very well tolerated.
The dosage regimen prescribed should call for the lowest concentration that will control the intraocular pressure around-the-clock. Where tonometry around-the-clock is not feasible, it is suggested that appointments for tension-taking be made at different times of the day so that inadequate control may be more readily detected. Two doses a day are preferred to one in order to maintain as smooth a diurnal tension curve as possible, although a single dose per day or every other day has been used with satisfactory results. Because of the long duration of action of the drug, it is never necessary or desirable to exceed a schedule of twice a day. The daily dose or one of the two daily doses should always be instilled just before retiring to avoid inconvenience due to the miosis.
Early Chronic Simple Glaucoma – Echothiophate iodide for ophthalmic solution 0.03% instilled twice a day, just before retiring and in the morning, may be prescribed advantageously for cases of early chronic simple glaucoma that are not controlled around-the-clock with other less potent agents. Because of prolonged action, control during the night and early morning hours may then sometimes be obtained. A change in therapy is indicated if, at any time, the tension fails to remain at an acceptable level on this regimen.
Advanced Chronic Simple Glaucoma and Glaucoma Secondary to Cataract Surgery – These cases may respond satisfactorily to echothiophate iodide for ophthalmic solution 0.03% twice a day as above. When the patient is being transferred to echothiophate iodide for ophthalmic solution because of unsatisfactory control with pilocarpine, carbachol, epinephrine, etc., one of the higher strengths, 0.06%, 0.125%, or 0.25% will usually be needed. In this case, a brief trial with the 0.03% eyedrops will be advantageous in that the higher strengths will then be more easily tolerated.
Concomitant Therapy – Echothiophate iodide for ophthalmic solution may be used concomitantly with epinephrine, a carbonic anhydrase inhibitor, or both.
Technique – Good technique in the administration of echothiophate iodide for ophthalmic solution requires that finger pressure at the inner canthus should be exerted for a minute or two following instillation of the eyedrops, to minimize drainage into the nose and throat. Excess solution around the eye should be removed with tissue and any medication on the hands should be rinsed off.
In Diagnosis – One drop of 0.125% may be instilled once a day in both eyes on retiring, for a period of two or three weeks. If the esotropia is accommodative, a favorable response will usually be noted which may begin within a few hours.
In Treatment – Echothiophate iodide for ophthalmic solution is prescribed at the lowest concentration and frequency which gives satisfactory results. After the initial period of treatment for diagnostic purposes, the schedule may be reduced to 0.125% every other day or 0.06% every day. These dosages can often be gradually lowered as treatment progresses. The 0.03% strength has proven to be effective in some cases. The maximum usually recommended dosage is 0.125% once a day, although more intensive therapy has been used for short periods.
Technique – (See “DOSAGE AND ADMINISTRATION, Glaucoma.”)
Duration of Treatment – In diagnosis, only a short period is required and little time will be lost in instituting other procedures if the esotropia proves to be unresponsive. In therapy, there is no definite limit so long as the drug is well tolerated. However, if the eyedrops, with or without eyeglasses, are gradually withdrawn after about a year or two and deviation recurs, surgery should be considered. As with other miotics, tolerance may occasionally develop after prolonged use. In such cases, a rest period will restore the original activity of the drug.
Each package contains sterile echothiophate iodide for ophthalmic solution, sterile diluent, and dropper for dispensing 5 mL eyedrops of the strength indicated on the label. Four potencies are available:
NDC 0046-1062-05 . . . . . . . . . . . . . . . . . 1.5 mg package for 0.03%
White amorphous deposit on bottle walls. Aluminum crimp seal is blue.
NDC 0046-1064-05 . . . . . . . . . . . . . . . . . 3 mg package for 0.06%
White amorphous deposit on bottle walls. Aluminum crimp seal is red.
NDC 0046-1065-05 . . . . . . . . . . . . . . . . . 6.25 mg package for 0.125%
White amorphous deposit on bottle walls. Aluminum crimp seal is green.
NDC 0046-1066-05 . . . . . . . . . . . . . . . . . 12.5 mg package for 0.25%
White amorphous deposit on bottle walls. Aluminum crimp seal is yellow.
Prior to reconstitution: Store under refrigeration (2° to 8° C).
