Thursday, 30 August 2012

Emeside Syrup (Blackcurrant)





1. Name Of The Medicinal Product



Emeside Syrup (Blackcurrant)


2. Qualitative And Quantitative Composition



Ethosuximide 5% (250 mg/5 mL)



3. Pharmaceutical Form



Elixir for oral use.



4. Clinical Particulars



4.1 Therapeutic Indications



Emeside gives selective control of absence seizures (petit mal) even when complicated by grand-mal. It is also indicated for myoclonic seizures.



4.2 Posology And Method Of Administration



Adults, the Elderly and Children over 6 Years : Start with a small dose - 500mg daily with increments of 250mg every five to seven days until control is achieved with 1000 - 1500 mg daily. Occasionally 2000 mg in divided doses may be necessary.



Children and Infants under 6 years : Begin with a daily dose of 250 mg ( 5 ml ) and increase the dose gradually by small increments every few days until control is achieved. The optimal dose in most children is 20mg/Kg/day. The maximum dose should be 1000 mg.



Effective plasma levels of ethosuximide normally lie between 40 and 100 mcg per ml, but the clinical response should be the criteria for the regulation of the dosage. The half-life of ethosuximide in the plasma is more than 24 hours but the daily dose if large is more comfortably divided between morning and evening.



Larger children and adults will normally take Emeside in capsule form.



4.3 Contraindications



Known hypersensitivity to succinimides. Porphyrias.



4.4 Special Warnings And Precautions For Use



Use with caution in hepatic or renal impairment. Monitor liver/renal function and ethosuximide concentrations.



If Emeside is being substituted for another anti-epileptic drug the latter must not be withdrawn abruptly but the replacement made gradually with overlap of the preparations otherwise petit mal may break through.



Emeside should always be withdrawn slowly.



It is advisable to brush the teeth or rinse the mouth after taking Emeside syrup.



4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction



The plasma concentrations of ethosuximide may be reduced by carbamazepine, primidone, phenobarbitone and lamotrigine and increased by isoniazide. No consistent changes in levels of ethosuximide occur when used in combination with phenytoin or sodium valproate.



Phenytoin levels however are increased by concomitant ethosuximide.



4.6 Pregnancy And Lactation



Ethosuximide may be excreted into breast milk. Mothers receiving the drug should not breast feed. There is a recognised small increase in the incidence of congenital malformations in children born to mothers receiving anti-convulsants. For women planning pregnancy or who are already pregnant the risk should be weighed carefully against the benefit of treatment.



4.7 Effects On Ability To Drive And Use Machines



Patients should be cautioned that ethosuximide may cause drowsiness and if this occurs should avoid driving or operating machinery.



4.8 Undesirable Effects



Blood dyscrasias (leucopoenia, agranulocytosis, aplastic anaemia, and pancytopaenia) have been reported, some with fatal outcome. In most cases of leucopoenia the blood picture has returned to normal on reduction of dose or discontinuation. In some instances, patients who become leucopenic on other anticonvulsant therapy have been satisfactorily treated with ethosuximide alone. Elevated neutrophil, monocyte and eosinophil counts have also been noted. Patients should be advised to seek immediate medical attention, for full blood count tests, if symptoms such as fever, sore throat, mouth ulcers, bruising or bleeding develop.



Ethosuximide when used alone in mixed types of epilepsy may increase the frequency of generalised tonic-clonic (grand mal) seizures in some patients.



Other adverse reactions reported include: weight loss, diarrhoea, abdominal pain, gum hypertrophy, swelling of the tongue, hiccoughs, irritability, hyperactivity, sleep disturbances, night terrors, inability to concentrate, aggressiveness, paranoid psychosis, increased libido, myopia, and vaginal bleeding.



Mild side effects, common at first but generally transient, include apathy, euphoria, fatigue, drowsiness, dizziness, headache, ataxia, dyskinesia, photophobia, depression and nausea, vomiting, anorexia, and gastric upset.



Psychotic states thought to be induced or exacerbated by anticonvulsant therapy have been reported.



Rarely cases of skin rash and isolated cases of erythema nodosum have been reported. Lupus-like reactions have occasionally been reported in children given ethosuximide, varying from severe systemic immunological disorders, eg the nephrotic syndrome generally with complete recovery on drug withdrawal, to the detection of antinuclear antibodies without clinical features. Stevens Johnson syndrome has also been reported.



4.9 Overdose



Where more than 2g has been thought to be ingested gastric lavage may be employed, if the time lapse is less than four hours. Routine observation of respiration and circulation will indicate the need for supportive measures.



5. Pharmacological Properties



5.1 Pharmacodynamic Properties



Ethosuximide gives selective control of absence seizures (petit-mal) even when complicated by grand-mal. It is also indicated for myoclonic seizures. Compared to other anti-convulsants, ethosuximide is more specific for pure petit-mal.



The reduction of seizure frequency is thought to be achieved by depression of the motor cortex and elevation of the threshold to convulsive stimuli as seen by the suppression of the characteristic spike and wave EEG pattern.



5.2 Pharmacokinetic Properties



Ethosuximide is readily absorbed from the gastro-intestinal tract and extensively metabolised in the liver. It is excreted in the urine mainly in the form of its metabolites. It is widely distributed throughout the body but is not significantly bound to plasma proteins so saliva concentrations may be useful for monitoring. Peak serum levels occur 1 to 7 hours after single oral dose. Therapeutic levels are between 40 and 100 mcg/ml. It has a long elimination half-life: adults: 40 – 60 hours; children 30 hours.



5.3 Preclinical Safety Data



None stated.



6. Pharmaceutical Particulars



6.1 List Of Excipients



Other Substances









Sucrose


61 % w/v




Saccharine sodium




0.044 % w/v




Water




to 100 %



Colouring, Flavouring and Perfume Compounds






Blackcurrant Juice




7.8 % v/v



6.2 Incompatibilities



Carbamazepine, phenytoin, sodium valproate, or isoniazid.



6.3 Shelf Life



5 years.



6.4 Special Precautions For Storage



Store at ambient temperature.



6.5 Nature And Contents Of Container



200 ml amber glass bottle with plastic cap with polycone liner.



6.6 Special Precautions For Disposal And Other Handling



No special instructions



7. Marketing Authorisation Holder



Laboratories for Applied Biology Ltd



91, Amhurst Park



London



N 16 5 DR ML (UK) 0118/01



8. Marketing Authorisation Number(S)



UK PL 0118/5004R



9. Date Of First Authorisation/Renewal Of The Authorisation



Granted 01.11.90.



Renewed until 26.02.06



10. Date Of Revision Of The Text



05.10 99 Changes to 5.6 Interactions



19.09.00 Rearranged to current format



06.02.2001 Corrected and expanded: 4. Clinical Particulars and 5.2 Pharmacokinetics.



14.06.2001 Changes to 4.2 and 4.8.



11. Legal Category


Prescription only medicine.




Wednesday, 29 August 2012

Mycostatin Topical


Generic Name: nystatin (Topical route)

nye-STAT-in

Commonly used brand name(s)

In the U.S.


  • Mycostatin

  • Nystop

  • Pedi-Dri

In Canada


  • Mycostatin Cream

  • Mycostatin Ointment

  • Mycostatin Powder

  • Nadostine

  • Nilstat Topical Cream

  • Nilstat Topical Ointment

  • Nyaderm Cream

  • Nyaderm Ointment

Available Dosage Forms:


  • Powder

  • Cream

  • Ointment

Therapeutic Class: Antifungal


Chemical Class: Polyene


Uses For Mycostatin


Nystatin belongs to the group of medicines called antifungals. Topical nystatin is used to treat some types of fungus infections of the skin.


Nystatin is available in the U.S. only with your doctor's prescription.


Before Using Mycostatin


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 this medicine, the following should be considered:


Allergies


Tell your doctor if you have ever had any unusual or allergic reaction to this medicine 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


Although there is no specific information comparing use of topical nystatin in children with use in other age groups, this medicine is not expected to cause different side effects or problems in children than it does in adults.


Geriatric


Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults or if they cause different side effects or problems in older people. There is no specific information comparing use of topical nystatin in the elderly with use in other age groups.


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. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.


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. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.


Proper Use of nystatin

This section provides information on the proper use of a number of products that contain nystatin. It may not be specific to Mycostatin. Please read with care.


Topical nystatin should not be used in the eyes.


Apply enough nystatin to cover the affected area.


For patients using the powder form of this medicine on the feet:


  • Sprinkle the powder between the toes, on the feet, and in socks and shoes.

The use of any kind of occlusive dressing (airtight covering, such as kitchen plastic wrap) over this medicine may increase the chance of irritation. Therefore, do not bandage, wrap, or apply any occlusive dressing over this medicine unless directed to do so by your doctor. When using this medicine on the diaper area of children, avoid tight-fitting diapers and plastic pants.


To help clear up your infection completely, keep using this medicine for the full time of treatment, even if your condition has improved. Do not miss any doses.


Dosing


The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.


The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.


  • For topical dosage forms (cream or ointment):
    • For fungus infections:
      • Adults and children—Apply to the affected area(s) of the skin two times a day.



  • For topical dosage form (powder):
    • For fungus infections:
      • Adults and children—Apply to the affected area(s) of the skin two or three times a day.



Missed Dose


If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.


Storage


Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.


Keep out of the reach of children.


Do not keep outdated medicine or medicine no longer needed.


Mycostatin 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 as soon as possible if any of the following side effects occur:


  • Skin irritation not present before use of this medicine

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: Mycostatin Topical 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 Mycostatin Topical resources


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


  • Mycostatin Topical Concise Consumer Information (Cerner Multum)

  • Nyamyc Prescribing Information (FDA)

  • Nystop Prescribing Information (FDA)

  • Nystop Powder MedFacts Consumer Leaflet (Wolters Kluwer)

  • Pediaderm AF Cream MedFacts Consumer Leaflet (Wolters Kluwer)



Compare Mycostatin Topical with other medications


  • Cutaneous Candidiasis
  • Vaginal Yeast Infection

Indapamide Katwijk




Indapamide Katwijk may be available in the countries listed below.


Ingredient matches for Indapamide Katwijk



Indapamide

Indapamide is reported as an ingredient of Indapamide Katwijk in the following countries:


  • Netherlands

International Drug Name Search

Saturday, 25 August 2012

Ezetrol 10mg Tablets





1. Name Of The Medicinal Product



EZETROL® 10 mg Tablets


2. Qualitative And Quantitative Composition



Each tablet contains 10 mg of ezetimibe.



