Atropine Sulphate Injection 600mcg in 1ml

Atropine Sulphate Injection

Important information about your medicine

• Your doctor or nurse will give you the injection.


• If this injection causes you any problems talk to your doctor, nurse or pharmacist.


• Please tell your doctor or pharmacist, if you have any other medical conditions or have an allergy to any of the ingredients of this medicine.


• Please tell your doctor or pharmacist, if you are taking any other medicines.

• 
  Read all of this leaflet carefully before you start using this medicine. In some circumstances this may not be possible and this leaflet will be kept in a safe place should you wish to read it.


• 
  Keep this leaflet. You may need to read it again.


• If you have any further questions, please ask your doctor or your pharmacist.


• This medicine has been prescribed for you personally and you should not pass it on to others. It may harm them, even if their symptoms are the same as yours.

Where to find information in this leaflet

• 1. What Atropine Sulphate Injection is and what it is used for


• 2. Before you are given Atropine Sulphate Injection


• 3. How to use Atropine Sulphate Injection


• 4. Possible side effects


• 5. Storing Atropine Sulphate Injection


• 6. Further information

What Atropine Sulphate Injection is and what it is used for

Atropine Sulphate Injection belongs to a group of medicines known as anticholinergics.

It is used:

• before general anaesthesia to reduce saliva secretions.


• to restore normal heartbeat during a cardiac arrest.


• as an antidote to some insecticides and in mushroom poisoning.


• in combination with other drugs to reverse the effect of muscle relaxants used during surgery.

Before you are given Atropine Sulphate Injection

You should NOT be given Atropine Sulphate Injection if you:

• are sensitive or allergic to Atropine Sulphate Injection or any of the other ingredients in this injection.


• suffer from closed-angle glaucoma (a condition that affects your eyes).


• are a man with an enlarged prostate.


• suffer from myasthenia gravis (weakness of breathing muscles).


• suffer from pyloric stenosis (a narrowing of the opening that takes food away from your stomach).


• suffer from paralytic lleus (your intestine stops functioning properly).


• suffer from ulcerative colitis - a disease of the colon and rectum.

Please tell your doctor or nurse before being given the injection if you have:

• 
  urinary difficulties


• heart failure


• had a heart attack


• had a heart transplant


• chronic pulmonary obstructive disease (a condition where the airflow to your lungs is restricted and you may cough and feel breathless)


• an overactive thyroid


• high blood pressure


• 
  fever
  


• 
  diarrhoea
  


• reflux oesophagitis (heartburn)

Using other medicines:

Please tell your doctor or nurse if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. This is especially important with the following medicines as they may interact with your Atropine Sulphate Injection:

• medicines to treat psychosis or depression.


• 
  amantadine (a medicine for Parkinson's Disease)


• 
  antihistamines (medicines used to treat hayfever and allergies


• medicines to regulate your heart (disopyramide and mexiletine)


• 
  ketoconazole (a medicine to treat fungal infections).


• Medicines that you take by allowing them to dissolve slowly in your mouth - atropine may cause your mouth to become dry, making it more difficult for these medicines to dissolve.

Pregnancy or breast feeding:

Please tell your doctor or nurse before being given this injection if you are pregnant or breast feeding. The doctor will then decide if the injection is suitable for you.

Driving and using machines:

You should not drive or use machinery if you are affected by the administration of Atropine Sulphate Injection.

How to use Atropine Sulphate Injection

Your nurse or doctor will give you the injection

Your doctor will decide the correct dosage for you and how and when the injection will be given.

Since the injection will be given to you by a doctor or nurse, it is unlikely that you will be given too much. If you think you have been given too much, you feel your heart beating very fast, you are breathing quickly, have a high temperature, feel restless, confused, have hallucinations, or lose co-ordination you must tell the person giving you the injection.

Possible side effects

Like all medicines, Atropine Sulphate Injection can cause side effects, although not everybody gets them.