After reconstitution: Store at room temperature (approximately 25° C). Do not refrigerate. Discard any unused solution after 4 weeks.
| This product's label may have been updated. For current package insert and further product information, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. |
PACKAGE LABEL - PRINCIPAL DISPLAY - 5 ML - DILUENT LABEL
(echothiophate iodide for ophthalmic solution)
PACKAGE LABEL - PRINCIPAL DISPLAY - 6.25 MG/5 ML - LABEL
(echothiophate iodide for ophthalmic solution)
Each 5 mL contains 6.25 mg of echothiophate iodide
With 40 mg Potassium Acetate for preparing 5 mL eyedrops.
See accompanying descriptive literature.
PACKAGE LABEL - PRINCIPAL DISPLAY - 6.25 MG/5 ML - CARTON
(echothiophate iodide for ophthalmic solution)
This package contains sterile echothiophate iodide with 40 mg potassium acetate (sodium hydroxide or acetic acid may have been incorporated to adjust pH during manufacturing) and 5 mL (1/6 fl oz) sterile aqueous diluent, in individual bottles for dispensing 5 mL of eyedrops of strength shown when reconstituted.
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| NDA | NDA011963 | 12/04/1959 | |
| Labeler - Wyeth Pharmaceuticals Inc. (828831441) |
Piperacillin/Tazobactam 4 g/0.5 g Powder for Solution for Injection or Infusion.
Each vial contains 4 g piperacillin (as sodium salt) and 0.5 g tazobactam (as sodium salt).
One vial of powder for solution for injection or infusion contains 9.44 mmol (217 mg) of sodium.
For a full list of excipients see section 6.1.
Powder for solution for injection or infusion.
White to off white powder.
Piperacillin/Tazobactam is indicated for the treatment of moderate to severe systemic and/or local bacterial infections in which betalactamase producing bacteria are suspected or have been detected, such as:
Adults/Adolescents and the Elderly
Nosocomial pneumonia
Complicated urinary tract infections ( including pyelonephritis)
Intra-abdominal infections
Skin and soft tissue infections
Bacterial infections in neutropenic adults
Children (2-12 years)
Bacterial infections in neutropenic children.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Piperacillin/Tazobactam may be given by slow intravenous injection (over at least three to five minutes) or by slow intravenous infusion (over 20-30 minutes).
For reconstitution instructions, see section 6.6.
The treatment of mixed infections caused by piperacillin susceptible organisms and betalactamase producing organisms susceptible to Piperacillin/Tazobactam generally do not require the addition of another antibiotic.
In patients with nosocomial pneumonia and infections in neutropenic patients Piperacillin/Tazobactam can be used with an aminoglycoside. If the use of an aminoglycoside is needed with piperacillin/tazobactam, both Piperacillin/Tazobactam and the aminoglycoside must be used in completely therapeutic doses.
Neutropenic patients with signs of infection (e.g. fever) should receive immediate empirical antibiotic therapy before laboratory results are available.
Adults and Children Over 12 Years, Each with Normal Renal Function
The usual dosage for adults and children over 12 years is Piperacillin/Tazobactam 4000/500 mg given every eight hours.
The total daily dose of Piperacillin/Tazobactam depends on the severity and localisation of the infection and can vary from Piperacillin/Tazobactam 2000/250 mg to Piperacillin/Tazobactam 4000/500 mg administered every six or eight hours.
In neutropenia the recommended dose is Piperacillin/Tazobactam 4000/500mg given every six hours in combination with an aminoglycoside.
Elderly with Normal Renal Function
Piperacillin/Tazobactam may be used at the same dose levels as adults except in cases of renal impairment (see below):
Renal Insufficiency in Adults, the Elderly and Children (over 40kg) Receiving the Adult Dose
In patients with renal insufficiency, the intravenous dose should be adjusted to the degree of actual renal impairment. The suggested daily doses are as follows:
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For patients on haemodialysis, the maximum daily dose is Piperacillin/Tazobactam 8/1 g. In addition, because haemodialysis removes 30%-50% of piperacillin in four hours, one additional dose of Piperacillin/Tazobactam 2000/250 mg should be administered following each dialysis period.
For patients with renal failure and hepatic insufficiency, measurement of serum levels of Piperacillin/Tazobactam will provide additional guidance for adjusting dosage.