Excipients(s):



Each tablet contains 55 mg of lactose monohydrate.



For a full list of excipients see section 6.1.



3. Pharmaceutical Form



Tablet.



White to off-white, capsule-shaped tablets debossed with '414' on one side.



4. Clinical Particulars



4.1 Therapeutic Indications



Primary hypercholesterolaemia



'Ezetrol', co-administered with an HMG



'Ezetrol' monotherapy is indicated as adjunctive therapy to diet for use in patients with primary (heterozygous familial and non-familial) hypercholesterolaemia in whom a statin is considered inappropriate or is not tolerated.



Homozygous Familial Hypercholesterolaemia (HoFH)



'Ezetrol' co-administered with a statin, is indicated as adjunctive therapy to diet for use in patients with HoFH. Patients may also receive adjunctive treatments (e.g. LDL apheresis).



Homozygous sitosterolaemia (phytosterolaemia)



'Ezetrol' is indicated as adjunctive therapy to diet for use in patients with homozygous familial sitosterolaemia.



A beneficial effect of Ezetrol on cardiovascular morbidity and mortality has not yet been demonstrated.



4.2 Posology And Method Of Administration



The patient should be on an appropriate lipid



Route of administration is oral. The recommended dose is one 'Ezetrol' 10 mg tablet daily. 'Ezetrol' can be administered at any time of the day, with or without food.



When 'Ezetrol' is added to a statin, either the indicated usual initial dose of that particular statin or the already established higher statin dose should be continued. In this setting, the dosage instructions for that particular statin should be consulted.



Co-administration with bile acid sequestrants



Dosing of 'Ezetrol' should occur either



Use in the elderly



No dosage adjustment is required for elderly patients (see section 5.2).



Use in paediatric patients



Initiation of treatment must be performed under review of a specialist.



Adolescents



When Ezetrol is administered with simvastatin, the dosage instructions for simvastatin, in adolescents should be consulted.



Children <10 years: 'Ezetrol' is not recommended for use in children below age 10 due to insufficient data on safety and efficacy (see section 5.2).



Use in hepatic impairment



No dosage adjustment is required in patients with mild hepatic insufficiency (Child Pugh score 5 to 6). Treatment with 'Ezetrol' is not recommended in patients with moderate (Child Pugh score 7 to 9) or severe (Child Pugh score>9) liver dysfunction. (See sections 4.4 and 5.2.)



Use in renal impairment



No dosage adjustment is required for renally impaired patients (see section 5.2).



4.3 Contraindications



Hypersensitivity to the active substance or to any of the excipients.



When 'Ezetrol' is co-administered with a statin, please refer to the SPC for that particular medicinal product.



Therapy with 'Ezetrol' co-administered with a statin is contraindicated during pregnancy and lactation.



'Ezetrol' co-administered with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases.



4.4 Special Warnings And Precautions For Use



When 'Ezetrol' is co-administered with a statin, please refer to the SPC for that particular medicinal product.



Liver enzymes



In controlled co-administration trials in patients receiving 'Ezetrol' with a statin, consecutive transaminase elevations (



Skeletal muscle



In post-marketing experience with 'Ezetrol', cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin concomitantly with 'Ezetrol'. However, rhabdomyolysis has been reported very rarely with 'Ezetrol' monotherapy and very rarely with the addition of 'Ezetrol' to other agents known to be associated with increased risk of rhabdomyolysis. If myopathy is suspected based on muscle symptoms or is confirmed by a creatine phosphokinase (CPK) level>10 times the ULN, 'Ezetrol', any statin, and any of these other agents that the patient is taking concomitantly should be immediately discontinued. All patients starting therapy with 'Ezetrol' should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness (see section 4.8).



Hepatic insufficiency



Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, 'Ezetrol' is not recommended (see section 5.2).



Paediatric (10 to 17 Years of Age) Patients



Efficacy and safety of Ezetrol co-administered with simvastatin in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial in adolescent boys (Tanner stage II or above) and in girls who were at least one year post-menarche.



In this limited controlled study, there was generally no detectable effect on growth or sexual maturation in the adolescent boys or girls, or any effect on menstrual cycle length in girls. However, the effects of ezetimibe for a treatment period> 33 weeks on growth and sexual maturation have not been studied (see sections 4.2 and 4.8)



The safety and efficacy of Ezetrol co-administered with doses simvastatin above 40mg daily have not been studied in paediatric patients 10 to 17 years of age.



Ezetrol has not been studied in patients younger than 10 years of age or in pre-menarchal girls. (See sections 4.2 and 4.8.)



The long-term efficacy of therapy with Ezetrol in patients below 17 years of age to reduce morbidity and mortality in adulthood has not been studied.



Fibrates



The safety and efficacy of 'Ezetrol' administered with fibrates have not been established.



If cholelithiasis is suspected in a patient receiving 'Ezetrol' and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued (see sections 4.5 and 4.8).



Ciclosporin



Caution should be exercised when initiating 'Ezetrol' in the setting of ciclosporin. Ciclosporin concentrations should be monitored in patients receiving 'Ezetrol' and ciclosporin (see section 4.5).



Anticoagulants



If 'Ezetrol' is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalised Ratio (INR) should be appropriately monitored (see section 4.5).



Excipient



Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.



4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction



Interaction studies have only been performed in adults.



In preclinical studies, it has been shown that ezetimibe does not induce cytochrome P450 drug metabolising enzymes. No clinically significant pharmacokinetic interactions have been observed between ezetimibe and drugs known to be metabolised by cytochromes P450 1A2, 2D6, 2C8, 2C9, and 3A4, or N-acetyltransferase.



In clinical interaction studies, ezetimibe had no effect on the pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives (ethinyl estradiol and levonorgestrel), glipizide, tolbutamide, or midazolam, during co-administration. Cimetidine, co-administered with ezetimibe, had no effect on the bioavailability of ezetimibe.



Antacids: Concomitant antacid administration decreased the rate of absorption of ezetimibe but had no effect on the bioavailability of ezetimibe. This decreased rate of absorption is not considered clinically significant.



Colestyramine: Concomitant colestyramine administration decreased the mean area under the curve (AUC) of total ezetimibe (ezetimibe + ezetimibe glucuronide) approximately 55%. The incremental low



Fibrates: In patients receiving fenofibrate and 'Ezetrol', physicians should be aware of the possible risk of cholelithiasis and gallbladder disease (see section 4.4 and 4.8).



If cholelithiasis is suspected in a patient receiving 'Ezetrol' and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued (see section 4.8).



Concomitant fenofibrate or gemfibrozil administration modestly increased total ezetimibe concentrations (approximately 1.5- and 1.7-fold respectively).



Co-administration of 'Ezetrol' with other fibrates has not been studied.



Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In animal studies, ezetimibe sometimes increased cholesterol in the gallbladder bile, but not in all species (see section 5.3). A lithogenic risk associated with the therapeutic use of 'Ezetrol' cannot be ruled out.



Statins: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin or rosuvastatin.



Ciclosporin: In a study of eight post-renal transplant patients with creatinine clearance of>50 ml/min on a stable dose of ciclosporin, a single 10-mg dose of 'Ezetrol' resulted in a 3.4-fold (range 2.3 to 7.9-fold) increase in the mean AUC for total ezetimibe compared to a healthy control population, receiving ezetimibe alone, from another study (n=17). In a different study, a renal transplant patient with severe renal insufficiency who was receiving ciclosporin and multiple other medications, demonstrated a 12-fold greater exposure to total ezetimibe compared to concurrent controls receiving ezetimibe alone. In a two-period crossover study in 12 healthy subjects, daily administration of 20 mg ezetimibe for 8 days with a single 100



Anticoagulants: Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males. However, there have been post-marketing reports of increased International Normalised Ratio (INR) in patients who had 'Ezetrol' added to warfarin or fluindione. If 'Ezetrol' is added to warfarin, another coumarin anticoagulant, or fluindione, INR should be appropriately monitored (see Section 4.4).



4.6 Pregnancy And Lactation



'Ezetrol' co-administered with a statin is contraindicated during pregnancy and lactation (see section 4.3), please refer to the SPC for that particular statin.



Pregnancy:



'Ezetrol' should be given to pregnant women only if clearly necessary. No clinical data are available on the use of 'Ezetrol' during pregnancy. Animal studies on the use of ezetimibe in monotherapy have shown no evidence of direct or indirect harmful effects on pregnancy, embryofoetal development, birth or postnatal development (see section 5.3).



Lactation:



'Ezetrol' should not be used during lactation. Studies on rats have shown that ezetimibe is secreted into breast milk. It is not known if ezetimibe is secreted into human breast milk.



4.7 Effects On Ability To Drive And Use Machines



No studies on the effects on the ability to drive and use machines have been performed. However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported.



4.8 Undesirable Effects



Clinical Studies



In clinical studies of up to 112 weeks duration, 'Ezetrol' 10 mg daily was administered alone in 2396 patients, or with a statin in 11,308 patients or with fenofibrate in 185 patients. Adverse reactions were usually mild and transient. The overall incidence of side effects was similar between 'Ezetrol' and placebo. Similarly, the discontinuation rate due to adverse experiences was comparable between 'Ezetrol' and placebo.



'Ezetrol' administered alone or co-administered with a statin:



The following adverse reactions were observed in patients treated with 'Ezetrol' (N=2396) and at a greater incidence than placebo (N=1159) or in patients treated with 'Ezetrol' co-administered with a statin (N=11308) and at a greater incidence than statin administered alone (N=9361):



Frequencies are defined as: very common (



































































'Ezetrol' monotherapy


  


System organ class




Adverse reactions




Frequency




Investigations




ALT and/or AST increased; blood CPK increased; gamma-glutamyltransferase increased; liver function test abnormal




Uncommon




Respiratory, Thoracic and Mediastinal Disorders




cough




Uncommon




Gastrointestinal Disorders




abdominal pain; diarrhoea; flatulence




Common




dyspepsia; gastrooesophageal reflux disease; nausea




Uncommon


 


Musculoskeletal and Connective Tissue Disorders




arthralgia; muscle spasms; neck pain




Uncommon




Metabolism and Nutrition Disorders




decreased appetite




Uncommon




Vascular Disorders




hot flush; hypertension




Uncommon




General Disorders and Administration Site Condition




fatigue




Common




chest pain, pain




Uncommon


 


Additional adverse reactions with 'Ezetrol' co-administered with a statin


  


System organ class




Adverse reactions




Frequency




Investigations




ALT and/or AST increased




Common




Nervous System Disorders




headache




Common




paraesthesia




Uncommon


 


Gastrointestinal Disorders




dry mouth; gastritis




Uncommon




Skin and Subcutaneous Tissue Disorders




pruritus; rash; urticaria




Uncommon




Musculoskeletal and Connective Tissue Disorders




myalgia




Common




back pain; muscular weakness; pain in extremity




Uncommon


 


General Disorders and Administration Site Condition




asthenia; oedema peripheral




Uncommon



'Ezetrol' co-administered with fenofibrate:



Gastrointestinal disorders: abdominal pain (common).