• 
  drowsiness
  


• 
  blurred vision
  


• dry mouth with difficulty swallowing


• 
  thirst
  


• dilation of the pupils


• 
  flushing
  


• dryness of the skin


• slow heart beat followed by fast heart beat


• 
  palpitations (you are aware of your heart beating)


• difficulty in passing urine or constipation


• 
  vomiting
  


• 
  rashes
  


• 
  confusion
  

If you think this injection is causing you any problems, or you are at all worried, talk to your doctor, nurse or pharmacist.

Storing Atropine Sulphate Injection

Your injection will be stored at less than 25°C and protected from light. The nurse or doctor will check that the injection is not past its expiry date before giving you the injection.

Further information

What Atropine Sulphate Injection contains:

This injection contains the active ingredient atropine sulphate. Each 1 ml of solution contains 600 micrograms in a sterile solution for injection.

This injection contains the following Inactive Ingredients: sulphuric acid and water for injections.

What Atropine Sulphate Injection looks like and contents of the pack:

Atropine Sulphate Injection is a supplied in 1 ml clear glass ampoules. 10 ampoules are supplied in each carton.

The marketing authorisation number of this medicine is: PL 01502/0016R

Marketing Authorisation Holder:

hameln pharmaceuticals ltd

Gloucester

United Kingdom

Manufacturer

hameln pharmaceuticals gmbh

Langes Feld 13

31789 Hameln

Germany

For any information about this medicine, please contact the Marketing Authorisation Holder

This leaflet was last approved 2008-08-18

44171/42/08

Methotrexate 2.5mg tablets

1. Name Of The Medicinal Product

Methotrexate 2.5 mg tablets

2. Qualitative And Quantitative Composition

One tablet contains 2.5 mg methotrexate.

Excipients: 39.9 mg lactose.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablet.

Yellow, round, convex, uncoated tablet engraved with M 2.5 on one side, diameter 6 mm.

4. Clinical Particulars

4.1 Therapeutic Indications

- Active rheumatoid arthritis in adult patients.

- Severe forms of psoriasis vulgaris, particularly of the plaque type, which cannot be sufficiently treated with conventional therapy such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis.

4.2 Posology And Method Of Administration

For doses not realisable/practicable with this strength another strength of this medicinal product is available.

Rheumatoid arthritis

The usual dose is 7.5 - 15 mg once weekly. The planned weekly dose may be administered in three divided doses over 36 hours. The schedule may be adjusted gradually to achieve an optimal response but should not exceed a total weekly dose of 20 mg. Thereafter the dose should be reduced to the lowest possible effective dose which in most cases is achieved within 6 weeks.

Psoriasis

Before starting treatment it is advisable to give the patient a test dose of 2.5–5.0 mg to exclude unexpected toxic effects. If, one week later, appropriate laboratory tests are normal, treatment may be initiated. The usual dose is 7.5–15 mg taken once weekly. The planned weekly dose administered as three divided doses over 24 hours. As necessary, the total weekly dose can be increased up to 25 mg. Thereafter the dose should be reduced to the lowest effective dose according to therapeutic response which in most cases is achieved within 4 to 8 weeks.

The patient should be fully informed of the risks involved and the clinician should pay particular attention to the appearance of liver toxicity by carrying out liver function tests before starting methotrexate treatment, and repeating these at 2 to 4 month intervals during therapy. The aim of therapy should be to reduce the dose to the lowest possible level with the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy which should be encouraged.

Use in elderly

Methotrexate should be used with extreme caution in elderly patients, a dose reduction should be considered due to reduced liver and kidney function as well as lower folate reserves which occurs with increased age.

Patients with hepatic impairment

Methotrexate should be administered with great caution, if at all, to patients with significant current or previous liver disease, especially if due to alcohol.

4.3 Contraindications

• Significantly impaired hepatic function

• Significantly impaired renal function

• Pre-existing blood dycrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anaemia

• Alcoholism

• Severe acute or chronic infections and immunodeficiency syndrome

• Pregnancy and breast-feeding (see also section 4.6).