Children Aged 2-12 Years with Normal Renal Function
Piperacillin/Tazobactam is only recommended for the treatment of children with neutropenia.
Neutropenia
For children weighing less than 40kg the dose should be adjusted to 90 mg/kg (Piperacillin/Tazobactam 80/10 mg) administered every six hours, in combination with an aminoglycoside, not exceeding Piperacillin/Tazobactam 4000/500 mg every six hours.
Renal Insufficiency in Children Aged 2-12 Years (or bodyweight less than 40kg)
In children with renal insufficiency the intravenous dosage should be adjusted to the degree of actual renal impairment as follows:
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For children weighing < 50kg on haemodialysis the recommended dose is 45mg (Piperacillin/Tazobactam 40/5 mg) /kg every eight hours.
The above dosage modifications are only an approximation. Each patient must be monitored closely for signs of drug toxicity. Drug dose and interval should be adjusted accordingly.
Children under 2 years
Piperacillin/tazobactam is not recommended for use in children below 2 years old due to insufficient data on safety.
Hepatic Impairment
No dose adjustment is necessary.
Duration of Therapy
The duration of therapy should be guided by the severity of the infection and the patient's clinical and bacteriological progress.
In acute infections, treatment with Piperacillin/Tazobactam should be continued for 48 hours beyond the resolution of clinical symptoms or the fever.
Hypersensitivity to piperacillin or any of the beta-lactam antibiotics and to tazobactam or any other beta-lactamase inhibitor.
Warnings
Serious and occasionally fatal hypersensitivity (anaphylactic / anaphylactoid [including shock]) reactions have been reported in patients receiving therapy with penicillins including Piperacillin/Tazobactam. These reactions are more likely to occur in persons with a history of sensitivity to multiple allergens.
There have been reports of patients with a history of penicillin hypersensitivity who have experienced severe reactions when treated with a cephalosporin. If an allergic reaction occurs during therapy with Piperacillin/Tazobactam, the antibiotic should be discontinued. Serious hypersensitivity reactions may require adrenaline and other emergency measures.
Before initiating therapy with Piperacillin/Tazobactam, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, and other allergens.
In case of severe, persistent diarrhoea, the possibility of antibiotic-induced, life threatening pseudomembranous colitis must be taken into consideration. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment. Therefore, Piperacillin/Tazobactam must be discontinued immediately in such cases, and suitable therapy should be initiated. .
Precautions
Leukopenia and neutropenia may occur, especially during prolonged therapy. Therefore, periodic assessment of a full blood count should be performed.
Periodic assessment of organ system functions including renal and hepatic during prolonged therapy is advisable.
Bleeding manifestations have occurred in some patients receiving β-lactam antibiotics. These reactions have sometimes been associated with abnormalities of coagulation tests such as clotting time, platelet aggregation and prothrombin time, and are more likely to occur in patients with renal failure. If bleeding manifestations occur, the antibiotic should be discontinued and appropriate therapy instituted.
The possibility of the emergence of resistant organisms, which might cause superinfections, should be kept in mind, particularly during prolonged treatment. Microbiological follow-up may be required to detect any important superinfection. If this occurs, appropriate measures should be taken.
Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously.
This medicinal product contains 9.44 mmol (217 mg) of sodium per vial of powder for solution for injection or infusion.. To be taken into account by patients on a controlled sodium diet.
Hypokalaemia may occur in patients with low potassium reserves or who are receiving concomitant medications that may lower potassium levels; periodic electrolyte determinations should be performed in such patients. Modest elevation of indices of liver function may be observed.
Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients (see also 4.8).
Until further experience is available, Piperacillin/Tazobactam should not be used in children who do not have neutropenia.
Interaction with probenecid:
Concurrent administration of probenecid and Piperacillin/Tazobactam produced a longer half-life and lower renal clearance for both piperacillin and tazobactam. However, peak plasma concentrations of either drug are unaffected.
Interaction with antibiotics:
No clinically relevant adverse pharmacokinetic interaction with tobramycin or vancomycin has been observed in healthy adults with a normal renal function. The clearance of tobramycin and gentamicin was enhanced in patients with severe renal dysfunction using Piperacillin/Tazobactam. In these patients mixing of Piperacillin/Tazobactam formulation with tobramycin and gentamicin was excluded.