In a multicentre, double-blind, placebo-controlled, clinical study in patients with mixed hyperlipidaemia, 625 patients were treated for up to 12 weeks and 576 patients for up to 1 year. In this study, 172 patients treated with 'Ezetrol' and fenofibrate completed 12 weeks of therapy, and 230 patients treated with 'Ezetrol' and fenofibrate (including 109 who received 'Ezetrol' alone for the first 12 weeks) completed 1 year of therapy. This study was not designed to compare treatment groups for infrequent events. Incidence rates (95% CI) for clinically important elevations (>3 X ULN, consecutive) in serum transaminases were 4.5% (1.9, 8.8) and 2.7% (1.2, 5.4) for fenofibrate monotherapy and 'Ezetrol' co-administered with fenofibrate, respectively, adjusted for treatment exposure. Corresponding incidence rates for cholecystectomy were 0.6% (0.0, 3.1) and 1.7% (0.6, 4.0) for fenofibrate monotherapy and 'Ezetrol' co-administered with fenofibrate, respectively (see sections 4.4 and 4.5).



Paediatric (10 to 17 years of age) Patients



In a study involving adolescent (10 to 17 years of age) patients with heterozygous familial hypercholesterolaemia (n = 248), elevations of ALT and/or AST (



This trial was not suited for comparison of rare adverse drug reactions.



Laboratory values



In controlled clinical monotherapy trials, the incidence of clinically important elevations in serum transaminases (ALT and/or AST



In clinical trials, CPK>10 X ULN was reported for 4 of 1,674 (0.2%) patients administered 'Ezetrol' alone vs 1 of 786 (0.1%) patients administered placebo, and for 1 of 917 (0.1%) patients co-administered 'Ezetrol' and a statin vs 4 of 929 (0.4%) patients administered a statin alone. There was no excess of myopathy or rhabdomyolysis associated with 'Ezetrol' compared with the relevant control arm (placebo or statin alone). (See section 4.4.)



Post-marketing Experience



The following additional adverse reactions have been reported in post-marketing experience. Because these adverse experiences have been identified from spontaneous reports, their true frequencies are not known and cannot be estimated.



Blood and lymphatic system disorders: thrombocytopenia



Nervous system disorders: dizziness; paraesthesia



Respiratory, thoracic and mediastinal disorders: dyspnoea



Gastro-intestinal disorders: pancreatitis; constipation



Skin and subcutaneous tissue disorders: erythema multiforme



Musculoskeletal and connective tissue disorders: myalgia; myopathy/rhabdomyolysis (see section 4.4).



General disorders and administration site conditions: asthenia



Immune system disorders: hypersensitivity, including rash, urticaria, anaphylaxis and angioedema



Hepatobiliary disorders: hepatitis, cholelithiasis, cholecystitis



Psychiatric disorders: depression.



4.9 Overdose



In clinical studies, administration of ezetimibe, 50 mg/day, to 15 healthy subjects for up to 14 days, or 40 mg/day to 18 patients with primary hypercholesterolaemia for up to 56 days, was generally well tolerated. In animals, no toxicity was observed after single oral doses of 5,000 mg/kg of ezetimibe in rats and mice and 3,000 mg/kg in dogs.



A few cases of overdosage with 'Ezetrol' have been reported: most have not been associated with adverse experiences. Reported adverse experiences have not been serious. In the event of an overdose, symptomatic and supportive measures should be employed.



5. Pharmacological Properties



5.1 Pharmacodynamic Properties



Pharmacotherapeutic group: Other lipid modifying agents. ATC code: C10A X09



'Ezetrol' is in a new class of lipid-lowering compounds that selectively inhibit the intestinal absorption of cholesterol and related plant sterols. 'Ezetrol' is orally active, and has a mechanism of action that differs from other classes of cholesterol



Ezetimibe localises at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver; statins reduce cholesterol synthesis in the liver and together these distinct mechanisms provide complementary cholesterol reduction. In a 2



A series of preclinical studies was performed to determine the selectivity of ezetimibe for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of [14C]-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or fat soluble vitamins A and D.



Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total



CLINICAL TRIALS



In controlled clinical studies, 'Ezetrol', either as monotherapy or co-administered with a statin significantly reduced total cholesterol (total



Primary hypercholesterolaemia



In a double-blind, placebo-controlled, 8-week study, 769 patients with hypercholesterolaemia already receiving statin monotherapy and not at National Cholesterol Education Program (NCEP) LDL



Among statin-treated patients not at LDL



In two, double-blind, randomised placebo-controlled, 12-week studies in 1,719 patients with primary hypercholesterolaemia, 'Ezetrol' 10 mg significantly lowered total



In a multicenter, double-blind, controlled clinical study (ENHANCE), 720 patients with heterozygous familial hypercholesterolemia were randomized to receive ezetimibe 10 mg in combination with simvastatin 80 mg (n = 357) or simvastatin 80 mg (n = 363) for 2 years. The primary objective of the study was to investigate the effect of ezetimibe/simvastatin combination therapy on carotid artery intima-media thickness (IMT) compared to simvastatin monotherapy. The impact of this surrogate marker on cardiovascular morbidity and mortality is still not demonstrated.



The primary endpoint, the change in the mean IMT of all six carotid segments, did not differ significantly (p=0.29) between the two treatment groups as measured by B-mode ultrasound. With ezetimibe 10 mg in combination with simvastatin 80 mg or simvastatin 80 mg alone, intima-medial thickening increased by 0.0111 mm and 0.0058 mm, respectively, over the study's 2 year duration (baseline mean carotid IMT 0.68 mm and 0.69 mm respectively).



Ezetimibe 10 mg in combination with simvastatin 80 mg lowered LDL-C, total-C, Apo B, and TG significantly more than simvastatin 80 mg. The percent increase in HDL-C was similar for the two treatment groups. The adverse reactions reported for ezetimibe 10 mg in combination with simvastatin 80 mg were consistent with its known safety profile.



Clinical Studies in Paediatric Patients (10 to 17 years of age)



In a multicentre, double-blind, controlled study, 142 boys (Tanner stage II and above) and 106 postmenarchal girls, 10 to 17 years of age (mean age 14.2 years) with heterozygous familial hypercholesterolaemia (HeFH) with baseline LDL-C levels between 4.1 and 10.4 mmol/l were randomised to either Ezetrol 10 mg co-administered with simvastatin (10, 20 or 40 mg) or simvastatin (10, 20 or 40 mg) alone for 6 weeks, co-administered Ezetrol and 40 mg simvastatin or 40 mg simvastatin alone for the next 27 weeks, and open-label co-administered Ezetrol and simvastatin (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter.



At Week 6, Ezetrol co-administered with simvastatin (all doses) significantly reduced total-C (38 % vs 26 %), LDL-C (49 % vs 34 %), Apo B (39 % vs 27 %), and non-HDL-C (47 % vs 33 %) compared to simvastatin (all doses) alone. Results for the two treatment groups were similar for TG and HDL-C (



The safety and efficacy of Ezetrol co-administered with doses of simvastatin above 40 mg daily have not been studied in paediatric patients 10 to 17 years of age. The long-term efficacy of therapy with Ezetrol in patients below 17 years of age to reduce morbidity and mortality in adulthood has not been studied.



Homozygous Familial Hypercholesterolaemia (HoFH)



A double



Homozygous sitosterolaemia (phytosterolaemia)



In a double-blind, placebo-controlled, 8-week trial, 37 patients with homozygous sitosterolaemia were randomised to receive 'Ezetrol' 10 mg (n=30) or placebo (n=7). Some patients were receiving other treatments (e.g. statins, resins). 'Ezetrol' significantly lowered the two major plant sterols, sitosterol and campesterol, by 21% and 24% from baseline, respectively. The effects of decreasing sitosterol on morbidity and mortality in this population are not known.



Aortic Stenosis



The Simvastatin and Ezetimibe for the Treatment of Aortic Stenosis (SEAS) study was a multi-center, double-blind, placebo-controlled study with a median duration of 4.4 years conducted in 1873 patients with asymptomatic aortic stenosis (AS), documented by Doppler-measured aortic peak flow velocity within the range of 2.5 to 4.0 m/s. Only patients who were considered not to require statin treatment for purposes of reducing atherosclerotic cardiovascular disease risk were enrolled. Patients were randomized 1:1 to receive placebo or co-administered ezetimibe 10 mg and simvastatin 40 mg daily.



The primary endpoint was the composite of major cardiovascular events (MCE) consisting of cardiovascular death, aortic valve replacement (AVR) surgery, congestive heart failure (CHF) as a result of progression of AS, nonfatal myocardial infarction, coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), hospitalization for unstable angina, and nonhemorrhagic stroke. The key secondary endpoints were composites of subsets of the primary endpoint event categories.



Compared to placebo, ezetimibe/simvastatin 10/40 mg did not significantly reduce the risk of MCE. The primary outcome occurred in 333 patients (35.3%) in the ezetimibe / simvastatin group and in 355 patients (38.2%) in the placebo group (hazard ratio in the ezetimibe / simvastatin group, 0.96; 95% confidence interval, 0.83 to 1.12; p = 0.59). Aortic valve replacement was performed in 267 patients (28.3%) in the ezetimibe / simvastatin group and in 278 patients (29.9%) in the placebo group (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; p = 0.97). Fewer patients had ischemic cardiovascular events in the ezetimibe / simvastatin group (n=148) than in the placebo group (n=187) (hazard ratio, 0.78; 95% CI, 0.63 to 0.97; p = 0.02), mainly because of the smaller number of patients who underwent coronary artery bypass grafting.



Cancer occurred more frequently in the ezetimibe / simvastatin group (105 versus 70, p=0.01). The clinical relevance of this observation is uncertain. In a meta-analysis including interim results from two large, long-term, ongoing studies with ezetimibe / simvastatin (n=10,319 actively treated, 10,298 control treated; patient-years = 18,246 actively treated, 18,255 control treated) there was not an increased rate of cancer (313 active treatment, 326 control; risk ratio, 0.96; 0.95% confidence interval, 0.82 to 1.12; p=0.61).



