Alvesco 80 Inhaler (Nycomed UK Ltd)

1. Name Of The Medicinal Product

Alvesco^® 80 Inhaler

2. Qualitative And Quantitative Composition

1 actuation (delivered dose from the mouthpiece) contains 80 micrograms of ciclesonide.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Pressurised inhalation, solution

Clear and colourless

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment to control persistent asthma in adults and adolescents (12 years and older).

4.2 Posology And Method Of Administration

The medicinal product is for inhalation use only.

Dosing recommendation for adults and adolescents:

The recommended dose of Alvesco is 160 micrograms once daily, which leads to asthma control in the majority of patients. However in severe asthmatics, a 12 week study has shown that a dose of 640 micrograms/day (given 320 micrograms twice daily) has demonstrated a reduction in the frequency of exacerbations but without an improvement in lung function (see section 5.1). Dose reduction to 80 micrograms once daily may be an effective maintenance dose for some patients.

Alvesco should preferably be administered in the evening although morning dosing of Alvesco has also been shown to be effective. The final decision on evening or morning dosing should be left to the discretion of the physician.

Symptoms start to improve with Alvesco within 24 hours of treatment. Once control is achieved, the dose of Alvesco should be individualised and titrated to the minimum dose needed to maintain good asthma control.

Patients with severe asthma are at risk of acute attacks and should have regular assessments of their asthma control including pulmonary function tests. Increasing use of short-acting bronchodilators to relieve asthma symptoms indicates deterioration of asthma control. If patients find that short-acting relief bronchodilator treatment becomes less effective, or they need more inhalations than usual, medical attention must be sought. In this situation, patients should be reassessed and consideration given to the need for increased anti-inflammatory treatment therapy (e.g. a higher dose of Alvesco for a short period [see section 5.1] or a course of oral corticosteroids). Severe asthma exacerbations should be managed the usual way.

To address specific patient needs, such as finding it difficult to press the inhaler and breathe in at the same time, Alvesco can be used with the AeroChamber Plus spacer device.

Specific patient groups:

There is no need to adjust the dose in elderly patients or those with hepatic or renal impairment.

To date, there are insufficient data available in the treatment of children under 12 years of age with ciclesonide.

Instructions for use / handling:

The patient needs to be instructed how to use the inhaler correctly.

If the inhaler is new or has not been used for one week or more, three puffs should be released into the air. No shaking is necessary as this is a solution aerosol.

During inhalation, the patient should preferably sit or stand, and the inhaler should be held upright with the thumb on the base, below the mouthpiece.

Instruct the patient to remove the mouthpiece cover, place the inhaler into their mouth, close their lips around the mouthpiece, and breathe in slowly and deeply. While breathing in through the mouth, the top of the inhaler should be pressed down. Then, patients should remove the inhaler from their mouth, and hold their breath for about 10 seconds, or as long as is comfortable. The patient is not to breathe out into the inhaler. Finally, patients should breathe out slowly and replace the mouthpiece cover.

The mouthpiece should be cleaned with a dry tissue or cloth weekly. The inhaler should not be washed or put in water.

For detailed instructions see Patient Information Leaflet.

4.3 Contraindications

Hypersensitivity to ciclesonide or any of the excipients.

4.4 Special Warnings And Precautions For Use

As with all inhaled corticosteroids, Alvesco should be administered with caution in patients with active or quiescent pulmonary tuberculosis, fungal, viral or bacterial infections, and only if these patients are adequately treated.

As with all inhaled corticosteroids, Alvesco is not indicated in the treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.

As with all inhaled corticosteroids, Alvesco is not designed to relieve acute asthma symptoms for which an inhaled short-acting bronchodilator is required. Patients should be advised to have such rescue medication available.

Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma, and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). It is therefore important that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.

It is recommended that the height of children and adolescents receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be reviewed with the aim of reducing the dose of inhaled corticosteroid, if possible to the lowest dose at which effective control of asthma is maintained. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.

There is no data available in patients with severe hepatic impairment. An increased exposure in patients with severe hepatic impairment is expected and these patients should therefore be monitored for potential systemic effects.

The benefits of inhaled ciclesonide should minimise the need for oral steroids. However, patients transferred from oral steroids remain at risk of impaired adrenal reserve for a considerable time after transferring to inhaled ciclesonide. The possibility of respective symptoms may persist for some time.

These patients may require specialised advice to determine the extent of adrenal impairment before elective procedures. The possibility of residual impaired adrenal response should always be considered in an emergency (medical or surgical) and elective situations likely to produce stress, and appropriate corticosteroid treatment considered.

For the transfer of patients being treated with oral corticosteroids:

The transfer of oral steroid-dependent patients to inhaled ciclesonide, and their subsequent management, needs special care as recovery from impaired adrenocortical function, caused by prolonged systemic steroid therapy, may take a considerable time.

Patients who have been treated with systemic steroids for long periods of time, or at a high dose, may have adrenocortical suppression. With these patients adrenocortical function should be monitored regularly and their dose of systemic steroid reduced cautiously.

After approximately a week, gradual withdrawal of the systemic steroid is started by reducing the dose by 1 mg prednisolone per week, or its equivalent. For maintenance doses of prednisolone in excess of 10 mg daily, it may be appropriate to cautiously use larger reductions in dose at weekly intervals.

Some patients feel unwell in a non-specific way during the withdrawal phase despite maintenance or even improvement of respiratory function. They should be encouraged to persevere with inhaled ciclesonide and to continue withdrawal of systemic steroid, unless there are objective signs of adrenal insufficiency.

Patients transferred from oral steroids whose adrenocortical function is still impaired should carry a steroid warning card indicating that they need supplementary systemic steroid during periods of stress, e.g. worsening asthma attacks, chest infections, major intercurrent illness, surgery, trauma, etc.

Replacement of systemic steroid treatment with inhaled therapy sometimes unmasks allergies such as allergic rhinitis or eczema previously controlled by systemic drug.

Paradoxical bronchospasm with an immediate increase of wheezing or other symptoms of bronchoconstriction after dosing should be treated with an inhaled short-acting bronchodilator, which usually results in quick relief. The patient should be assessed and therapy with Alvesco should only be continued, if after careful consideration the expected benefit is greater than the possible risk. Correlation between severity of asthma and general susceptibility for acute bronchial reactions should be kept in mind (see section 4.8).

Patients inhaler technique should be checked regularly to make sure that inhaler actuation is synchronised with inhaling to ensure optimum delivery to the lungs.