For information related to the administration of Piperacillin/Tazobactam with aminoglycosides please refer to section 6.2.
Interaction with anticoagulants:
During simultaneous administration of heparin, oral anticoagulants and other drugs which may affect the blood coagulation system including thrombocyte function, appropriate coagulation tests should be performed more frequently and monitored regularly.
Interaction with vecuronium:
Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Due to their similar mechanism of action, it is expected that the neuromuscular blockade produced by any of the non-polarizing muscle relaxants could be prolonged in the presence of piperacillin. This should be taken into account when piperacillin/tazobactam is used peri-operatively.
Interaction with methotrexate:
Piperacillin may reduce the excretion of methotrexate. Serum levels of methotrexate should be monitored in patients on methotrexate therapy.
Interaction with laboratory test results:The administration of Piperacillin/Tazobactam may result in a false-positive reaction for glucose in the urine using a copper-reduction method. It is recommended that glucose tests based on enzymatic glucose oxidase reaction be used.
There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving Piperacillin-Tazobactam injection who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving Piperacillin-Tazobactam should be interpreted cautiously and confirmed by other diagnostic methods.
There are no adequate and well-controlled studies with Piperacillin-Tazobactam in combination or with piperacillin or tazobactam alone in pregnant women. Studies in animals have shown reproductive toxicity (see 5.3). Piperacillin and tazobactam cross the placenta. Piperacillin/Tazobactam should only be used during pregnancy if clearly indicated.
Piperacillin is excreted in low concentrations in breast milk Tazobactam concentrations in human milk have not been studied. The effect on the suckling infant is unknown. Women who are breast-feeding should be treated only ifclearly indicated. Diarrhoea and fungal infections of the mucous membranes as well as sensitisation could occur in the breast-fed infant.
No studies on the effects on the ability to drive and use machines have been performed.
However, side effects may occur (see also 4.8), which may influence the ability to drive and use machines.
Undesirable effects are listed by frequency as follows: Very common (
The most commonly reported adverse reactions are diarrhoea, nausea, vomiting, and rash, each having a frequency of
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The administration of high doses of beta-lactams, particularly in patients with renal insufficiency, can lead to encephalopathies (consciousness fluctuation, myoclonus and convulsions).
Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.
Symptoms
There have been post-marketing reports of overdose with Piperacillin/Tazobactam. The majority of those events experienced including nausea, vomiting, and diarrhoea have also been reported with the usual recommended dosages. Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure).
Treatment of Intoxication
In the event of an overdose, Piperacillin/Tazobactam treatment should be discontinued.
No specific antidote is known.
Treatment should be supportive and symptomatic according to the patient's clinical presentation. In the event of an emergency, all required intensive medical measures are indicated as in the case of piperacillin.
Excessive serum concentrations of either piperacillin or tazobactam will be reduced by haemodialysis (for more details see section 5.2).
Pharmacotherapeutic group: Combinations of penicillins, including beta-lactamase inhibitors.
ATC Classification: J01CR05
Mechanism of action:
Piperacillin, a broad spectrum, semisynthetic penicillin active against many Gram-positive and Gram-negative aerobic and anaerobic bacteria, exerts bactericidal activity by inhibition of both septum and cell wall synthesis. Tazobactam, a triazolylmethyl penicillanic acid sulphone, is a potent inhibitor of many beta-lactamases, in particular the plasmid mediated enzymes which commonly cause resistance to penicillins and cephalosporins including third-generation cephalosporins. The presence of tazobactam in the Piperacillin/Tazobactam formulation enhances and extends the antibiotic spectrum of piperacillin to include many beta-lactamase producing bacteria normally resistant to it and other beta-lactam antibiotics. Thus, Piperacillin/Tazobactam combines the properties of a broad spectrum antibiotic and a beta-lactamase inhibitor.
Mechanism of resistance:
The presence of tazobactam expands the spectrum of activity of piperacillin to include microorganisms that would otherwise, due to the formation of beta-lactamase, be resistant to piperacillin and other beta-lactam antibiotics. In vitro investigation has demonstrated that the type I beta-lactamase inducing ability of tazobactam is insignificant with regard to Gram-negative bacteria. In vitro studies have demonstrated a synergetic effect of Piperacillin/Tazobactam and aminoglycosides against Pseudomonas aeruginosa and other bacteria, including beta-lactamase producing strains.