• Hypersensitivity to methotrexate or to any of the excipients

• During methotrexate therapy concurrent vaccination with live vaccines must not be carried out

4.4 Special Warnings And Precautions For Use

Warnings

Methotrexate must be used only by physicians experienced in antimetabolite chemotherapy.

Concomitant administration of hepatotoxic or haematotoxic DMARDs (disease-modifying antirheumatic drug, e.g. leflunomide) is not advisable.

Due to the possibility of fatal or severe toxic reactions, the patient should be fully informed by the physician of the risks involved and be under constant supervision.

Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Symptoms typically include dyspnoea, cough (especially a dry non-productive cough) and fever for which patients should be monitored at each follow-up visit. Patients should be informed of the risk of pneumonitis and advised to contact their doctor immediately should they develop persistent cough or dyspnoea. Methotrexate should be withdrawn from patients with pulmonary symptoms and a thorough investigation undertaken to exclude infection. If methotrexate induced lung disease is suspected treatment with corticosteroids should be initiated and treatment with methotrexate should not be restarted.

Deaths have been reported associated with the use of methotrexate in the treatment of psoriasis.

For the treatment of psoriasis, methotrexate should be restricted to severe recalcitrant, disabling psoriasis which is not adequately responsive to other forms of therapy, but only when the diagnosis has been established by biopsy and/or after dermatological consultation.

The patient should be informed clearly that in the treatment of psoriasis and rheumatoid arthritis the administration is in most cases once weekly and that wrong daily administration can result in severe toxic reactions.

Full blood counts should be closely monitored before, during and after treatment. If a clinically significant drop in white-cell or platelet count develops, methotrexate should be withdrawn immediately. Patients should be advised to report all symptoms or signs suggestive of infection.

Methotrexate may be hepatotoxic, particularly at high doses or with prolonged therapy. Liver atrophy, necrosis, cirrhosis, fatty changes, and periportal fibrosis have been reported. Since changes may occur without previous signs of gastrointestinal or haematological toxicity, it is imperative that hepatic function be determined prior to initiation of treatment and monitored regularly throughout therapy.

Liver function tests: Particular attention should be given to the appearance of liver toxicity. Treatment should not be instituted or should be discontinued if any abnormality of liver function tests, or liver biopsy, is present or develops during therapy. Such abnormalities should return to normal within two weeks after which treatment may be recommenced at the discretion of the physician.

Check of liver-related enzymes in serum: Temporary increases in transaminases to twice or three times of the upper limit of normal have been reported by patients at a frequency of 13 - 20 %. In the case of a constant increase in liver-related enzymes, a reduction of the dose or discontinuation of therapy should be taken into consideration.

Due to its potentially toxic effect on the liver, additional hepatotoxic medicinal products should not be taken during treatment with methotrexate unless clearly necessary and the consumption of alcohol should be avoided or greatly reduced (see section 4.5). Closer monitoring of liver enzymes should be exercised in Patients taking other hepatotoxic medicinal products concomitantly (e.g. leflunomide). The same should be taken into account with the simultaneous administration of haematotoxic medicinal products (e.g. leflunomide).

There is no evidence to support use of a liver biopsy to monitor hepatic toxicity in rheumatological indications. In case of longer-term treatment of severe forms of psoriasis with methotrexate, liver biopsies should be performed on account of the hepatotoxic potential.

It has proven useful to differentiate between patients with normal and elevated risk of hepatotoxicity.

a) Patients without risk factors

According to current medical standard of knowledge, liver biopsy is not necessary before a cumulative dose of 1.0-1.5 g is reached.

b) Patients with risk factors

These primarily include:

- anamnestic alcohol abuse

- persistent increase in liver enzymes

- anamnestic hepatopathy including chronic hepatitis B or C

- familial anamnesis with hereditary hepatopathy and secondarily (with possibly lower relevance):

- diabetes mellitus

- adiposity

- anamnestic exposure to hepatotoxic medicines or chemicals.