Concomitant treatment with ketoconazole or other potent CYP3A4 inhibitors should be avoided unless the benefit outweighs the increased risk of systemic side effects of corticosteroids (see section 4.5).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In vitro data indicate that CYP3A4 is the major enzyme involved in the metabolism of the active metabolite of ciclesonide M1 in man.

In a drug-drug interaction study at steady state with ciclesonide and ketoconazole as a potent CYP3A4 inhibitor, the exposure to the active metabolite M1 increased approximately 3.5-fold, whereas the exposure to ciclesonide was not affected. Therefore the concomitant administration of potent inhibitors of CYP 3A4 (e.g. ketoconazole, itraconazole and ritonavir or nelfinavir) should be avoided unless the benefit outweighs the increased risk of systemic side effects of corticosteroids.

4.6 Pregnancy And Lactation

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

In animal studies glucocorticoids have been shown to induce malformations (see section 5.3). This is not likely to be relevant for humans given recommended inhalation doses.

As with other glucocorticoids, ciclesonide should only be used during pregnancy if the potential benefit to the mother justifies the potential risk to the fetus. The lowest effective dose of ciclesonide needed to maintain adequate asthma control should be used.

Infants born of mothers who received corticosteroids during pregnancy are to be observed carefully for hypoadrenalism.

It is unknown whether inhaled ciclesonide is excreted in human breast milk. Administration of ciclesonide to women who are breast-feeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.

4.7 Effects On Ability To Drive And Use Machines

Inhaled ciclesonide has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

Approximately 5% of patients experienced adverse reactions in clinical trials with Alvesco given in the dose range 40 to 1280 micrograms per day. In the majority of cases, these were mild and did not require discontinuation of treatment with Alvesco.

Frequency	Uncommon (>1/1,000, <1/100)	Rare (1/10,000 – 1/,1000)	Unknown
System Organ Class
Cardiac Disorders		Palpitations**
Gastrointestinal Disorders	Nausea, vomiting* Bad taste	Abdominal pain* Dyspepsia*
General disorders and administration site conditions	Application site reactions Application site dryness
Immune System Disorders		Angioedema Hypersensitivity
Infections and infestations	Oral fungal infections*
Nervous System Disorders	Headache*
Psychiatric Disorders			Psychomotor hyperactivity, sleep disorders, anxiety, depression, aggression, behavioural changes (predominantly in children)
Respiratory, thoracic and mediastinal disorders	Dysphonia Cough after inhalation* Paradoxical bronchospasm*
Skin and subcutaneous tissue disorders	Eczema and rash
Vascular disorders		Hypertension

* Similar or lower incidence when compared with placebo

** Palpitations were observed in clinical trials in cases mostly confounded with concomitant medication with known cardiac effects (e.g. theophylline or salbutamol).

Paradoxical bronchospasm may occur immediately after dosing and is an unspecific acute reaction to all inhaled medicinal products, which may be related to the active substance, the excipient, or evaporation cooling in the case of metered dose inhalers. In severe cases, withdrawal of Alvesco should be considered.

Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma (see also section 4.4).

4.9 Overdose

Acute:

Inhalation by healthy volunteers of a single dose of 2880 micrograms of ciclesonide was well tolerated.

The potential for acute toxic effects following overdose of inhaled ciclesonide is low. After acute overdosage no specific treatment is necessary.

Chronic:

After prolonged administration of 1280 micrograms of ciclesonide, no clinical signs of adrenal suppression were observed. However, if higher than recommended dosage is continued over prolonged periods, some degree of adrenal suppression cannot be excluded. Monitoring of adrenal reserve may be necessary.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other drugs for obstructive airway diseases, Inhalants, Glucocorticoids, ATC Code: R03B A08

Ciclesonide exhibits low binding affinity to the glucocorticoid-receptor. Once orally inhaled, ciclesonide is enzymatically converted in the lungs to the principal metabolite (C21-des-methylpropionyl-ciclesonide) which has a pronounced anti-inflammatory activity and is thus considered as the active metabolite.

In four clinical trials, ciclesonide has been shown to reduce airway hyperresponsiveness to adenosine monophosphate in hyperreactive patients with maximal effect observed at the dose of 640 micrograms. In another trial, pretreatment with ciclesonide for seven days significantly attenuated the early and late phase reactions following inhaled allergen challenge. Inhaled ciclesonide treatment was also shown to attenuate the increase in inflammatory cells (total eosinophils) and inflammatory mediators in induced sputum.

A controlled study compared 24-hour plasma cortisol AUC in 26 adult asthmatic patients following 7 days of treatment. Compared to placebo, treatment with ciclesonide 320, 640, and 1,280 micrograms/day did not statistically significantly lower the 24-hour time averages of plasma cortisol (AUC_(0-24)/24 hours) nor was a dose-dependent effect seen.

In a clinical trial involving 164 adult male and female asthmatic patients, ciclesonide was given at doses of 320 micrograms or 640 micrograms/day over 12 weeks. After stimulation with 1 and 250 micrograms cosyntropin, no significant changes in plasma cortisol levels were observed versus placebo.

Double-blind placebo-controlled trials of 12-weeks duration in adults and adolescents have shown that treatment with ciclesonide resulted in improved lung function as measured by FEV₁ and peak expiratory flow, improved asthma symptom control, and decreased need for inhaled beta-2 agonist.

In a 12-week study of 680 severe asthmatics, previously treated with 500-1,000 micrograms fluticasone propionate per day or equivalent, 87.3% and 93.3% of patients remained exacerbation-free during treatment with 160 or 640 micrograms of ciclesonide, respectively. At the end of the 12 week study period, the results showed a statistically significant difference between the doses of 160 micrograms and 640 micrograms/day ciclesonide with regard to the occurrence of an exacerbation after the first day of the study: 43 patients/339 (= 12.7%) in the 160 micrograms/day group and 23 patients/341 (6.7%) in the 640 micrograms/day group (Hazard ratio=0.526; p= 0.0134). Both ciclesonide doses resulted in comparable FEV1 values at 12 weeks. Treatment-related adverse events were seen in 3.8% and 5% of patients treated with 160 or 640 micrograms per day of ciclesonide respectively. No study was performed to compare 160 micrograms, 320 micrograms and 640 micrograms daily dose in patients with severe asthma.

5.2 Pharmacokinetic Properties

Ciclesonide is presented in HFA-134a propellant and ethanol as a solution aerosol, which demonstrates a linear relationship between different doses, puff strengths and systemic exposure.