5.2 Pharmacokinetic Properties



Absorption: After oral administration, ezetimibe is rapidly absorbed and extensively conjugated to a pharmacologically-active phenolic glucuronide (ezetimibe-glucuronide). Mean maximum plasma concentrations (Cmax) occur within 1 to 2 hours for ezetimibe-glucuronide and 4 to 12 hours for ezetimibe. The absolute bioavailability of ezetimibe cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection.



Concomitant food administration (high fat or non-fat meals) had no effect on the oral bioavailability of ezetimibe when administered as 'Ezetrol' 10



Distribution: Ezetimibe and ezetimibe



Biotransformation: Ezetimibe is metabolised primarily in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20 % and 80 to 90 % of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma with evidence of significant enterohepatic recycling. The half-life for ezetimibe and ezetimibe-glucuronide is approximately 22 hours.



Elimination: Following oral administration of 14C



Special populations:



Paediatric patients



The absorption and metabolism of ezetimibe are similar between children and adolescents (10 to 18 years) and adults. Based on total ezetimibe, there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the paediatric population <10 years of age are not available. Clinical experience in paediatric and adolescent patients includes patients with HoFH, HeFH, or sitosterolaemia.



Geriatric patients



Plasma concentrations for total ezetimibe are about 2



Hepatic insufficiency



After a single 10



Renal insufficiency



After a single 102), the mean AUC for total ezetimibe was increased approximately 1.5



An additional patient in this study (post-renal transplant and receiving multiple medications, including ciclosporin) had a 12



Gender



Plasma concentrations for total ezetimibe are slightly higher (approximately 20%) in women than in men. LDL



5.3 Preclinical Safety Data



Animal studies on the chronic toxicity of ezetimibe identified no target organs for toxic effects. In dogs treated for four weeks with ezetimibe (



In co-administration studies with ezetimibe and statins the toxic effects observed were essentially those typically associated with statins. Some of the toxic effects were more pronounced than observed during treatment with statins alone. This is attributed to pharmacokinetic and pharmacodynamic interactions in co-administration therapy. No such interactions occurred in the clinical studies. Myopathies occurred in rats only after exposure to doses that were several times higher than the human therapeutic dose (approximately 20 times the AUC level for statins and 500 to 2,000 times the AUC level for the active metabolites).



In a series of in vivo and in vitro assays ezetimibe, given alone or co-administered with statins, exhibited no genotoxic potential. Long-term carcinogenicity tests on ezetimibe were negative.



Ezetimibe had no effect on the fertility of male or female rats, nor was it found to be teratogenic in rats or rabbits, nor did it affect prenatal or postnatal development. Ezetimibe crossed the placental barrier in pregnant rats and rabbits given multiple doses of 1,000 mg/kg/day. The co-administration of ezetimibe and statins was not teratogenic in rats. In pregnant rabbits a small number of skeletal deformities (fused thoracic and caudal vertebrae, reduced number of caudal vertebrae) were observed. The co-administration of ezetimibe with lovastatin resulted in embryolethal effects.



6. Pharmaceutical Particulars



6.1 List Of Excipients



Croscarmellose sodium



Lactose monohydrate



Magnesium stearate



Microcrystalline cellulose



Povidone (K29-32)



Sodium laurilsulphate



6.2 Incompatibilities



Not applicable.



6.3 Shelf Life



3 years.



6.4 Special Precautions For Storage



Do not store above 30°C.



Blisters: Store in the original package in order to protect from moisture.



Bottles: Keep the bottle tightly closed in order to protect from moisture.



6.5 Nature And Contents Of Container



Unit Dose peelable blisters of clear polychlorotrifluoroethylene/PVC sealed to vinyl coated aluminium backed with paper and polyester in packs of 7, 10, 14, 20, 28, 30, 50, 98, 100, or 300 tablets.



Push through blisters of clear polychlorotrifluoroethylene/PVC sealed to vinyl coated aluminium in packs of 7, 10, 14, 20, 28, 30, 50, 84, 90, 98, 100, or 300 tablets.



Unit dose push through blisters of clear polychlorotrifluoroethylene/PVC coated aluminium in packs of 50, 100, or 300 tablets.



HDPE bottles with polypropylene cap, containing 100 tablets.



Not all pack sizes may be marketed.



6.6 Special Precautions For Disposal And Other Handling



No special requirements.



7. Marketing Authorisation Holder



MSD-SP Limited



Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK



8. Marketing Authorisation Number(S)



PL 19945/0001



9. Date Of First Authorisation/Renewal Of The Authorisation



June 2009



10. Date Of Revision Of The Text



September 2010



LEGAL CATEGORY


POM



© Merck Sharp & Dohme Limited, 2010. All rights reserved.



EZETROL SPC.EZE.09.UK.3124




Microgestin FE 1.5/30


Generic Name: ethinyl estradiol and norethindrone (ETH in il ess tra DYE ole and nor ETH in drone)

Brand Names: Aranelle, Balziva, Brevicon, Briellyn, Cyclafem 1/35, Cyclafem 7/7/7, Estrostep Fe, Femcon FE, Generess Fe, Gildess FE 1.5/0.03, Gildess FE 1/0.2, Junel 1.5/30, Junel 1/20, Junel Fe 1.5/30, Junel Fe 1/20, Leena, Lo Loestrin Fe, Loestrin 21 1.5/30, Loestrin 21 1/20, Loestrin 24 Fe, Loestrin Fe 1.5/30, Loestrin Fe 1/20, Microgestin 1.5/30, Microgestin 1/20, Microgestin FE 1.5/30, Microgestin FE 1/20, Modicon, Necon 0.5/35, Necon 1/35, Necon 10/11, Necon 7/7/7, Norinyl 1+35, Nortrel 0.5/35, Nortrel 1/35, Nortrel 7/7/7, Ortho-Novum 1/35, Ortho-Novum 7/7/7, Ovcon 35, Ovcon 35 Fe, Ovcon 50, Tilia Fe, Tri-Legest Fe, Tri-Norinyl, Zenchent Fe, Zeosa


What is Microgestin FE 1.5/30 (ethinyl estradiol and norethindrone)?

Ethinyl estradiol and norethindrone contains a combination of female hormones that prevent ovulation (the release of an egg from an ovary). This medication also causes changes in your cervical mucus and uterine lining, making it harder for sperm to reach the uterus and harder for a fertilized egg to attach to the uterus.


Ethinyl estradiol and norethindrone are used as contraception to prevent pregnancy. It is also used to treat severe acne.


Ethinyl estradiol and norethindrone may also be used for purposes not listed in this medication guide.


What is the most important information I should know about Microgestin FE 1.5/30 (ethinyl estradiol and norethindrone)?


Do not use birth control pills if you are pregnant or if you have recently had a baby. Do not use this medication if you have any of the following conditions: a history of stroke or blood clot, circulation problems, a hormone-related cancer such as breast or uterine cancer, abnormal vaginal bleeding, liver disease or liver cancer, or a history of jaundice caused by birth control pills.

You may need to use back-up birth control, such as condoms or a spermicide, when you first start using this medication. Follow your doctor's instructions.


Taking hormones can increase your risk of blood clots, stroke, or heart attack, especially if you smoke and are older than 35.

Some drugs can make birth control pills less effective, which may result in pregnancy. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.


What should I discuss with my healthcare provider before taking Microgestin FE 1.5/30 (ethinyl estradiol and norethindrone)?


This medication can cause birth defects. Do not use if you are pregnant. Tell your doctor right away if you become pregnant, or if you miss two menstrual periods in a row. If you have recently had a baby, wait at least 4 weeks before taking birth control pills (6 weeks if you are breast-feeding). You should not take birth control pills if you have:

  • coronary artery disease, a severe or uncontrolled heart valve disorder, untreated or uncontrolled high blood pressure;




  • a history of a stroke, blood clot, or circulation problems;




  • a hormone-related cancer such as breast or uterine cancer;




  • unusual vaginal bleeding that has not been checked by a doctor;




  • liver disease or liver cancer;




  • severe migraine headaches; or




  • a history of jaundice caused by pregnancy or birth control pills.



To make sure you can safely take this medication, tell your doctor if you have any of these other conditions:



  • high blood pressure or a history of heart disease;




  • high cholesterol, gallbladder disease, or diabetes;




  • migraine headaches or a history of depression; or




  • a history of breast cancer or an abnormal mammogram.




The hormones in birth control pills can pass into breast milk and may harm a nursing baby. This medication may also slow breast milk production. Do not use if you are breast-feeding a baby.

How should I take Microgestin FE 1.5/30 (ethinyl estradiol and norethindrone)?


Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label. Take your first pill on the first day of your period or on the first Sunday after your period begins (follow your doctor's instructions).


You may need to use back-up birth control, such as condoms or a spermicide, when you first start using this medication. Follow your doctor's instructions.


The 28-day birth control pack contains seven "reminder" pills to keep you on your regular cycle. Your period will usually begin while you are using these reminder pills.


You may have breakthrough bleeding, especially during the first 3 months. Tell your doctor if this bleeding continues or is very heavy.

Take one pill every day, no more than 24 hours apart. When the pills run out, start a new pack the following day. You may get pregnant if you do not use this medication regularly. Get your prescription refilled before you run out of pills completely.


The chewable tablet may be chewed or swallowed whole. If chewed, drink a full glass of water just after you swallow the pill.


If you need surgery or medical tests or if you will be on bed rest, you may need to stop using this medication for a short time. Any doctor or surgeon who treats you should know that you are using birth control pills.


Your doctor will need to check your progress on a regular basis. Do not miss any scheduled appointments.


Store at room temperature away from moisture and heat.

What happens if I miss a dose?


Missing a pill increases your risk of becoming pregnant. If you miss one "active" pill, take two pills on the day that you remember. Then take one pill per day for the rest of the pack.


If you miss two "active" pills in a row in week one or two, take two pills per day for two days in a row. Then take one pill per day for the rest of the pack. Use back-up birth control for at least 7 days following the missed pills.


If you miss two "active" pills in a row in week three, or if you miss three pills in a row during any of the first 3 weeks, throw out the rest of the pack and start a new one the same day if you are a Day 1 starter. If you are a Sunday starter, keep taking a pill every day until Sunday. On Sunday, throw out the rest of the pack and start a new one that day.