Liver biopsy is recommended for these patients during or shortly after initiation of therapy with methotrexate. Since a small percentage of patients discontinues therapy for various reasons after 2-4 months, the first biopsy can be delayed to a time after this initial phase. It should be performed when longer-term therapy can be assumed.

Repeated liver biopsies are recommended after a cumulative dose of 1.0-1.5 g is achieved.

No liver biopsy is necessary in the following cases:

- elderly patients

- patients with an acute disease

- patients with contraindication for liver biopsy (e.g. cardiac instability, altered blood coagulation parameters)

- patients with poor expectance of life.

More frequent check-ups may become necessary

- during the initial phase of treatment

- when the dose is increased

- during episodes of a higher risk of elevated methotrexate blood levels (e.g. dehydration, impaired renal function, additional or elevated dose of medicines administered concomitantly, such as non-steroidal anti-inflammatory drugs).

Methotrexate has been shown to be teratogenic; it has caused foetal death and/or congenital anomalies. Therefore it is not recommended in women of childbearing potential unless there is appropriate medical evidence that the benefits can be expected to outweigh the considered risks. Pregnant psoriatic patients must not receive methotrexate (see section 4.6).

Renal function should be closely monitored before, during and after treatment. Caution should be exercised if significant renal impairment is disclosed. The dose of methotrexate in patients with renal impairment should be reduced. High doses may cause the precipitation of methotrexate or its metabolites in the renal tubules. A high fluid throughput and alkalinisation of the urine to pH 6.5 – 7.0, by oral or intravenous administration of sodium bicarbonate (5 x 625 mg tablets every three hours) or acetazolamide (500 mg orally four times a day) is recommended as a preventative measure. Methotrexate is excreted primarily by the kidneys. Its use in the presence of impaired renal function may result in accumulation of toxic amounts or even additional renal damage.

Diarrhoea and ulcerative stomatitis are frequent toxic effects and require interruption of therapy, otherwise haemorrhagic enteritis and death from intestinal perforation may occur.

Methotrexate affects gametogenesis during the period of its administration and may result in decreased fertility which is thought to be reversible on discontinuation of therapy.

Methotrexate has some immunosuppressive activity and immunological responses to concurrent vaccination may be decreased. Vaccination with live vaccines should be avoided during therapy.

The immunosuppressive effect of methotrexate should be taken into account when immune responses of patients are important or essential. Special attention should be paid in cases of inactive chronic infections (e.g. herpes zoster, tuberculosis, hepatitis B or C) because of their potential activation.

A chest X-ray is recommended prior to initiation of methotrexate therapy.

Pleural effusions and ascites should be drained prior to initiation of methotrexate therapy.

Serious adverse reactions including deaths have been reported with concomitant administration of methotrexate (usually in high doses) along with some non-steroidal anti-inflammatory drugs (NSAIDs).

In the treatment of rheumatoid arthritis, treatment with acetylsalicylic acid and non-steroidal anti-inflammatory drugs (NSAID) as well as small-dose steroids can be continued. One has to take into consideration, however, that coadministration of NSAIDs and methotrexate may involve an increased risk of toxicity. The steroid dose can be reduced gradually in patients who exhibit therapeutic response to methotrexate therapy.

Interaction between methotrexate and other antirheumatic agents, such as gold, penicillamin, hydroxychloroquine, sulphasalazine or other cytotoxic agents, have not been studied comprehensively, and coadministration may involve an increased frequency of adverse reactions.

Concomitant administration of folate antagonists such as trimethoprim/sulphamethoxazole has been reported to cause an acute megaloblastic pancytopenia in rare instances.

If acute methotrexate toxicity occurs, patients may require folinic acid.

Precautions

Before beginning methotrexate therapy or reinstituting methotrexate after a rest period, assessment of renal function, liver function and a bone marrow function should be made by history, physical examination and laboratory tests.