Absorption:

Studies with oral and intravenous dosing of radiolabeled ciclesonide have shown an incomplete extent of oral absorption (24.5%). The oral bioavailability of both ciclesonide and the active metabolite is negligible (<0.5% for ciclesonide, <1% for the metabolite). Based on a γ-scintigraphy experiment, lung deposition in healthy subjects is 52%. In line with this figure, the systemic bioavailability for the active metabolite is >50% by using the ciclesonide metered dose inhaler. As the oral bioavailability for the active metabolite is <1%, the swallowed portion of the inhaled ciclesonide does not contribute to systemic absorption.

Distribution:

Following intravenous administration to healthy subjects, the initial distribution phase for ciclesonide was rapid and consistent with its high lipophilicity. The volume of distribution averaged 2.9 l/kg. The total serum clearance of ciclesonide is high (average 2.0 l/h/kg) indicating a high hepatic extraction. The percentage of ciclesonide bound to human plasma proteins averaged 99%, and that of the active metabolite 98-99%, indicating an almost complete binding of circulating ciclesonide/active metabolite to plasma proteins.

Metabolism:

Ciclesonide is primarily hydrolysed to its biologically active metabolite by esterase enzymes in the lung. Investigation of the enzymology of further metabolism by human liver microsomes showed that this compound is mainly metabolized to hydroxylated inactive metabolites by CYP3A4 catalysis. Furthermore, reversible lipophilic fatty acid ester conjugates of the active metabolite were detected in the lung.

Excretion:

Ciclesonide is predominantly excreted via the faeces (67%), after oral and intravenous administration, indicating that excretion via the bile is the major route of elimination.

Pharmacokinetic characteristics in patients:

Asthmatic patients

Ciclesonide shows no pharmacokinetic changes in mild asthmatic patients compared to healthy subjects.

Renal or hepatic insufficiency, elderly

According to population pharmacokinetics, age has no impact on the systemic exposure of the active metabolite.

Reduced liver function may affect the elimination of corticosteroids. In a study including patients with hepatic impairment suffering from liver cirrhosis, a higher systemic exposure to the active metabolite was observed.

Due to the lack of renal excretion of the active metabolite, studies on renal impaired patients have not been performed.

5.3 Preclinical Safety Data

Preclinical data with ciclesonide reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, or carcinogenic potential.

In animal studies on reproductive toxicity, glucocorticosteroids have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal results do not seem to be relevant for humans given recommended doses.

A treatment-related effect on the ovaries (namely atrophy) was observed at the top dose in two 12-month studies in dogs. This effect occurred at systemic exposures 5.27-8.34 times those noted at the 160 µg daily dose. The relevance of this finding to humans is unknown.

Animal studies with other glucocorticoids indicate that administration of pharmacological doses of glucocorticoids during pregnancy may increase the risk for intrauterine growth retardation, adult cardiovascular and/or metabolic disease and/or permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behaviour. The relevance of these data to humans administered ciclesonide by inhalation is unknown.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Norflurane (HFA-134a)

Ethanol, anhydrous

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

30 metered actuations – 1 year

60 and 120 metered actuations – 3 years

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

The container contains a pressurised liquid. Do not expose to temperatures higher than 50°C.

The container should not be punctured, broken or burnt even when apparently empty.

6.5 Nature And Contents Of Container

The inhaler comprises a pressurised container made from aluminium and is sealed with a metering valve, mouthpiece, and cap.

30 metered actuations

60 metered actuations

120 metered actuations

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Patients should be carefully instructed in the proper use of their inhaler (see Patient Information Leaflet).

As with most inhaled medicinal products in pressurised containers, the therapeutic effect of this medicinal product may decrease when the container is cold. However, Alvesco delivers a consistent dose from –10°C to 40°C.

7. Marketing Authorisation Holder

Nycomed GmbH

Byk-Gulden-Str. 2

D-78467 Konstanz

Germany

8. Marketing Authorisation Number(S)

PL 31752/0005

9. Date Of First Authorisation/Renewal Of The Authorisation

16 April 2004/28 September 2009

10. Date Of Revision Of The Text

18 May 2011

Zelnorm

Generic Name: tegaserod (te GAS e rod)

Brand Names: Zelnorm

What is tegaserod?

Tegaserod was withdrawn from the U.S. market on March 30, 2007. This medication may still be used in limited emergency situations.

Tegaserod increases the action of a chemical called serotonin in the intestines. This speeds the movement of stools through the bowels.

Tegaserod is used to treat severe, chronic, irritable bowel syndrome (IBS) in women who have constipation (and not diarrhea) as their main bowel problem.

Tegaserod is also used to treat chronic constipation in patients younger than 55 years old.

Tegaserod may also be used for other purposes not listed in this medication guide.

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

Tegaserod was withdrawn from the U.S. market on March 30, 2007. This medication may still be used in limited emergency situations.

Tegaserod is not for use in people with diarrhea as the main symptom of their irritable bowel condition.

You should not use this medication if you are allergic to tegaserod, or if you have a history of stroke or heart attack, high blood pressure, uncontrolled angina, high cholesterol or triglycerides, diabetes, depression, or anxiety.

You also should not use tegaserod if you smoke, if you are older than 55 years, if you are overweight, or if you have a history of suicidal thoughts or actions.

Before taking tegaserod, tell your doctor if you have gallbladder problems, a blockage in your intestines, other stomach or intestinal disorders, kidney disease, or liver disease.

Tegaserod has not been shown to be helpful for men with irritable bowel syndrome. Stop taking tegaserod and call your doctor at once if you have new or worsening stomach pain, blood in your stools, ongoing diarrhea, severe stomach pain or cramps, or feel like you might pass out.

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

You should not use this medication if you are allergic to tegaserod, or if you have:

• 
  

  a history of stroke or heart attack;

  
  


• 
  

  untreated or uncontrolled angina (chest pain);

  
  


• 
  

  high blood pressure;

  
  


• 
  

  high cholesterol or triglycerides;

  
  


• 
  

  diabetes;

  
  


• 
  

  depression or anxiety;

  
  


• 
  

  if you smoke;

  
  


• 
  

  if you are older than 55 years;

  
  


• 
  

  if you are overweight; or

  
  


• 
  

  if you have a history of suicidal thoughts or actions.