If you miss two or more pills, you may not have a period during the month. If you miss a period for two months in a row, call your doctor because you might be pregnant.

If you miss any reminder pills, throw them away and keep taking one pill per day until the pack is empty. You do not need back-up birth control if you miss a reminder pill.


What happens if I overdose?


Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. Overdose symptoms may include nausea, vomiting, and vaginal bleeding.

What should I avoid while taking Microgestin FE 1.5/30 (ethinyl estradiol and norethindrone)?


Do not smoke while using birth control pills, especially if you are older than 35. Smoking can increase your risk of blood clots, stroke, or heart attack caused by birth control pills.

Birth control pills will not protect you from sexually transmitted diseases--including HIV and AIDS. Using a condom is the only way to protect yourself from these diseases.


Microgestin FE 1.5/30 (ethinyl estradiol and norethindrone) side effects


Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using this medication and call your doctor at once if you have any of these serious side effects:

  • sudden numbness or weakness, especially on one side of the body;




  • sudden severe headache, confusion, problems with vision, speech, or balance;




  • sudden cough, wheezing, rapid breathing, coughing up blood;




  • pain, swelling, warmth, or redness in one or both legs;




  • chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling;




  • a change in the pattern or severity of migraine headaches;




  • pain in your upper stomach, jaundice (yellowing of the skin or eyes);




  • a lump in your breast;




  • swelling in your hands, ankles, or feet; or




  • symptoms of depression (sleep problems, weakness, mood changes).



Less serious side effects may include:



  • mild nausea or vomiting, appetite or weight changes;




  • breast swelling or tenderness;




  • headache, nervousness, dizziness;




  • problems with contact lenses;




  • freckles or darkening of facial skin, loss of scalp hair; or




  • vaginal itching or discharge.



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.


What other drugs will affect Microgestin FE 1.5/30 (ethinyl estradiol and norethindrone)?


Some drugs can make ethinyl estradiol and norethindrone less effective, which may result in pregnancy. Before using ethinyl estradiol and norethindrone, tell your doctor if you are using any of the following drugs:



  • acetaminophen (Tylenol) or ascorbic acid (vitamin C);




  • bosentan (Tracleer);




  • prednisolone (Orapred);




  • St. John's wort;




  • theophylline (Elixophyllin, Theo-24, Uniphyl);




  • an antibiotic;




  • HIV or AIDS medications;




  • phenobarbital (Solfoton) and other barbiturates; or




  • seizure medication.



This list is not complete and other drugs may interact with birth control pills. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.



More Microgestin FE 1.5/30 resources


  • Microgestin FE 1.5/30 Side Effects (in more detail)
  • Microgestin FE 1.5/30 Use in Pregnancy & Breastfeeding
  • Drug Images
  • Microgestin FE 1.5/30 Drug Interactions
  • Microgestin FE 1.5/30 Support Group
  • 3 Reviews for Microgestin FE.5/30 - Add your own review/rating


  • Aranelle Prescribing Information (FDA)

  • Balziva Prescribing Information (FDA)

  • Brevicon Prescribing Information (FDA)

  • Briellyn Prescribing Information (FDA)

  • Cyclafem 1/35 Prescribing Information (FDA)

  • Cyclafem 7/7/7 Prescribing Information (FDA)

  • Estrostep Fe Prescribing Information (FDA)

  • Femcon FE Prescribing Information (FDA)

  • Femcon Fe Chewable Tablets MedFacts Consumer Leaflet (Wolters Kluwer)

  • Femhrt Consumer Overview

  • Femhrt Prescribing Information (FDA)

  • Femhrt MedFacts Consumer Leaflet (Wolters Kluwer)

  • Jevantique Prescribing Information (FDA)

  • Jinteli Prescribing Information (FDA)

  • Leena Prescribing Information (FDA)

  • Lo Loestrin Fe MedFacts Consumer Leaflet (Wolters Kluwer)

  • Lo Loestrin Fe Consumer Overview

  • Lo Loestrin Fe Advanced Consumer (Micromedex) - Includes Dosage Information

  • Lo Loestrin Fe Prescribing Information (FDA)

  • Loestrin 24 FE Prescribing Information (FDA)

  • Loestrin 24 Fe Consumer Overview

  • Loestrin Fe 1/20 MedFacts Consumer Leaflet (Wolters Kluwer)

  • Ovcon 35 MedFacts Consumer Leaflet (Wolters Kluwer)

  • Tilia FE Prescribing Information (FDA)

  • Tri-Norinyl Prescribing Information (FDA)

  • Zenchent FE Prescribing Information (FDA)

  • Zeosa Prescribing Information (FDA)



Compare Microgestin FE 1.5/30 with other medications


  • Abnormal Uterine Bleeding
  • Acne
  • Birth Control
  • Endometriosis
  • Gonadotropin Inhibition
  • Menstrual Disorders
  • Polycystic Ovary Syndrome
  • Postmenopausal Symptoms
  • Prevention of Osteoporosis


Where can I get more information?


  • Your pharmacist can provide more information about ethinyl estradiol and norethindrone.

See also: Microgestin FE.5/30 side effects (in more detail)


Wednesday, 22 August 2012

Midazolam Injection





Dosage Form: injection
Midazolam Injection, USP

iSecure™ Syringe


 Preservative-Free 


CIV


Sterile Cartridge Unit For Single-use only.


Rx only




WARNING


Adult and Pediatric: Intravenous midazolam has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings. In some cases, where this was not recognized promptly and treated effectively, death or hypoxic encephalopathy has resulted. Intravenous midazolam should be used only in hospital or ambulatory care settings, including physicians’ and dental offices, that provide for continuous monitoring of respiratory and cardiac function, ie, pulse oximetry. Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured (see WARNINGS). For deeply sedated pediatric patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.


The initial intravenous dose for sedation in adult patients may be as little as 1 mg, but should not exceed 2.5 mg in a normal healthy adult. Lower doses are necessary for older (over 60 years) or debilitated patients and in patients receiving concomitant narcotics or other central nervous system (CNS) depressants. The initial dose and all subsequent doses should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. The use of the 1 mg/mL formulation or dilution of the 1 mg/mL or 5 mg/mL formulation is recommended to facilitate slower injection. Doses of sedative medications in pediatric patients must be calculated on a mg/kg basis, and initial doses and all subsequent doses should always be titrated slowly. The initial pediatric dose of midazolam for sedation/anxiolysis/amnesia is age, procedure, and route dependent (see DOSAGE AND ADMINISTRATION for complete dosing information).


Neonates: Midazolam should not be administered by rapid injection in the neonatal population. Severe hypotension and seizures have been reported following rapid IV administration, particularly with concomitant use of fentanyl (see DOSAGE AND ADMINISTRATION for complete information).




Midazolam Injection Description


Midazolam hydrochloride is a water-soluble benzodiazepine available as a sterile, nonpyrogenic parenteral dosage form for intravenous or intramuscular injection. Each mL contains midazolam hydrochloride equivalent to 1 mg or 5 mg midazolam compounded with 0.8% sodium chloride. The pH is approximately 3 (2.9 to 3.5) and is adjusted with hydrochloric acid and, if necessary, sodium hydroxide.


Midazolam is a white to light yellow crystalline compound, insoluble in water. The hydrochloride salt of midazolam, which is formed in situ, is soluble in aqueous solutions. Chemically, midazolam HCl is 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine hydrochloride. Midazolam hydrochloride has the chemical formula C18H13ClFN3•HCl, a calculated molecular weight of 362.25 and the following structural formula:



Under the acidic conditions required to solubilize midazolam in the product, midazolam is present as an equilibrium mixture (shown below) of the closed ring form shown above and an open-ring structure formed by the acid-catalyzed ring opening of the 4,5-double bond of the diazepine ring. The amount of open-ring form is dependent upon the pH of the solution. At the specified pH of the product, the solution may contain up to about 25% of the open-ring compound. At the physiologic conditions under which the product is absorbed (pH of 5 to 8) into the systemic circulation, any open-ring form present reverts to the physiologically active, lipophilic, closed-ring form (midazolam) and is absorbed as such.



The following chart plots the percentage of midazolam present as the open-ring form as a function of pH in aqueous solutions. As indicated in the graph, the amount of open-ring compound present in solution is sensitive to changes in pH over the pH range specified for the product: 3.0 to 4.0 for the 1 mg/mL concentration and 3.0 to 3.6 for the 5 mg/mL concentration. Above pH 5, at least 99% of the mixture is present in the closed-ring form.




Midazolam Injection - Clinical Pharmacology


Midazolam is a short-acting benzodiazepine central nervous system (CNS) depressant.


The effects of midazolam on the CNS are dependent on the dose administered, the route of administration, and the presence or absence of other medications. Onset time of sedative effects after IM administration in adults is 15 minutes, with peak sedation occurring 30 to 60 minutes following injection. In one adult study, when tested the following day, 73% of the patients who received midazolam intramuscularly had no recall of memory cards shown 30 minutes following drug administration; 40% had no recall of the memory cards shown 60 minutes following drug administration. Onset time of sedative effects in the pediatric population begins within 5 minutes and peaks at 15 to 30 minutes depending upon the dose administered. In pediatric patients, up to 85% had no recall of pictures shown after receiving intramuscular midazolam compared with 5% of the placebo controls.


Sedation in adult and pediatric patients is achieved within 3 to 5 minutes after intravenous (IV) injection; the time of onset is affected by total dose administered and the concurrent administration of narcotic premedication. Seventy-one percent of the adult patients in endoscopy studies had no recall of introduction of the endoscope; 82% of the patients had no recall of withdrawal of the endoscope. In one study of pediatric patients undergoing lumbar puncture or bone marrow aspiration, 88% of patients had impaired recall vs 9% of the placebo controls. In another pediatric oncology study, 91% of midazolam treated patients were amnestic compared with 35% of patients who had received fentanyl alone.


When midazolam is given IV as an anesthetic induction agent, induction of anesthesia occurs in approximately 1.5 minutes when narcotic premedication has been administered and in 2 to 2.5 minutes without narcotic premeditation or other sedative premedication. Some impairment in a test of memory was noted in 90% of the patients studied. A dose response study of pediatric patients premedicated with 1.0 mg/kg intramuscular (IM) meperidine found that only 4 out of 6 pediatric patients who received 600 mcg/kg IV midazolam lost consciousness, with eye closing at 108 ± 140 seconds. This group was compared with pediatric patients who were given thiopental 5 mg/kg IV; 6 out of 6 closed their eyes at 20 ± 3.2 seconds. Midazolam did not dependably induce anesthesia at this dose despite concomitant opioid administration in pediatric patients.