Breakpoints
The minimum inhibitory concentration (MIC) breakpoints separating susceptible, intermediately susceptible and resistant organisms have been defined as follows:
EUCAST clinical MIC breakpoints 2008 (version 1.2):
For susceptibility testing purposes, the concentration of tazobactam is fixed at 4 mg/L
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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.
Commonly susceptible species
Gram positive aerobes
Brevibacterium spp
Enterococcus faecalis
Listeria monocytogenes
Staphylococcus spp. methicillin-sensitive
Streptococcus pneumoniae
Streptococcus pyogenes
Group B streptococci
Streptococcus spp*
Gram negative aerobes
Branhamella catarrhalis
Citrobacter koseri
Haemophilus influenzae*
Haemophilus spp.
Proteus mirabilis
Salmonella spp.
Shigella spp.
Gram positive anaerobes
Clostridium spp.
Eubacterium spp.
Peptococcus spp.
Peptostreptococcus spp.
Gram negative anaerobes
Bacteroides fragilis*
Bacteroides fragilis group
Fusobacterium spp.
Porphyromonas spp.
Prevotella spp*
Species for which resistance may be a problem
Gram positive aerobes
Staphylococcus aureus, methicillin-sensitive
Staphylococcus epidermis, methicillin-sensitive
Enterococcus avium ($)
Enterococcus faecium (+ $)
Propionibacterium acnes ($)
Viridans streptococci
Gram negative aerobes
Actinobacter spp (+ $)
Burkholderia cepacia
Citrobacter freundii
Enterobacter spp.
Escherichia coli *
Klebsiella spp.
Proteus, indole positive
Pseudomonas aeruginosa*
Pseudomonas spp. *
Pseudomonas stutzeri $
Serratia spp.
Gram negative anaerobes
Bacteroides spp. *
Inherently resistant organisms
Gram positive aerobes
Corynebacterium jeikeium
Staphylococcus spp. methicillin resistant
Gram negative aerobes
Legionella spp
Stenotrophomonas maltophilia +$
* Clinical effectiveness against this has been demonstrated in the registered indications.
($) Species showing natural intermediate susceptibility
(+) Species for which high resistance rates (more than 50%) have been observed in one or more areas/countries/regions within the EU.
Distribution
Peak piperacillin and tazobactam plasma concentrations are attained immediately after completion of an intravenous infusion or injection. Piperacillin plasma levels produced when given with tazobactam are similar to those attained when equivalent doses of piperacillin are administered alone.
There is a greater proportional (approximately 28%) increase in plasma levels of piperacillin and tazobactam with increasing dose over the dosage range of Piperacillin/Tazobactam 2000/250 mg to Piperacillin/Tazobactam 4000/500 mg.
Both piperacillin and tazobactam are 20 to 30% bound to plasma proteins. The protein binding of either piperacillin or tazobactam is unaffected by the presence of the other compound. Protein binding of the tazobactam metabolite is negligible.
Piperacillin/Tazobactam is widely distributed in tissue and body fluids including intestinal mucosa, gallbladder, lung, bile and bone.
Biotransformation
Piperacillin is metabolised to a minor microbiologically active desethyl metabolite. Tazobactam is metabolised to a single metabolite, which has been found to be micro-biologically inactive.
Elimination
Piperacillin and tazobactam are eliminated by the kidney via glomerular filtration and tubular secretion.
Piperacillin is excreted rapidly as unchanged drug with 68% of the administered dose appearing in the urine. Tazobactam and its metabolite are eliminated primarily by renal excretion with 80% of the administered dose appearing as unchanged drug and the remainder as the single metabolite. Piperacillin, tazobactam, and desethyl piperacillin are also secreted into the bile.
Following single or multiple doses of Piperacillin/Tazobactam to healthy subjects, the plasma half-life of piperacillin and tazobactam ranged from 0.7 to 1.2 hours and was unaffected by dose or duration of infusion. The elimination half-lives of both piperacillin and tazobactam are increased with decreasing renal clearance.
There are no significant changes in piperacillin pharmacokinetics due to tazobactam. Piperacillin appears to reduce the rate of elimination of tazobactam.