  
  

Before taking tegaserod, tell your doctor if you are allergic to any drugs, or if you have:

• 
  

  diarrhea or if diarrhea is your main symptom of IBS;

  
  


• 
  

  gallbladder problems;

  
  


• 
  

  a blockage in your intestines;

  
  


• 
  

  any other stomach or intestinal disorders;

  
  


• 
  

  kidney disease; or

  
  


• liver disease.

If you have any of these conditions, you may need a dose adjustment or special tests to safely use tegaserod.

FDA pregnancy category B. This medication is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether tegaserod passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. Tegaserod has not been shown to be helpful for men with irritable bowel syndrome.

How should I take tegaserod?

Take this medication exactly as prescribed by your doctor. Do not take it in larger amounts or for longer than recommended. Follow the directions on your prescription label.

Take this medication with a full glass of water. Take tegaserod on an empty stomach.

Tegaserod is usually taken twice daily. Follow your doctor's instructions.

It may take up to 2 weeks of using this medicine before your symptoms improve. For best results, keep using the medication as directed. Talk with your doctor if your symptoms do not improve after 4 to 6 weeks of treatment.

Tegaserod is not a cure for irritable bowel syndrome. If you stop taking tegaserod, your symptoms may return within 1 or 2 weeks.

Store tegaserod at room temperature away from moisture and heat.

See also: Zelnorm dosage (in more detail)

What happens if I miss a dose?

If you miss a dose or forget to take your medicine, wait until it is time for your next dose and skip the missed dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

Overdose symptoms may include diarrhea, stomach pain, nausea, and vomiting.

What should I avoid while taking tegaserod?

Follow your doctor's instructions about any restrictions on food, beverages, or activity while you are using tegaserod.

Tegaserod 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 taking tegaserod and call your doctor at once if you have a serious side effect such as:

• 
  

  new or worsening stomach pain;

  
  


• 
  

  blood in your stools;

  
  


• 
  

  ongoing diarrhea;

  
  


• 
  

  severe stomach pain or cramps; or

  
  


• 
  

  feeling like you might pass out.

  
  

Less serious side effects may include:

• 
  

  headache, dizziness or migraine;

  
  


• 
  

  back pain or joint pain; or

  
  


• 
  

  mild stomach pain, nausea or gas.

  
  

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect.

What other drugs will affect tegaserod?

Other drugs may interact with tegaserod. Talk your doctor and pharmacist before taking any prescription or over-the-counter medicines, including herbal products.

More Zelnorm resources

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

• Zelnorm Prescribing Information (FDA)


• Zelnorm Monograph (AHFS DI)


• Zelnorm Advanced Consumer (Micromedex) - Includes Dosage Information


• Zelnorm MedFacts Consumer Leaflet (Wolters Kluwer)


• Zelnorm Consumer Overview

Compare Zelnorm with other medications

• Constipation, Chronic
• Irritable Bowel Syndrome

Where can I get more information?

• Your doctor or pharmacist can provide more information about tegaserod.

See also: Zelnorm side effects (in more detail)

Insulin Lispro Vials

Pronunciation: IN-su-lin LIS-pro
Generic Name: Insulin Lispro
Brand Name: Humalog

Insulin Lispro Vials are used for:

Treating diabetes mellitus. Insulin Lispro Vials are usually used with a longer-acting insulin or insulin pump therapy. In some patients, it may be used with a sulfonylurea antidiabetic instead of a longer-acting insulin.

Insulin Lispro Vials are a fast-acting form of the hormone insulin. It works by helping your body to use sugar properly. This lowers the amount of glucose in the blood, which helps to treat diabetes.

Do NOT use Insulin Lispro Vials if:

• you are allergic to any ingredient in Insulin Lispro Vials


• you are having an episode of low blood sugar

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

Before using Insulin Lispro Vials:

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

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


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


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


• if you drink alcoholic beverages or smoke


• if you have kidney or liver problems; nerve problems; adrenal, pituitary or thyroid problems; or diabetic ketoacidosis


• if you use 3 or more insulin injections per day


• if you are fasting, have high blood sodium levels, or are on a low salt diet

Some MEDICINES MAY INTERACT with Insulin Lispro Vials. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Beta-blockers (eg, propranolol), clonidine, guanethidine, lithium, or reserpine because they may increase the risk of high or low blood sugar or may hide the signs and symptoms of low blood sugar, if it occurs


• Angiotensin-converting (ACE) inhibitors (eg, enalapril), disopyramide, fenfluramine, fibrates (eg, clofibrate, gemfibrozil), fluoxetine, monoamine oxidase inhibitors (MAOIs) (eg, phenelzine), oral medicine for diabetes (eg, glipizide, metformin, nateglinide), pentamidine, propoxyphene, salicylates (eg, aspirin), somatostatin analogs (eg, octreotide), or sulfonamide antibiotics (eg, sulfamethoxazole) because the risk of low blood sugar may be increased


• Corticosteroids (eg, prednisone), danazol, diuretics (eg, furosemide, hydrochlorothiazide), estrogen, hormonal contraceptives (eg, birth control pills), isoniazid, niacin, phenothiazines (eg, chlorpromazine), progesterones (eg, medroxyprogesterone), somatropin, sympathomimetics (eg, albuterol, epinephrine, terbutaline), or thyroid hormones (eg, levothyroxine) because they may decrease Insulin Lispro Vials's effectiveness, resulting in high blood sugar

This may not be a complete list of all interactions that may occur. Ask your health care provider if Insulin Lispro Vials may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Insulin Lispro Vials:

Use Insulin Lispro Vials as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Insulin Lispro Vials. Talk to your pharmacist if you have questions about this information.


• Use Insulin Lispro Vials within 15 minutes before or immediately after a meal, unless directed otherwise by your doctor.


• If you will be using Insulin Lispro Vials at home, a health care provider will teach you how to use it. Be sure you understand how to use Insulin Lispro Vials. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions.


• You may use Insulin Lispro Vials in an insulin pump if you are directed to do so by your doctor. If you are using an insulin pump, do NOT dilute Insulin Lispro Vials or mix it together with any other type of insulin.


• Insulin Lispro Vials should be clear and colorless. Do not use Insulin Lispro Vials if it contains particles, is cloudy and discolored, or if the vial is cracked or damaged.


• If you are mixing Insulin Lispro Vials with another insulin, draw Insulin Lispro Vials into the syringe first. Inject the dose immediately after mixing, as directed by your doctor.


• Use the proper technique taught to you by your doctor. Inject deep under the skin, NOT into a vein or muscle.