Midazolam, used as directed, does not delay awakening from general anesthesia in adults. Gross tests of recovery after awakening (orientation, ability to stand and walk, suitability for discharge from the recovery room, return to baseline Trieger competency) usually indicate recovery within 2 hours but recovery may take up to 6 hours in some cases. When compared with patients who received thiopental, patients who received midazolam generally recovered at a slightly slower rate. Recovery from anesthesia or sedation for procedures in pediatric patients depends on the dose of midazolam administered, coadministration of other medications causing CNS depression and duration of the procedure.


In patients without intracranial lesions, induction of general anesthesia with IV midazolam is associated with a moderate decrease in cerebrospinal fluid pressure (lumbar puncture measurements), similar to that observed following IV thiopental. Preliminary data in neurosurgical patients with normal intracranial pressure but decreased compliance (subarachnoid screw measurements) show comparable elevations of intracranial pressure with midazolam and with thiopental during intubation. No similar studies have been reported in pediatric patients.


The usual recommended intramuscular premedicating doses of midazolam do not depress the ventilatory response to carbon dioxide stimulation to a clinically significant extent in adults. Intravenous induction doses of midazolam depress the ventilatory response to carbon dioxide stimulation for 15 minutes or more beyond the duration of ventilatory depression following administration of thiopental in adults. Impairment of ventilatory response to carbon dioxide is more marked in adult patients with chronic obstructive pulmonary disease (COPD). Sedation with IV midazolam does not adversely affect the mechanics of respiration (resistance, static recoil, most lung volume measurements); total lung capacity and peak expiratory flow decrease significantly but static compliance and maximum expiratory flow at 50% of awake total lung capacity (Vmax) increase. In one study of pediatric patients under general anesthesia, intramuscular midazolam (100 or 200 mcg/kg) was shown to depress the response to carbon dioxide in a dose-related manner.


In cardiac hemodynamic studies in adults, IV induction of general anesthesia with midazolam was associated with a slight to moderate decrease in mean arterial pressure, cardiac output, stroke volume and systemic vascular resistance. Slow heart rates (less than 65/minute), particularly in patients taking propranolol for angina, tended to rise slightly; faster heart rates (e.g., 85/minute) tended to slow slightly. In pediatric patients, a comparison of IV midazolam (500 mcg/kg) with propofol (2.5 mg/kg) revealed a mean 15% decrease in systolic blood pressure in patients who had received IV midazolam vs a mean 25% decrease in systolic blood pressure following propofol.


Pharmacokinetics:


Midazolam’s activity is primarily due to the parent drug. Elimination of the parent drug takes place via hepatic metabolism of midazolam to hydroxylated metabolites that are conjugated and excreted in the urine. Six single-dose pharmacokinetic studies involving healthy adults yield pharmacokinetic parameters for midazolam in the following ranges: volume of distribution (Vd), 1.0 to 3.1 L/kg; elimination half-life, 1.8 to 6.4 hours (mean approximately 3 hours); total clearance (Cl), 0.25 to 0.54 L/hr/kg. In a parallel group study, there was no difference in the clearance, in subjects administered 0.15 mg/kg (n=4) and 0.30 mg/kg (n=4) IV doses indicating linear kinetics. The clearance was successively reduced by approximately 30% at doses of 0.45 mg/kg (n=4) and 0.6 mg/kg (n=5) indicating non-linear kinetics in this dose range.


Absorption: The absolute bioavailability of the intramuscular route was greater than 90% in a cross-over study in which healthy subjects (n=17) were administered a 7.5 mg IV or IM dose. The mean peak concentration (Cmax) and time to peak (Tmax) following the IM dose was 90 ng/mL (20% CV) and 0.5 hr (50% CV). Cmax for the 1-hydroxy metabolite following the IM dose was 8 ng/mL (Tmax=1.0 hr).


Following IM administration, Cmax for midazolam and its 1-hydroxy metabolite were approximately one-half of those achieved after intravenous injection.


Distribution: The volume of distribution (Vd) determined from six single-dose pharmacokinetic studies involving healthy adults ranged from 1.0-3.1 L/kg. Female gender, old age, and obesity are associated with increased values of midazolam Vd. In humans, midazolam has been shown to cross the placenta and enter into fetal circulation and has been detected in human milk and CSF (see Special Populations).


In adults and children older than 1 year, midazolam is approximately 97% bound to plasma protein, principally albumin.


Metabolism: In vitro studies with human liver microsomes indicate that the biotransformation of midazolam is mediated by cytochrome P450-3A4. This cytochrome also appears to be present in gastrointestinal tract mucosa as well as liver. Sixty to seventy percent of the biotransformation products is 1-hydroxy-midazolam (also termed alpha-hydroxy-midazolam) while 4-hydroxy-midazolam constitutes 5% or less. Small amounts of a dihydroxy derivative have also been detected but not quantified. The principal urinary excretion products are glucuronide conjugates of the hydroxylated derivatives.


Drugs that inhibit the activity of cytochrome P450-3A4 may inhibit midazolam clearance and elevate steady-state midazolam concentrations.


Studies of the intravenous administration of 1-hydroxy-midazolam in humans suggest that 1-hydroxy-midazolam is at least as potent as the parent compound and may contribute to the net pharmacologic activity of midazolam. In vitro studies have demonstrated that the affinities of 1- and 4-hydroxy-midazolam for the benzodiazepine receptor are approximately 20% and 7%, respectively, relative to midazolam.


Excretion: Clearance of midazolam is reduced in association with old age, congestive heart failure, liver disease (cirrhosis) or conditions which diminish cardiac output and hepatic blood flow.


The principal urinary excretion product is 1-hydroxy-midazolam in the form of a glucuronide conjugate; smaller amounts of the glucuronide conjugates of 4-hydroxy- and dihydroxy-midazolam are detected as well. The amount of midazolam excreted unchanged in the urine after a single IV dose is less than 0.5% (n=5). Following a single IV infusion in 5 healthy volunteers, 45% to 57% of the dose was excreted in the urine as 1-hydroxymethyl midazolam conjugate.


Pharmacokinetics-continuous infusion: The pharmacokinetic profile of midazolam following continuous infusion, based on 282 adult subjects, has been shown to be similar to that following single-dose administration for subjects of comparable age, gender, body habitus and health status. However, midazolam can accumulate in peripheral tissues with continuous infusion. The effects of accumulation are greater after long-term infusions than after short-term infusions. The effects of accumulation can be reduced by maintaining the lowest midazolam infusion rate that produces satisfactory sedation.


Infrequent hypotensive episodes have occurred during continuous infusion; however, neither the time to onset nor the duration of the episode appeared to be related to plasma concentrations of midazolam or alpha-hydroxy-midazolam. Further, there does not appear to be an increased chance of occurrence of a hypotensive episode with increased loading doses.


Patients with renal impairment may have longer elimination half-lives for midazolam (see Special Populations: Renal Failure).


Special Populations:


Changes in the pharmacokinetic profile of midazolam due to drug interactions, physiological variables, etc., may result in changes in the plasma concentration-time profile and pharmacological response to midazolam in these patients. For example, patients with acute renal failure appear to have a longer elimination half-life for midazolam and may experience delayed recovery (see Special Populations: Renal Failure). In other groups, the relationship between prolonged half-life and duration of effect has not been established.


Pediatrics and Neonates: In pediatric patients aged 1 year and older, the pharmacokinetic properties following a single dose of midazolam reported in 10 separate studies of midazolam are similar to those in adults. Weight-normalized clearance is similar or higher (0.19 to 0.80 L/hr/kg) than in adults and the terminal elimination half-life (0.78 to 3.3 hours) is similar to or shorter than in adults. The pharmacokinetic properties during and following continuous intravenous infusion in pediatric patients in the operating room as an adjunct to general anesthesia and in the intensive care environment are similar to those in adults.


In seriously ill neonates, however, the terminal elimination half-life of midazolam is substantially prolonged (6.5 to 12.0 hours) and the clearance reduced (0.07 to 0.12 L/hr/kg) compared to healthy adults or other groups of pediatric patients. It cannot be determined if these differences are due to age, immature organ function or metabolic pathways, underlying illness or debility.


Obese: In a study comparing normals (n=20) and obese patients (n=20) the mean half-life was greater in the obese group (5.9 vs 2.3 hrs). This was due to an increase of approximately 50% in the Vd corrected for total body weight. The clearance was not significantly different between groups.


Geriatric: In three parallel group studies, the pharmacokinetics of midazolam administered IV or IM were compared in young (mean age 29, n=52) and healthy elderly subjects (mean age 73, n=53). Plasma half-life was approximately two-fold higher in the elderly. The mean Vd based on total body weight increased consistently between 15% to 100% in the elderly. The mean Cl decreased approximately 25% in the elderly in two studies and was similar to that of the younger patients in the other.


Congestive Heart Failure: In patients suffering from congestive heart failure, there appeared to be a two-fold increase in the elimination half-life, a 25% decrease in the plasma clearance and a 40% increase in the volume of distribution of midazolam.


Hepatic Insufficiency: Midazolam pharmacokinetics were studied after an IV single dose (0.075 mg/kg) was administered to 7 patients with biopsy proven alcoholic cirrhosis and 8 control patients. The mean half-life of midazolam increased 2.5-fold in the alcoholic patients. Clearance was reduced by 50% and the Vd increased by 20%. In another study in 21 male patients with cirrhosis, without ascites and with normal kidney function as determined by creatinine clearance, no changes in the pharmacokinetics of midazolam or 1-hydroxy-midazolam were observed when compared to healthy individuals.


Renal Failure: Patients with renal impairment may have longer elimination half-lives for midazolam and its metabolites which may result in slower recovery.


Midazolam and 1-hydroxy-midazolam pharmacokinetics in 6 ICU patients who developed acute renal failure (ARF) were compared with a normal renal function control group. Midazolam was administered as an infusion (5 to 15 mg/hr). Midazolam clearance was reduced (1.9 vs 2.8 mL/min/kg) and the half-life was prolonged (7.6 vs 13 hr) in the ARF patients. The renal clearance of the 1-hydroxy-midazolam glucuronide was prolonged in the ARF group (4 vs 136 mL/min) and the half-life was prolonged (12 hr vs >25 hr). Plasma levels accumulated in all ARF patients to about ten times that of the parent drug. The relationship between accumulating metabolite levels and prolonged sedation is unclear.