Systemic toxicity of methotrexate may also be enhanced in patients with renal dysfunction, ascites, or other effusions due to prolongation of serum half-life.

Malignant lymphomas may occur in patients receiving low dose methotrexate, in which case therapy must be discontinued. Failure of the lymphoma to show signs of spontaneous regression requires the initiation of cytotoxic therapy.

Methotrexate has been reported to cause impairment of fertility, oligospermia, menstrual dysfunction and amenorrhoea in humans, during and for a short period after cessation of therapy. In addition, methotrexate causes embryotoxicity, abortion and foetal defects in humans. Therefore the possible risks of effects on reproduction should be discussed with patients of childbearing potential (see section 4.6).

Patients undergoing therapy should be subject to appropriate supervision so that signs or symptoms of possible toxic effects or adverse reactions may be detected and evaluated with minimal delay. Pre-treatment and periodic haematological studies are essential for the safe use of methotrexate in chemotherapy because of its common effect of haematopoietic suppression. This may occur without warning when a patient is on an apparently safe dose, and any profound drop in blood cell count indicates immediate stopping of the drug and appropriate therapy.

In general, the following laboratory tests are recommended as part of essential clinical evaluation and appropriate monitoring of patients chosen for or receiving methotrexate: complete haemogram; haematocrit; urinalysis; renal function tests; liver function tests and chest X-ray.

The purpose is to determine any existing organ dysfunction or system impairment. The tests should be performed prior to therapy, at appropriate periods during therapy and after termination of therapy.

Methotrexate is bound in part to serum albumin after absorption, and toxicity may be increased because of displacement by certain drugs such as salicylates, sulphonamides, phenytoin, and some antibacterials such as tetracycline, chloramphenicol and para-aminobenzoic acid. These drugs, especially salicylates and sulphonamides, whether antibacterial, hypoglycaemic or diuretic, should not be given concurrently until the significance of these findings is established.

Vitamin preparations containing folic acid or its derivatives may alter response to methotrexate.

Methotrexate should be used with extreme caution in the presence of infection, peptic ulcer, ulcerative colitis, debility, and in extreme youth and old age. If profound leukopenia occurs during therapy, bacterial infection may occur or become a threat. Cessation of the drug and appropriate antibiotic therapy is usually indicated. In severe bone marrow depression, blood or platelet transfusions may be necessary.

The tablets contain lactose. 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

After absorption methotrexate binds partly to serum albumin. Certain medicinal products (e.g. salicylates, sulfonamides and phenytoin) decrease this binding. In such instances the toxicity of methotrexate may increase when coadministered. Since probenecid and weak organic acids, such as ”loop-diuretics” as well as pyrazols, reduce tubular secretion, great caution should be exercised when these medicinal products are coadministered with methotrexate.

Penicillins can decrease the renal clearance of methotrexate and haematological and gastrointestinal toxicity has been observed in combination with high- and low-dose methotrexate.

Oral antibiotics, such as tetracycline, chloramphenicol, and non-absorbable broad spectrum antibiotics, may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of methotrexate by bacteria.

Coadministration of other, potentially nephro- and hepatotoxic agents (e.g. sulphasalazine, leflunomide and alcohol) with methotrexate should be avoided. Special caution should be exercised when observing patients receiving methotrexate therapy in combination with azathioprine or retinoids.

Methotrexate in combination with leflunomide can increase the risk for pancytopenia.

Enhancement of nephrotoxicity may be seen with high-dose methotrexate is administered in combination with a potentially nephrotoxic chemotherapeutic agent (e.g. cisplatin).

NSAIDs should not be administered before or concurrently with high-dose methotrexate. Concomitant use of some NSAIDs and high-dose methotrexate has been reported to increase and prolong the serum methotrexate concentration in serum and to increase gastrointestinal and haematological toxicity. When using smaller doses of methotrexate, these medicinal products have been found in animals to decrease the tubular secretion of methotrexate and possibly to increase its toxicity. In addition to methotrexate, patients with rheumatoid arthritis have generally been treated, however, with NSAIDs with no problems. It should be noted, however, that the doses of methotrexate used in the treatment of rheumatoid arthritis (7.5 - 15 mg/week) are slightly lower than those used for psoriasis and that higher doses can result in unexpected toxicity.