• Injection sites within an injection area (abdomen, thigh, upper arm) must be rotated from one injection to the next.


• Be sure you have purchased the correct insulin. Insulin comes in a variety of containers, including vials, cartridges, and pens. Make sure that you understand how to properly measure and prepare your dose. If you have any questions about measuring and preparing your dose, contact your doctor or pharmacist for information.


• Insulin Lispro Vials begins lowering blood sugar within minutes after an injection. The peak effect occurs within 30 to 90 minutes after a dose. The effect lasts for up to 2 to 5 hours.


• Keep this product, as well as syringes and needles, out of the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.


• It is very important to follow your insulin regimen exactly. Do NOT miss any doses. Ask your doctor for specific instructions to follow in case you should ever miss a dose of insulin.

Ask your health care provider any questions you may have about how to use Insulin Lispro Vials.

Important safety information:

• Insulin Lispro Vials may cause dizziness, drowsiness, or changes in vision. These effects may be worse if you take it with alcohol or certain medicines. Use Insulin Lispro Vials with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Do not drink alcohol without discussing it with your doctor. Drinking alcohol may increase the risk of developing high or low blood sugar.


• Do not use more than the recommended dose, use Insulin Lispro Vials more often than prescribed, or change the type or dose of insulin you are using without checking with your doctor.


• Any change of insulin should be made cautiously and only under medical supervision. Changes in purity, strength, brand (manufacturer), type (regular, NPH, lente), species (beef, pork, beef-pork, human), and/or method of manufacture may require a change in dose.


• Illness, especially with nausea and vomiting, may cause your insulin requirements to change. Even if you are not eating, you will still require insulin. You and your doctor should establish a sick day plan to use in case of illness. When you are sick, test your blood/urine frequently and call your doctor as instructed.


• Tell your doctor or dentist that you take Insulin Lispro Vials before you receive any medical or dental care, emergency care, or surgery.


• If you will be traveling across time zones, consult your doctor concerning adjustments in your insulin schedule.


• Carry an ID card at all times that says you have diabetes.


• An insulin reaction resulting from low blood sugar levels (hypoglycemia) may occur if you take too much insulin, skip a meal, or exercise too much. Low blood sugar may make you anxious, sweaty, weak, dizzy, drowsy, or faint. It may also make your heart beat faster; make your vision change; give you a headache, chills, or tremors; or make you more hungry. It is a good idea to carry a reliable source of glucose (eg, tablets or gel) to treat low blood sugar. If this is not available, you should eat or drink a quick source of sugar like table sugar, honey, candy, orange juice, or non-diet soda. This will raise your blood sugar level quickly. Tell your doctor right away if this happens. To prevent low blood sugar, eat meals at the same time each day and do not skip meals.


• Developing a fever or infection, eating significantly more than prescribed, or missing your dose of insulin may cause high blood sugar (hyperglycemia). High blood sugar may make you feel confused, drowsy, or thirsty. It can also make you flush, breathe faster, or have a fruit-like breath odor. If not treated, loss of consciousness, coma, or death may occur. If these symptoms occur, tell your doctor right away.


• Check with your doctor if you notice a depression in the skin or skin thickening at the injection site. You may need to change your injection technique.


• Proper diet, regular exercise, and regular testing of blood sugar are important for best results when using Insulin Lispro Vials.


• Lab tests, including fasting blood glucose levels and hemoglobin A_1c levels, may be performed while you use Insulin Lispro Vials. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Use Insulin Lispro Vials with caution in the ELDERLY; if low blood sugar occurs, it may be more difficult to recognize in these patients.


• Insulin Lispro Vials should be used with extreme caution in CHILDREN younger than 3 years old; safety and effectiveness in these children have not been confirmed.


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

Possible side effects of Insulin Lispro Vials:

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

Redness, swelling, itching, or mild pain at the injection site.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; wheezing; muscle pain); changes in vision; chills; confusion; dizziness; drowsiness; fainting; fast or irregular heartbeat; headache; loss of consciousness; mood changes; seizures; slurred speech; swelling; tremor; trouble breathing; trouble concentrating; unusual hunger; unusual sweating; weakness; wheezing.

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

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center or emergency room immediately. Symptoms may include chills; dizziness; drowsiness; fainting; fast or irregular heartbeat; headache; loss of consciousness; nervousness; seizures; shakiness; sweating; tremor; vision changes; weakness.

Proper storage of Insulin Lispro Vials:

Store new (unopened) vials in a refrigerator, between 36 and 46 degrees F (2 and 8 degrees C). Do not freeze Insulin Lispro Vials. Store used (open) vials either in the refrigerator, between 36 and 46 degrees F (2 and 8 degrees C), or at room temperature, below 86 degrees F (30 degrees C). Store away from heat and light. If Insulin Lispro Vials has been frozen or overheated, throw it away. Throw away unrefrigerated or opened vials after 28 days, even if they still contain medicine.

Avoid temperatures above 98.6 degrees F (37 degrees C). Do not leave Insulin Lispro Vials in a car on a warm or sunny day. Do not use Insulin Lispro Vials after the expiration date stamped on the label. Keep Insulin Lispro Vials, as well as syringes and needles, out of the reach of children and away from pets. If you are using Insulin Lispro Vials in an insulin pump, or if Insulin Lispro Vials has been mixed with other medicines or diluted, you may need to store it differently. Ask your doctor, pharmacist, or other health care provider how to store Insulin Lispro Vials.

General information:

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


• Insulin Lispro Vials are to be used only by the patient for whom it is prescribed. Do not share it with other people.


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


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

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

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Insulin Lispro resources

• Insulin Lispro Use in Pregnancy & Breastfeeding
• Insulin Lispro Drug Interactions
• Insulin Lispro Support Group
• 4 Reviews for Insulin Lispro - Add your own review/rating

Compare Insulin Lispro with other medications

• Diabetes, Type 1
• Diabetes, Type 2

Johnson&apos;s Baby Cream

Pronunciation: dye-METH-i-kone
Generic Name: Dimethicone
Brand Name: Examples include Aveeno Moisturizing Lotion and Johnson's Baby Cream

Johnson's Baby Cream is used for:

Treating or preventing dry, itchy skin or minor skin irritations.

This product is an emollient. It works by moisturizing the skin.

Do NOT use Johnson's Baby Cream if:

• you are allergic to any ingredient in Johnson's Baby Cream

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

Before using Johnson's Baby Cream:

Tell your health care provider if you have any medical conditions, especially if any of the following apply to you:

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


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


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


• if you have an open wound, serious burn, or damaged, broken, or irritated skin

Some MEDICINES MAY INTERACT with Johnson's Baby Cream. However, no specific interactions with Johnson's Baby Cream are known at this time.