In a study of chronic renal failure patients (n=15) receiving a single IV dose, there was a two-fold increase in the clearance and volume of distribution but the half-life remained unchanged. Metabolite levels were not studied.


Plasma Concentration-Effect Relationship: Concentration-effect relationships (after an IV dose) have been demonstrated for a variety of pharmacodynamic measures (eg, reaction time, eye movement, sedation) and are associated with extensive intersubject variability. Logistic regression analysis of sedation scores and steady-state plasma concentration indicated that at plasma concentrations greater than 100 ng/mL there was at least a 50% probability that patients would be sedated, but respond to verbal commands (sedation score = 3). At 200 ng/mL there was at least a 50% probability that patients would be asleep, but respond to glabellar tap (sedation score = 4).


Drug Interactions: For information concerning pharmacokinetic drug interactions with midazolam, see PRECAUTIONS.



Indications and Usage for Midazolam Injection


Midazolam Injection is indicated:


  • intramuscularly or intravenously for preoperative sedation/anxiolysis/amnesia;

  • intravenously as an agent for sedation/anxiolysis/amnesia prior to or during diagnostic, therapeutic or endoscopic procedures, such as bronchoscopy, gastroscopy, cystoscopy, coronary angiography, cardiac catheterization, oncology procedures, radiologic procedures, suture of lacerations and other procedures either alone or in combination with other CNS depressants;

  • intravenously for induction of general anesthesia, before administration of other anesthetic agents. With the use of narcotic premedication, induction of anesthesia can be attained within a relatively narrow dose range and in a short period of time. Intravenous midazolam can also be used as a component of intravenous supplementation of nitrous oxide and oxygen (balanced anesthesia);

  • continuous intravenous infusion for sedation of intubated and mechanically ventilated patients as a component of anesthesia or during treatment in a critical care setting.

Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours (see CLINICAL PHARMACOLOGY).



Contraindications


Midazolam Injection is contraindicated in patients with a known hypersensitivity to the drug. Benzodiazepines are contraindicated in patients with acute narrow-angle glaucoma. Benzodiazepines may be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction with midazolam; patients with glaucoma have not been studied.



Warnings


Midazolam must never be used without individualization of dosage particularly when used with other medications capable of producing central nervous system depression. Prior to the intravenous administration of midazolam in any dose, the immediate availability of oxygen, resuscitative drugs, age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and skilled personnel for the maintenance of a patent airway and support of ventilation should be ensured. Patients should be continuously monitored with some means of detection for early signs of hypoventilation, airway obstruction, or apnea, i.e., pulse oximetry. Hypoventilation, airway obstruction, and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately. The immediate availability of specific reversal agents (flumazenil) is highly recommended. Vital signs should continue to be monitored during the recovery period. Because intravenous midazolam depresses respiration (see CLINICAL PHARMACOLOGY) and because opioid agonists and other sedatives can add to this depression, midazolam should be administered as an induction agent only by a person trained in general anesthesia and should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintaining a patent airway and supporting ventilation. When used for sedation/anxiolysis/amnesia, midazolam should always be titrated slowly in adult or pediatric patients. Adverse hemodynamic events have been reported in pediatric patients with cardiovascular instability; rapid intravenous administration should also be avoided in this population. See DOSAGE AND ADMINISTRATION for complete information.


Serious cardiorespiratory adverse events have occurred after administration of midazolam. These have included respiratory depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest and/or cardiac arrest, sometimes resulting in death or permanent neurologic injury. There have also been rare reports of hypotensive episodes requiring treatment during or after diagnostic or surgical manipulations particularly in adult or pediatric patients with hemodynamic instability. Hypotension occurred more frequently in the sedation studies in patients premedicated with a narcotic.


Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients. These reactions may be due to inadequate or excessive dosing or improper administration of midazolam; however, consideration should be given to the possibility of cerebral hypoxia or true paradoxical reactions. Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding. Reversal of such responses with flumazenil has been reported in pediatric patients.


Concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect. Narcotic premeditation also depresses the ventilatory response to carbon dioxide stimulation.


Higher risk adult and pediatric surgical patients, elderly patients and debilitated adult and pediatric patients require lower dosages, whether or not concomitant sedating medications have been administered. Adult or pediatric patients with COPD are unusually sensitive to the respiratory depressant effect of midazolam. Pediatric and adult patients undergoing procedures involving the upper airway such as upper endoscopy or dental care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction. Adult and pediatric patients with chronic renal failure and patients with congestive heart failure eliminate midazolam more slowly (see CLINICAL PHARMACOLOGY). Because elderly patients frequently have inefficient function of one or more organ systems and because dosage requirements have been shown to decrease with age, reduced initial dosage of midazolam is recommended, and the possibility of profound and/or prolonged effect should be considered.


Injectable midazolam should not be administered to adult or pediatric patients in shock or coma, or in acute alcohol intoxication with depression of vital signs. Particular care should be exercised in the use of intravenous midazolam in adult or pediatric patients with uncompensated acute illnesses, such as severe fluid or electrolyte disturbances.


There have been limited reports of intra-arterial injection of midazolam. Adverse events have included local reactions, as well as isolated reports of seizure activity in which no clear causal relationship was established. Precautions against unintended intra-arterial injection should be taken. Extravasation should also be avoided.


The safety and efficacy of midazolam following nonintravenous and nonintramuscular routes of administration have not been established. Midazolam should only be administered intramuscularly or intravenously.


The decision as to when patients who have received injectable midazolam, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized. Gross tests of recovery from the effects of midazolam (see CLINICAL PHARMACOLOGY) cannot be relied upon to predict reaction time under stress. It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided or until one full day after anesthesia and surgery, whichever is longer. For pediatric patients, particular care should be taken to assure safe ambulation.


Usage in Pregnancy: An increased risk of congenital malformations associated with the use of benzodiazepine drugs (diazepam and chlordiazepoxide) has been suggested in several studies. If this drug is used during pregnancy, the patient should be apprised of the potential hazard to the fetus.


Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE).


Usage In Preterm Infants And Neonates: Rapid injection should be avoided in the neonatal population. Midazolam administered rapidly as an intravenous injection (less than 2 minutes) has been associated with severe hypotension in neonates, particularly when the patient has also received fentanyl. Likewise, severe hypotension has been observed in neonates receiving a continuous infusion of midazolam who then receive a rapid intravenous injection of fentanyl. Seizures have been reported in several neonates following rapid intravenous administration.


The neonate also has reduced and/or immature organ function and is also vulnerable to profound and/or prolonged respiratory effects of midazolam.



Precautions


General: Intravenous doses of midazolam should be decreased for elderly and for debilitated patients (see WARNINGS and DOSAGE AND ADMINISTRATION). These patients will also probably take longer to recover completely after midazolam administration for the induction of anesthesia.


Midazolam does not protect against the increase in intracranial pressure or against the heart rate rise and/or blood pressure rise associated with endotracheal intubation under light general anesthesia.


Use with Other CNS Depressants: The efficacy and safety of midazolam in clinical use are functions of the dose administered, the clinical status of the individual patient, and the use of concomitant medications capable of depressing the CNS. Anticipated effects range from mild sedation to deep levels of sedation virtually equivalent to a state of general anesthesia where the patient may require external support of vital functions. Care must be taken to individualize and carefully titrate the dose of midazolam to the patient's underlying medical/surgical conditions, administer to the desired effect being certain to wait an adequate time for peak CNS effects of both midazolam and concomitant medications, and have the personnel and size-appropriate equipment and facilities available for monitoring and intervention (see Boxed WARNING, WARNINGS and DOSAGE AND ADMINISTRATION). Practitioners administering midazolam must have the skills necessary to manage reasonably foreseeable adverse effects, particularly skills in airway management. For information regarding withdrawal see DRUG ABUSE AND DEPENDENCE.


Information for Patients: To assure safe and effective use of benzodiazepines, the following information and instructions should be communicated to the patient when appropriate:


1.      Inform your physician about any alcohol consumption and medicine you are now taking, especially blood pressure medication and antibiotics, including drugs you buy without a prescription. Alcohol has an increased effect when consumed with benzodiazepines; therefore, caution should be exercised regarding simultaneous ingestion of alcohol during benzodiazepine treatment.


2.      Inform your physician if you are pregnant or are planning to become pregnant.


3.      Inform your physician if you are nursing.


4.      Patients should be informed of the pharmacological effects of midazolam, such as sedation and amnesia, which in some patients may be profound. The decision as to when patients who have received injectable midazolam, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized.


5.      Patients receiving continuous infusion of midazolam in critical care settings over an extended period of time, may experience symptoms of withdrawal following abrupt discontinuation.


Drug Interactions: The sedative effect of intravenous midazolam is accentuated by any concomitantly administered medication, which depresses the central nervous system, particularly narcotics (e.g., morphine, meperidine and fentanyl) and also secobarbital and droperidol. Consequently, the dosage of midazolam should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response (see DOSAGE AND ADMINISTRATION).


Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the P450-3A4 enzyme system such as cimetidine (not ranitidine), erythromycin, diltiazem, verapamil, ketoconazole and itraconazole. These drug interactions may result in prolonged sedation due to a decrease in plasma clearance of midazolam.


The effect of single oral doses of 800 mg cimetidine and 300 mg ranitidine on steady-state concentrations of midazolam was examined in a randomized crossover study (n=8). Cimetidine increased the mean midazolam steady-state concentration from 57 to 71 ng/mL. Ranitidine increased the mean steady-state concentration to 62 ng/mL. No change in choice reaction time or sedation index was detected after dosing with the H2 receptor antagonists.


In a placebo-controlled study, erythromycin administered as a 500 mg dose, tid, for 1 week (n=6), reduced the clearance of midazolam following a single 0.5 mg/kg IV dose. The half-life was approximately doubled.


Caution is advised when midazolam is administered to patients receiving erythromycin since this may result in a decrease in the plasma clearance of midazolam.


The effects of diltiazem (60 mg tid) and verapamil (80 mg tid) on the pharmacokinetics and pharmacodynamics of midazolam were investigated in a three-way crossover study (n=9). The half-life of midazolam increased from 5 to 7 hours when midazolam was taken in conjunction with verapamil or diltiazem. No interaction was observed in healthy subjects between midazolam and nifedipine.


In a placebo-controlled study, saquinavir administered as a 1200 mg dose, tid, for 5 days (n=12), a 56% reduction in the clearance of midazolam following a single 0.05 mg/kg IV dose was observed. The half-life was approximately doubled.