Vitamin preparations containing folic acid or its derivatives may change the response to methotrexate.

Trimethoprim/sulfamethoxazole has been reported in rare cases to increase bone marrow suppression in patients treated with methotrexate, presumably because of the increased antifolate effect.

Bone marrow suppression and reduced folate concentrations have been reported when triamterene and methotrexate were coadministered.

There is evidence that coadministration of methotrexate and omeprazole prolongs the elimination of methotrexate via the kidneys. Coadministration of proton pump inhibitors, such as omeprazole or pantoprazole, can cause interactions.

Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate.

Methotrexate increases the plasma levels of mercaptopurine. Combinations of methotrexate and mercaptopurine may therefore require dose adjustment.

Vaccination with a live vaccine in patients receiving chemotherapeutic agents may result in severe and fatal infections. Concomitant use with a live vaccine is not recommended.

Risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic drug or risk of toxicity enhancement or lose of efficacy of the cytotoxic drug due to increased hepatic metabolism by phenytoin.

Cyclosporine may potentiate methotrexate efficacy and toxicity. There is a risk of excessive immunosuppression with risk of lymphoproliferation when the combination is used.

4.6 Pregnancy And Lactation

Pregnancy

Use of methotrexate is contraindicated throughout pregnancy (see section 4.3), since there is evidence of a teratogenic risk in humans (craniofacial, cardiovascular and extremital malformations) and in several animal species (see section 5.3).

In women of child-bearing age, any existing pregnancy must be excluded with certainty by taking appropriate measures, e.g. pregnancy test, prior to initiating therapy.

Women must not become pregnant during and at least 6 months after treatment with methotrexate and must therefore practise an effective form or contraception.

If, nevertheless, pregnancy occurs during this period, medical advice should be given regarding the risk of harmful effects on the child associated with treatment.

As methotrexate may be genotoxic, women who wish to become pregnant are advised to consult a genetic councelling centre, if possible, already prior to therapy.

Lactation

As methotrexate passes into breast milk and may cause toxicity in nursing infants, treatment is contraindicated during the lactation period (see section 4.3). Breast-feeding is therefore to be stopped prior to treatment.

Male fertility

Methotrexate may be genotoxic. Men treated with methotrexate are therefore recommended not to father a child during treatment and up to 6 months afterwards. Since treatment with methotrexate can lead to severe and possibly irreversible disorders in spermatogenesis, men should seek advice about the possibility of sperm preservation before starting therapy.

Both men and women receiving methotrexate should be informed of the potential risk of adverse effects on reproduction. Women of childbearing potential should be fully informed of the potential hazard to the foetus should they become pregnant during methotrexate therapy.

Defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, and infertility have been reported in patients receiving methotrexate.

4.7 Effects On Ability To Drive And Use Machines

Central nervous system symptoms, such as fatigue and dizziness, can occur during treatment with methotrexate which may have minor or moderate influence onthe ability to drive and use machines.

4.8 Undesirable Effects

Generally the frequency and severity of adverse reactions are dependent of the size of the dose, the dosing frequency, the method of administration and the duration of exposure.

If adverse reactions occur, the dose should be reduced or therapy discontinued and necessary corrective therapeutic measures undertaken, such as administration of calcium folinate (see sections 4.2 and 4.4).

The most common adverse reactions of methotrexate are bone marrow suppression and mucosal damage which manifest as ulcerative stomatitis, leucopaenia, nausea and other gastrointestinal disorders. These adverse reactions are generally reversible and corrected in about two weeks after the single dose of methotrexate has been reduced or dose interval increased and/or calcium folinate is used. Other frequently occurring adverse reactions include e.g. malaise, abnormal fatigue, chills and fever, dizziness and reduced immunity to infections.