Ask your health care provider if Johnson's Baby Cream may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Johnson's Baby Cream:

Use Johnson's Baby Cream as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Johnson's Baby Cream is for external use only. Do not get Johnson's Baby Cream in your eyes, nose, or mouth. If you get Johnson's Baby Cream in your eyes, rinse immediately with cool tap water.


• Wash your hands before and after using Johnson's Baby Cream unless your hands are a part of the treated area.


• Wash and completely dry the affected area. Apply only enough of Johnson's Baby Cream to completely cover the affected area and gently rub in until it is evenly distributed.


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


• If you miss using Johnson's Baby Cream for 1 or more days, there is no cause for concern. If your doctor recommended that you use it, try to remember every day.

Ask your health care provider any questions you may have about how to use Johnson's Baby Cream.

Important safety information:

• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Johnson's Baby Cream while you are pregnant. If you are or will be breast-feeding while you use Johnson's Baby Cream, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Johnson's Baby Cream:

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

Mild itching, burning, or stinging.

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

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

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

See also: Johnson's Baby side effects (in more detail)

If OVERDOSE is suspected:

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

Proper storage of Johnson's Baby Cream:

Store Johnson's Baby Cream at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not freeze. Keep Johnson's Baby Cream out of the reach of children and away from pets.

General information:

• If you have any questions about Johnson's Baby Cream, please talk with your doctor, pharmacist, or other health care provider.


• Johnson's Baby Cream is to be used only by the patient for whom it is prescribed. Do not share it with other people.


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


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

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

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Johnson's Baby resources

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

Compare Johnson's Baby with other medications

• Dry Skin

Gildess FE 1.5/30

norethindrone acetate, ethinyl estradiol and ferrous fumarate

Dosage Form: tablets
GILDESS® FE 1.5/30

(NORETHINDRONE ACETATE AND ETHINYL ESTRADIOL TABLETS, USP AND FERROUS FUMARATE TABLETS, USP)

NORETHINDRONE ACETATE (1.5 mg) AND ETHINYL ESTRADIOL (0.03 mg) TABLETS, USP AND FERROUS FUMARATE (75 mg) TABLETS, USP

(Each light green tablet contains 1.5 mg norethindrone acetate and 0.03 mg ethinyl estradiol.  Each white-speckled brown tablet contains 75 mg ferrous fumarate.)

Rx only

Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Gildess FE 1.5/30 Description

Norethindrone acetate and ethinyl estradiol tablets, USP are progestogen-estrogen combinations.

Norethindrone acetate and ethinyl estradiol tablets, USP and ferrous fumarate tablets, USP: Each provides a continuous dosage regimen consisting of 21 oral contraceptive tablets and seven ferrous fumarate tablets, USP. The ferrous fumarate tablets, USP are present to facilitate ease of drug administration via a 28-day regimen, are non-hormonal, and do not serve any therapeutic purpose.

Each light green tablet contains norethindrone acetate (17 alpha-ethinyl-19-nortestosterone acetate), 1.5 mg; ethinyl estradiol (17 alpha-ethinyl-1,3,5(10)-estratriene-3, 17 beta-diol), 0.03 mg. Also contains colloidal silicon dioxide, compressible sugar, croscarmellose sodium, D&C Yellow #10 aluminum lake, FD&C Blue #1 aluminum lake, FD&C Yellow #6 aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol 400, polyethylene glycol 8000, pregelatinized starch, sodium lauryl sulfate and Vitamin E.

The structural formulas are as follows:

Each white-speckled brown tablet contains ferrous fumarate, microcrystalline cellulose, magnesium stearate and pregelatinized starch.

Gildess FE 1.5/30 - Clinical Pharmacology

Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).

Pharmacokinetics

The pharmacokinetics of norethindrone acetate and ethinyl estradiol tablets have not been characterized; however, the following pharmacokinetic information regarding norethindrone acetate and ethinyl estradiol is taken from the literature.

Absorption

Norethindrone acetate appears to be completely and rapidly deacetylated to norethindrone after oral administration, since the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone (1). Norethindrone acetate and ethinyl estradiol are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for norethindrone and 43% for ethinyl estradiol (1 to 3).

Distribution

Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg (1 to 3). Plasma protein binding of both steroids is extensive (> 95%); norethindrone binds to both albumin and sex hormone binding globulin, whereas ethinyl estradiol binds only to albumin (4).

Metabolism

Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites (5). A small amount of norethindrone acetate is metabolically converted to ethinyl estradiol. Ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. Sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. The primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the CYP3A4 isoform of cytochrome P450. Part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic circulation (6).

Excretion

Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites (5,6). Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg) (1 to 3).

Special Population

Race

The effect of race on the disposition of norethindrone acetate and ethinyl estradiol tablets have not been evaluated.

Renal Insufficiency

The effect of renal disease on the disposition of norethindrone acetate and ethinyl estradiol tablets has not been evaluated. In premenopausal women with chronic renal failure undergoing peritoneal dialysis who received multiple doses of an oral contraceptive containing ethinyl estradiol and norethindrone, plasma ethinyl estradiol concentrations were higher and norethindrone concentrations were unchanged compared to concentrations in premenopausal women with normal renal function.

Hepatic Insufficiency

The effect of hepatic disease on the disposition of norethindrone acetate and ethinyl estradiol tablets has not been evaluated. However, ethinyl estradiol and norethindrone may be poorly metabolized in patients with impaired liver function.

Drug-Drug Interactions

Numerous drug-drug interactions have been reported for oral contraceptives. A summary of these is found under PRECAUTIONS, Drug Interactions.

Indications and Usage for Gildess FE 1.5/30

Norethindrone acetate and ethinyl estradiol tablets, USP and ferrous fumarate tablets, USP are indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.