Impaired Renal Function
Piperacillin and tazobactam are haemodialysable: 31% (piperacillin) and 39% (tazobactam) of administered doses are filtrated. During peritoneal dialysis, 5% of administered piperacillin and 12% of administered tazobactam are found in the dialysis liquid. Patients treated by chronic ambulatory peritoneal dialysis should receive the same dose as non dialysed patients with severe renal insufficiency.
Impaired Liver Function
Plasma concentrations of piperacillin and tazobactam are prolonged in hepatically impaired patients. The half-life of piperacillin and of tazobactam increases by approximately 25% and 18%, respectively, in patients with hepatic cirrhosis compared to healthy subjects. However, dosage adjustments in patients with hepatic impairment are not necessary.
Paediatric patients
The pharmacokinetics of Piperacillin/Tazobactam has been studied in paediatric patients with intra-abdominal infections and other kinds of infections. In every age group, renal fraction of elimination of piperacillin and tazobactam was approximately 70% and 80%, respectively, like in adults.
Mean pharmacokinetic parameters of Piperacillin/Tazobactam of paediatric patients of different age groups.
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Preclinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity and genotoxicity. Carcinogenicity studies have not been conducted with Piperacillin/Tazobactam.
A fertility study of Piperacillin/Tazobactam reported a decrease in litter size and an increase in fetuses with ossification delays and variations of ribs following i.p. administration to rats. Fertility of the F1 generation and embryonic development of the F2 generation was not impaired. A teratogenicity study in rats, did not show teratogenic effects after i.v. administration. In the rat, effects on the embryonic development were observed at maternal toxic doses. Peri/postnatal development was impaired (reduced fetal weights, increase in pup mortality, increase in stillbirths) concurrently with maternal toxicity after i.p. administration in the rat.
None
Whenever Piperacillin/Tazobactam is used concurrently with another antibiotic (e.g. aminoglycosides), the drugs must be administered separately. The mixing of Piperacillin/Tazobactam with an aminoglycoside in vitro can result in substantial inactivation of the aminoglycoside.
Piperacillin/Tazobactam should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established.
Piperacillin/Tazobactam should be administered through an infusion set separately from any other drugs unless compatibility is proven.
Because of chemical instability, Piperacillin/Tazobactam should not be used with solutions containing only sodium bicarbonate.
Lactated Ringer's solution is not compatible with Piperacillin/Tazobactam.
Piperacillin/Tazobactam should not be added to blood products or albumin hydrolysates
Unopened - 3 years
When reconstituted with water for injections or saline, reconstituted solutions will remain stable for 24 hours at 25°C and for 48 hours at 4°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.
Unopened: Do not store above 25°C.
After reconstitution: Store at 2-8oC (see 6.3 Shelf Life).
Packs of one two, five and ten* Type II glass vial with butyl rubber stopper and aluminium/plastic seal
*Not all pack sizes may be marketed.
Intravenous Injection
Each vial of Piperacillin/Tazobactam 4 g/0.5 g Powder for Solution for Injection or Infusion should be reconstituted with 20ml of one of the following diluents:
• Sterile water for injections
• 0.9% sodium chloride for injection
Swirl until dissolved. Intravenous injection should be given over at least three to five minutes.
Intravenous Infusion
Each vial of Piperacillin/Tazobactam 4 g/0.5 g Powder for Solution for Injection or Infusion should be reconstituted with 20ml of one of the above diluents.
The reconstituted solution should be further diluted to at least 50ml with one of the reconstitution diluents, or with Dextrose 5% in Water.
Displacement Volume
Each gram of Piperacillin/Tazobactam 4 g/0.5 g Powder for Solution for Injection or Infusion has a displacement volume of 0.7ml.
Piperacillin/Tazobactam 4 g/0.5 g Powder for Solution for Injection or Infusion will displace 3.15ml.
The reconstitution/dilution is to be made under aseptic conditions. The solution is to be inspected visually for particulate matter and discoloration prior to administration. The solution should only be used if the solution is clear and free from particles.
Any unused product or waste material should be disposed of in accordance with local requirements.
Wockhardt UK Limited
Ash Road North
Wrexham LL13 9UF
United Kingdom
PL 29831/0341
PA 1339/1/2
17 April 2009