A moderate reduction in induction dosage requirements of thiopental (about 15%) has been noted following use of intramuscular midazolam for premedication in adults.


The intravenous administration of midazolam decreases the minimum alveolar concentration (MAC) of halothane required for general anesthesia. This decrease correlates with the dose of midazolam administered; no similar studies have been carried out in pediatric patients but there is no scientific reason to expect that pediatric patients would respond differently than adults.


Although the possibility of minor interactive effects has not been fully studied, midazolam and pancuronium have been used together in patients without noting clinically significant changes in dosage, onset or duration in adults. Midazolam does not protect against the characteristic circulatory changes noted after administration of succinylcholine or pancuronium and does not protect against the increased intracranial pressure noted following administration of succinylcholine. Midazolam does not cause a clinically significant change in dosage, onset or duration of a single intubating dose of succinylcholine; no similar studies have been carried out in pediatric patients but there is no scientific reason to expect that pediatric patients would respond differently than adults.


No significant adverse interactions with commonly used premedications or drugs used during anesthesia and surgery (including atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, d-tubocurarine, succinylcholine and other nondepolarizing muscle relaxants) or topical local anesthetics (including lidocaine, dyclonine HCl and Cetacaine) have been observed in adults or pediatric patients. In neonates, however, severe hypotension has been reported with concomitant administration of fentanyl. This effect has been observed in neonates on an infusion of midazolam who received a rapid injection of fentanyl and in patients on an infusion of fentanyl who have received a rapid injection of midazolam.


Drug/Laboratory Test Interactions: Midazolam has not been shown to interfere with results obtained in clinical laboratory tests.


Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Midazolam maleate was administered with diet in mice and rats for 2 years at dosages of 1, 9 and 80 mg/kg/day. In female mice in the highest dose group there was a marked increase in the incidence of hepatic tumors. In high-dose male rats there was a small but statistically significant increase in benign thyroid follicular cell tumors. Dosages of 9 mg/kg/day of midazolam maleate (25 times a human dose of 0.35 mg/kg) do not increase the incidence of tumors. The pathogenesis of induction of these tumors is not known. These tumors were found after chronic administration, whereas human use will ordinarily be of single or several doses.


Mutagenesis: Midazolam did not have mutagenic activity in Salmonella typhimurium (5 bacterial strains), Chinese hamster lung cells (V79), human lymphocytes or in the micronucleus test in mice.


Impairment of Fertility: A reproduction study in male and female rats did not show any impairment of fertility at dosages up to 10 times the human IV dose of 0.35 mg/kg.


Pregnancy: Teratogenic Effects: Pregnancy Category D (see WARNINGS).


Segment II teratology studies, performed with midazolam maleate injectable in rabbits and rats at 5 and 10 times the human dose of 0.35 mg/kg, did not show evidence of teratogenicity.


Nonteratogenic Effects: Studies in rats showed no adverse effects on reproductive parameters during gestation and lactation. Dosages tested were approximately 10 times the human dose of 0.35 mg/kg.


Labor and Delivery: In humans, measurable levels of midazolam were found in maternal venous serum, umbilical venous and arterial serum and amniotic fluid, indicating placental transfer of the drug. Following intramuscular administration of 0.05 mg/kg of midazolam, both the venous and the umbilical arterial serum concentrations were lower than maternal concentrations.


The use of injectable midazolam in obstetrics has not been evaluated in clinical studies. Because midazolam is transferred transplacentally and because other benzodiazepines given in the last weeks of pregnancy have resulted in neonatal CNS depression, midazolam is not recommended for obstetrical use.


Nursing Mothers: Midazolam is excreted in human milk. Caution should be exercised when midazolam is administered to a nursing woman.


Pediatric Use: The safety and efficacy of midazolam for sedation/anxiolysis/amnesia following single dose intramuscular administration, intravenously by intermittent injections and continuous infusion have been established in pediatric and neonatal patients. For specific safety monitoring and dosage guidelines (see Boxed WARNING, CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE, WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, OVERDOSAGE and DOSAGE AND ADMINISTRATION). UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require closer monitoring. In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.


Midazolam should not be administered by rapid injection in the neonatal population. Severe hypotension and seizures have been reported following rapid IV administration, particularly, with concomitant use of fentanyl.


Geriatric Use: Because geriatric patients may have altered drug distribution and diminished hepatic and/or renal function, reduced doses of midazolam are recommended. Intravenous and intramuscular doses of midazolam should be decreased for elderly and for debilitated patients (see WARNINGS and DOSAGE AND ADMINISTRATION) and subjects over 70 years of age may be particularly sensitive. These patients will also probably take longer to recover completely after midazolam administration for the induction of anesthesia. Administration of IM and IV midazolam to elderly and/or high risk surgical patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression. In most of these cases, the patients also received other central nervous system depressants capable of depressing respiration, especially narcotics (see DOSAGE AND ADMINISTRATION).


Specific dosing and monitoring guidelines for geriatric patients are provided in the DOSAGE AND ADMINISTRATION section for premedicated patients for sedation/anxiolysis/amnesia following IV and IM administration, for induction of anesthesia following IV administration and for continuous infusion.



Adverse Reactions


See WARNINGS concerning serious cardiorespiratory events and possible paradoxical reactions. Fluctuations in vital signs were the most frequently seen findings following parenteral administration of midazolam in adults and included decreased tidal volume and/or respiratory rate decrease (23.3% of patients following IV and 10.8% of patients following IM administration) and apnea (15.4% of patients following IV administration), as well as variations in blood pressure and pulse rate. The majority of serious adverse effects, particularly those associated with oxygenation and ventilation, have been reported when midazolam is administered with other medications capable of depressing the central nervous system. The incidence of such events is higher in patients undergoing procedures involving the airway without the protective effect of an endotracheal tube (e.g., upper endoscopy and dental procedures).


Adults: The following additional adverse reactions were reported after intramuscular administration:


                        headache (1.3%)                            Local effects at IM Injection site


                                                                              pain (3.7%)


                                                                              induration (0.5%)


                                                                              redness (0.5%)


                                                                              muscle stiffness (0.3%)


Administration of IM midazolam to elderly and/or higher risk surgical patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression. In most of these cases, the patients also received other central nervous system depressants capable of depressing respiration, especially narcotics (see DOSAGE AND ADMINISTRATION).


The following additional adverse reactions were reported subsequent to intravenous administration as a single sedative/anxiolytic/amnestic agent in adult patients:


                        hiccoughs (3.9%)                            Local effects at the IV site


                        nausea (2.8%)                                tenderness (5.6%)


                        vomiting (2.6%)                              pain during injection (5.0%)


                        coughing (1.3%)                             redness (2.6%)


                        “oversedation” (1.6%)                    induration (1.7%)


                        headache (1.5%)                            phlebitis (0.4%)


                        drowsiness (1.2%)


Pediatric Patients: The following adverse events related to the use of IV midazolam in pediatric patients were reported in the medical literature: desaturation 4.6%, apnea 2.8%, hypotension 2.7%, paradoxical reactions 2.0%, hiccough 1.2 %, seizure-like activity 1.1% and nystagmus 1.1%. The majority of airway-related events occurred in patients receiving other CNS depressing medications and in patients where midazolam was not used as a single sedating agent.


Neonates: For information concerning hypotensive episodes and seizures following the administration of midazolam to neonates, (see Boxed WARNING, CONTRAINDICATIONS, WARNINGS and PRECAUTIONS).


Other adverse experiences, observed mainly following IV injection as a single sedative/anxiolytic/amnesia agent and occurring at an incidence of <1.0% in adult and pediatric patients, are as follows:


Respiratory: Laryngospasm, bronchospasm, dyspnea, hyperventilation, wheezing, shallow respirations, airway obstruction, tachypnea


Cardiovascular: Bigeminy, premature ventricular contractions, vasovagal episode, bradycardia, tachycardia, nodal rhythm


Gastrointestinal: Acid taste, excessive salivation, retching


CNS/Neuromuscular: Retrograde amnesia, euphoria, hallucination, confusion, argumentativeness, nervousness, anxiety, grogginess, restlessness, emergence delirium or agitation, prolonged emergence from anesthesia, dreaming during emergence, sleep disturbance, insomnia, nightmares, athetoid movements, seizure-like activity, ataxia, dizziness, dysphoria, slurred speech, dysphonia, paresthesia


Special Senses: Blurred vision, diplopia, nystagmus, pinpoint pupils, cyclic movements of eyelids, visual disturbance, difficulty focusing eyes, ears blocked, loss of balance, light-headedness


Integumentary: Hive-like elevation at injection site, swelling or feeling of burning, warmth or coldness at injection site


Hypersensitivity: Allergic reactions including anaphylactoid reactions, hives, rash, pruritus


Miscellaneous: Yawning, lethargy, chills, weakness, toothache, faint feeling, hematoma



Drug Abuse and Dependence


Midazolam is subject to Schedule IV control under the Controlled Substances Act of 1970.


Midazolam was actively self-administered in primate models used to assess the positive reinforcing effects of psychoactive drugs.


Midazolam produced physical dependence of a mild to moderate intensity in cynomolgus monkeys after 5 to 10 weeks of administration. Available data concerning the drug abuse and dependence potential of midazolam suggest that its abuse potential is at least equivalent to that of diazepam.


Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol (convulsions, hallucinations, tremor, abdominal and muscle cramps, vomiting and sweating), have occurred following abrupt discontinuation of benzodiazepines, including midazolam. Abdominal distention, nausea, vomiting, and tachycardia are prominent symptoms of withdrawal in infants. The more severe withdrawal symptoms have usually been limited to those patients who had received excessive doses over an extended period of time. Generally milder withdrawal symptoms (e.g., dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed. There is no consensus in the medical literature regarding tapering schedules; therefore, practitioners are advised to individualize therapy to meet patient's needs. In some case reports, patients who have had severe withdrawal reactions due to abrupt discontinuation of high-dose long-term midazolam, have been successfully weaned off of midazolam over a period of several days.



Overdosage


The manifestations of midazolam overdosage reported are similar to those observed with other benzodiazepines, including sedation, somnolence, confusion, impaired coordination, diminished reflexes, coma and untoward effects on vital signs. No evidence of specific organ toxicity from midazolam overdosage has been reported.


Treatment of Overdosage: Treatment of injectable midazolam overdosage is the same as that followed for overdosage with other benzodiazepines. Respiration, pulse rate and blood pressure should be monitored and general supportive measures should be employed. Attention should be given to the maintenance of a patent airway and support of ventilation, including administration of oxygen. An intrav