Oral contraceptives are highly effective. Table I lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

TABLE I: LOWEST EXPECTED AND TYPICAL FAILURE RATES DURING THE FIRST YEAR OF CONTINUOUS USE OF A METHOD

* The authors' best guess of the percentage of women expected to experience an accidental pregnancy among couples who initiate a method (not necessarily for the first time) and who use it consistently and correctly during the first year if they do not stop for any other reason. † This term represents "typical" couples who initiate use of a method (not necessarily for the first time), who experience an accidental pregnancy during the first year if they do not stop use for any other reason. ‡ N/A--Data not available.
% of Women Experiencing an Unintended Pregnancy in the First Year of Continuous Use
Method	Lowest Expected*	Typical†
(No contraception)	(85)	(85)
Oral contraceptives		3
combined	0.1	N/A‡
progestin only	0.5	N/A‡
Diaphragm with spermicidal cream or jelly	6	20
Spermicides alone (foam, creams, gels,    vaginal suppositories, and vaginal film)	6	26
Vaginal Sponge
nulliparous	9	20
parous	20	40
Implant	0.05	0.05
Injection: depot medroxyprogesterone acetate	0.3	0.3
IUD
progesterone T	1.5	2.0
copper T 380A	0.6	0.8
LNg 20	0.1	0.1
Condom without spermicides
female	5	21
male	3	14
Cervical Cap with spermicidal cream or jelly
nulliparous	9	20
parous	26	40
Periodic abstinence (all methods)	1 to 9	25
Withdrawal	4	19
Female sterilization	0.5	0.5
Male sterilization	0.10	0.15

Adapted from RA Hatcher et al., Reference 7.

Contraindications

Oral contraceptives should not be used in women who currently have the following conditions:

• Thrombophlebitis or thromboembolic disorders


• A past history of deep vein thrombophlebitis or thromboembolic disorders


• Cerebral vascular or coronary artery disease


• Known or suspected carcinoma of the breast


• Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia


• Undiagnosed abnormal genital bleeding


• Cholestatic jaundice of pregnancy or jaundice with prior pill use


• Hepatic adenomas or carcinomas


• Known or suspected pregnancy

Warnings

Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.

The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity, and diabetes.

Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks.

The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and progestogens remains to be determined.

Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population (adapted from References 8 and 9 with the author's permission). For further information, the reader is referred to a text on epidemiological methods.

1. Thromboembolic Disorders and Other Vascular Problems

a. Myocardial Infarction

An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six (10 to 16). The risk is very low under the age of 30.

Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases (17). Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and non-smokers over the age of 40 (Table II) among women who use oral contraceptives.

 

TABLE II: CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN YEARS BY AGE, SMOKING STATUS AND ORAL CONTRACEPTIVE USE

Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity (19). In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism (20 to 24). Oral contraceptives have been shown to increase blood pressure among users (see section 9 in WARNINGS). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

b. Thromboembolism

An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to non-users to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease (9,10,25 to 30). Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization (31). The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped (8).

A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives (15,32). The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions (15,32). If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four to six weeks after delivery in women who elect not to breast feed.

c. Cerebrovascular Diseases

Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (> 35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes (33 to 35).

In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension (36). The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users, and 25.7 for users with severe hypertension (36). The attributable risk is also greater in older women (9).

d. Dose-Related Risk of Vascular Disease from Oral Contraceptives

A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease (37 to 39). A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents (20 to 22). A decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestin and the nature of the progestin used in the contraceptives. The amount and activity of both hormones should be considered in the choice of an oral contraceptive.

Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular oral contraceptive, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest dose of estrogen which produces satisfactory results for the patient.

e. Persistence of Risk of Vascular Disease

There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40 to 49 years who had used oral contraceptives for 5 or more years, but this increased risk was not demonstrated in other age groups (14). In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small (40). However, both studies were performed with oral contraceptive formulations containing 50 mcg or higher of estrogens.

2. Estimates of Mortality from Contraceptive Use

One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table III). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth. The observation of a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970's but not reported until 1983 (41). However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral contraceptive use to women who do not have the various risk factors listed in this labeling.

Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed (Porter JB, Hunter J, Jick H, et al. Oral contraceptives and nonfatal vascular disease. Obstet Gynecol 1985;66:1-4; and Porter JB, Hershel J, Walker AM. Mortality among oral contraceptive users. Obstet Gynecol 1987;70:29-32), the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989. The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception.

Therefore, the Committee recommended that the benefits of oral contraceptive use by healthy non-smoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective.

TABLE III: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NON-STERILE WOMEN BY FERTILITY CONTROL METHOD ACCORDING TO AGE

* Deaths are birth related. † Deaths are method related.
Method of control and  outcome	15 to 19	20 to 24	25 to 29	30 to 34	35 to 39	40 to 44
No fertility control methods*	7.0	7.4	9.1	14.8	25.7	28.2
Oral contraceptives non-  smoker†	0.3	0.5	0.9	1.9	13.8	31.6
Oral contraceptives smoker†	2.2	3.4	6.6	13.5	51.1	117.2
IUD†	0.8	0.8	1.0	1.0	1.4	1.4
Condom*	1.1	1.6	0.7	0.2	0.3	0.4
Diaphragm/spermicide*	1.9	1.2	1.2	1.3	2.2	2.8
Periodic abstinence*	2.5	1.6	1.6	1.7	2.9	3.6

Adapted from H.W. Ory, Reference 41.

3. Carcinoma of the Reproductive Organs

Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian, and cervical cancer in women using oral contraceptives. Most of the studies on breast cancer and oral contraceptive use report that the use of oral contraceptives is not associated with an increase in the risk of developing breast cancer (42,44,89). Some studies have reported an increased risk of developing breast cancer in certain subgroups of oral contraceptive users, but the findings reported in these studies are not consistent (43,45 to 49,85 to 88).

Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women (51 to 54). However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

In spite of many studies of the relationship between oral contraceptive use and breast and cervical cancers, a cause and effect relationship has not been established.

4. Hepatic Neoplasia

Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use (55). Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage (56 to 57).

Studies from Britain have shown an increased risk of developing hepatocellular carcinoma (58 to 60) in long-term (> 8 years) oral contraceptive users. However, these cancers are extremely rare in the U.S., and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users.

5. Ocular Lesions

There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately.

6. Oral Contraceptive Use Before and During Early Pregnancy

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy (61 to 63). Studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb reduction defects are concerned (61,62,64,65) when taken inadvertently during early pregnancy.

The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion.

It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out before continuing oral contraceptive use. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period. Oral contraceptive use should be discontinued if pregnancy is confirmed.

7. Gallbladder Disease

Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens (66,67). More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal (68 to 70). The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.

8. Carbohydrate and Lipid Metabolic Effects

Oral contraceptives have shown to cause glucose intolerance in a significant percentage of users (23). Oral contraceptives containing greater than 75 mcg of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance (71). Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents (23,72). However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose (73). Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives.