Methotrexate causes adverse reactions most at high and frequently repeated doses, e.g. in the treatment of cancer diseases. Adverse reactions reported on methotrexate are given below according to organ systems.

The frequencies of the adverse reactions are classified as follows: Very common (

	Common	Uncommon	Rare	Very rare
Infections and infestations	Infections	Opportunistic infections	Herpes zoster Sepsis
Neoplasms benign, malignant and unspecified (including cysts and polyps)		Lymphoma1
Blood and lymphatic system disorders	Leucopaenia	Bone marrow depression Thrombocytopaenia Anaemia		Hypogammaglobulinaemia
Immune system disorders		Anaphylactic-type reaction
Endocrine disorders			Diabetes mellitus
Psychiatric disorders			Depression Confusion
Nervous system disorders	Headache Dizziness Fatigue		Hemiparesis	Irritation Dysarthria Aphasia Lethargy
Eye disorders				Conjunctivitis Blurred vision
Cardiac disorders				Pericardial effusion Pericarditis
Vascular disorders		Nosebleed	Hypotension Thromboembolism	Vasculitis
Respiratory, thoracic and mediastinal disorders		Pneumonitis Interstitial pneumonitis (can be fatal) Interstitial fibrosis	Dyspnoea Pharyngitis2	Pneumocystis carinii – pneumonia Chronic interstitial obstructive lung disease Pleuritis Dry cough
Gastrointestinal disorders3	Stomatitis Anorexia Nausea Vomiting Diarrhoea		Gingivitis Gastrointestinal ulcerations and haemorrhage Enteritis	Haematemesis
Hepatobiliary disorders	Elevated transaminase concentrations		Hepatotoxicity Periportal fibrosis Liver cirrhosis Acute hepatitis
Skin and subcutaneous tissue disorders	Erythematous rash Alopaecia	Pruritus Stevens-Johnson´s syndrome Toxic epidermal necrolysis	Photohypersensitivity Acne Depigmentation Urticaria Erythema multiforme Painful damage to psoriatic lesion Skin ulceration	Telangiectasis Furunculosis Ecchymoses
Musculoskeletal and connective tissue disorders			Osteoporosis Arthralgia Myalgia Increased rheumatic nodules
Renal and urinary disorders		Renal insufficiency Nephropathy		Dysuria Azotaemia Cystitis Haematuria
Reproductive system and breast disorders		Vaginal ulceration	Decreased libido Impotence Menstrual disorders	Formation of defective oocytes or sperm cells Transient oligospermia, infertility Vaginal bleeding Gynaecomastia

¹ Can be reversible (see 4.4).

² See section 4.4.

³ Gastrointestinal severe adverse reactions require often dose reduction. Ulcerative stomatitis and diarrhoea require discontinuation of methotrexate therapy because of the risk of ulcerative enteritis and fatal intestinal perforation.

The following adverse reactions have also been reported, but their frequency is not known: pancytopaenia, sepsis resulting in death, miscarriage, fetal damages, increased risk of toxic reactions (soft tissue necrosis, osteonecrosis) during radiotherapy, eosinophilia, alveolitis.

The psoriatic lesions may get worse from simultaneous exposure to methotrexate and ultraviolet radiation.

4.9 Overdose

The toxicity of methotrexate affects mainly the haematopoietic organs. Calcium folinate neutralises effectively the immediate haematopoietic toxic effects of methotrexate. Parenteral calcium folinate therapy should be started within one hour after the administration of methotrexate. The dose of calcium folinate should be at least as high as the dose of methotrexate received by the patient.

Massive overdose requires hydration and alkalinisation of the urine to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. Haemodialysis or peritoneal dialysis has not been found to affect the elimination of methotrexate. Instead, effective clearance of methotrexate has been achieved by intermittent haemodialysis using a so-called ”high-flux” dialysator.