A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1a. and 1d.), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.

9. Elevated Blood Pressure

An increase in blood pressure has been reported in women taking oral contraceptives (74) and this increase is more likely in older oral contraceptive users (75) and with continued use (74). Data from the Royal College of General Practitioners (18) and subsequent randomized trials have shown that the incidence of hypertension increases with increasing concentrations of progestogens.

Women with a history of hypertension or hypertension-related diseases or renal disease (76) should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely, and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives (75), and there is no difference in the occurrence of hypertension among ever and never users (74,76,77).

10. Headache

The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause.

11. Bleeding Irregularities

Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. Non-hormonal causes should be considered, and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out.

Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was preexistent.

Precautions

1. Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

2. Physical Examination and Follow-Up

It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.

3. Lipid Disorders

Women who are being treated for hyperlipidemia should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult.

4. Liver Function

If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function.

5. Fluid Retention

Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention.

6. Emotional Disorders

Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.

7. Contact Lenses

Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.

8. Drug Interactions

Effects of Other Drugs on Oral Contraceptives (78)

Rifampin

Metabolism of both norethindrone and ethinyl estradiol is increased by rifampin. A reduction in contraceptive effectiveness and increased incidence of breakthrough bleeding and menstrual irregularities have been associated with concomitant use of rifampin.

Anticonvulsants

Anticonvulsants such as phenobarbital, phenytoin, and carbamazepine, have been shown to increase the metabolism of ethinyl estradiol and/or norethindrone, which could result in a reduction in contraceptive effectiveness.

Troglitazone

Administration of troglitazone with an oral contraceptive containing ethinyl estradiol and norethindrone reduced the plasma concentrations of both by approximately 30%, which could result in a reduction in contraceptive effectiveness.

Antibiotics

Pregnancy while taking oral contraceptives has been reported when the oral contraceptives were administered with antimicrobials such as ampicillin, tetracycline, and griseofulvin. However, clinical pharmacokinetic studies have not demonstrated any consistent effect of antibiotics (other than rifampin) on plasma concentrations of synthetic steroids.

Atorvastatin

Coadministration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol by approximately 30% and 20%, respectively.

Other

Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. A reduction in contraceptive effectiveness and increased incidence of breakthrough bleeding has been suggested with phenylbutazone.

Effects of Oral Contraceptives on Other Drugs

Oral contraceptive combinations containing ethinyl estradiol may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporine, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives. In addition, oral contraceptives may induce the conjugation of other compounds. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine, and clofibric acid have been noted when these drugs were administered with oral contraceptives.

9. Interactions with Laboratory Tests

Certain endocrine and liver function tests and blood components may be affected by oral contraceptives:

1. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.


2. Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered.


3. Other binding proteins may be elevated in serum.


4. Sex-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged.


5. Triglycerides may be increased.


6. Glucose tolerance may be decreased.


7. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.

10. Carcinogenesis

See WARNINGS section.

11. Pregnancy

Pregnancy Category X

See CONTRAINDICATIONS and WARNINGS sections.

12. Nursing Mothers

Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers, and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child.

13. Pediatric Use

Safety and efficacy of norethindrone acetate and ethinyl estradiol tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.

INFORMATION FOR THE PATIENT

See patient labeling printed below.

Adverse Reactions

An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS section):

• Thrombophlebitis


• Arterial thromboembolism


• Pulmonary embolism


• Myocardial infarction


• Cerebral hemorrhage


• Cerebral thrombosis


• Hypertension


• Gallbladder disease


• Hepatic adenomas or benign liver tumors

There is evidence of an association between the following conditions and the use of oral contraceptives, although additional confirmatory studies are needed:

• Mesenteric thrombosis


• Retinal thrombosis

The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related:

• Nausea


• Vomiting


• Gastrointestinal symptoms (such as abdominal cramps and bloating)


• Breakthrough bleeding


• Spotting


• Change in menstrual flow


• Amenorrhea


• Temporary infertility after discontinuation of treatment


• Edema


• Melasma which may persist


• Breast changes: tenderness, enlargement, secretion


• Change in weight (increase or decrease)


• Change in cervical erosion and secretion


• Diminution in lactation when given immediately postpartum


• Cholestatic jaundice


• Migraine


• Rash (allergic)


• Mental depression


• Reduced tolerance to carbohydrates


• Vaginal candidiasis


• Change in corneal curvature (steepening)


• Intolerance to contact lenses

The following adverse reactions have been reported in users of oral contraceptives and the association has been neither confirmed nor refuted:

• Pre-menstrual syndrome


• Cataracts


• Changes in appetite


• Cystitis-like syndrome


• Headache


• Nervousness


• Dizziness


• Hirsutism


• Loss of scalp hair


• Erythema multiforme


• Erythema nodosum


• Hemorrhagic eruption


• Vaginitis


• Porphyria


• Impaired renal function


• Hemolytic uremic syndrome


• Budd-Chiari syndrome


• Acne


• Changes in libido


• Colitis

Overdosage

Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea, and withdrawal bleeding may occur in females.

NON-CONTRACEPTIVE HEALTH BENEFITS

The following non-contraceptive health benefits related to the use of oral contraceptives are supported by epidemiological studies which largely utilized oral contraceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg of mestranol (79 to 84).

Effects on menses:

• Increased menstrual cycle regularity


• Decreased blood loss and decreased incidence of iron deficiency anemia


• Decreased incidence of dysmenorrhea

Effects related to inhibition of ovulation:

• Decreased incidence of functional ovarian cysts


• Decreased incidence of ectopic pregnancies

Effects from long-term use:

• Decreased incidence of fibroadenomas and fibrocystic disease of the breast


• Decreased incidence of acute pelvic inflammatory disease


• Decreased incidence of endometrial cancer


• Decreased incidence of ovarian cancer

Gildess FE 1.5/30 Dosage and Administration

The tablet dispenser has been designed to make oral contraceptive dosing as easy and as convenient as possible. The tablets are arranged four rows of seven tablets each, with the days of the week appearing on the tablet dispenser above the first row of tablets.

Note: Each tablet dispenser has been preprinted with the days of the week, starting with Sunday, to facilitate a Sunday-Start regimen. Six different day label strips have been provided with the Detailed Patient & Brief Summary Patient Package Insert in order to accommodate a Day-1 Start regimen. If the patient is using the Day-1 Start regimen, she should place the self-adhesive day label strip that corresponds to her starting day over the preprinted days.

Important: The patient should be instructed to use an additional