Observation of serum methotrexate concentrations is relevant in determining the right dose of calcium folinate and the duration of the therapy.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other immunosuppressive agents, ATC code: L04AX03.

Methotrexate (4-amino-10-methylfolic acid) is a folic acid antagonist which inhibits the reduction of folic acid and increase of tissue cells. Methotrexate enters the cell through an active transport mechanism of reduced folates. As a result of polyglutamation of methotrexate caused by the folylpolyglutamylate enzyme, the duration of the cytotoxic effect of the drug substance in the cell increases. Methotrexate is a phase-specific substance the main action of which is directed to the S-phase of cell mitosis. It acts generally most effectively on actively increasing tissues, such as malignant cells, bone marrow, fetal cells, skin epithelium, oral and intestinal mucosa as well as urinary bladder cells. As the proliferation of malignant cells is higher than that of most normal cells, methotrexate can slow down the proliferation of malignant cells without causing, however, irreversible damage to normal tissue.

Calcium folinate is a folinic acid which is used to protect normal cells from the toxic effects of methotrexate. Calcium folinate enters the cell through a specific transport mechanism, is converted in the cell into active folates and reverses the inhibition of the precursor synthesis caused by the DNA and RNA.

5.2 Pharmacokinetic Properties

The effect of orally administered methotrexate seems to be dependent on the size of the dose. Peak concentrations in serum are reached within 1–2 hours. Generally a dose of methotrexate of 30 mg/m² or less is absorbed rapidly and completely. The bioavailability of orally administered methotrexate is high (80–100%) at doses of 30 mg/m² or less. Saturation of the absorption starts at doses above 30 mg/m2 and absorption at doses exceeding 80 mg/m² is incomplete.

About half of the absorbed methotrexate binds reversibly to serum protein, but is readily distributed in tissues. The elimination follows a triphasic pattern. Excretion takes place mainly via the kidneys. Approximately 41% of the dose is excreted unchanged in the urine within the first six hours, 90% within 24 hours. A minor part of the dose is excreted in the bile of which there is pronounced enterohepatic circulation. The half-life is approximaltey 3–10 hours following low dose treatment and 8–15 hours following high dose treatment.If the renal function is impaired, the concentration of methotrexate in serum and in tissues may increase rapidly.

5.3 Preclinical Safety Data

Chronic toxicity studies in mice, rats and dogs showed toxic effects in the form of gastrointestinal lesions, myelosuppression and hepatotoxicity. Animal studies show that methotrexate impairs fertility, and is embryo- and foetotoxic. Teratogenic effects have been identified in four species (rats, mice, rabbits, cats). In rhesus monkeys no malformations occurred. Methotrexate is mutagenic in vivo and in vitro. There is evidence that methotrexate causes cromosomal aberrations in animal cells and in human bone marrow cells, but the clinical significance of these findings has not been established. Rodent carcinogenicity studies do not indicate an increased incidence of tumours.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose monohydrate

Maize starch

Starch, pregelatinised (potato starch)

Polysorbate 80

Cellulose, microcrystalline

Magnesium stearate.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Keep the tablet container in the outer carton, in order to protect from light.

6.5 Nature And Contents Of Container

HDPE tablet container with a HDPE screw cap. Pack sizes: 12, 16, 24, 28, 30 and 100 tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Orion Corporation

Orionintie 1

FI-02200 Espoo

Finland

8. Marketing Authorisation Number(S)

PL27925/0018

9. Date Of First Authorisation/Renewal Of The Authorisation

01.09.2008

10. Date Of Revision Of The Text

December 2009

Adams-Stokes Syndrome Medications

Definition of Adams-Stokes Syndrome: Transient asystole or ventricular fibrillation in the presence of atrioventricular block.

Drugs associated with Adams-Stokes Syndrome

The following drugs and medications are in some way related to, or used in the treatment of Adams-Stokes Syndrome. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.

Learn more about Adams-Stokes Syndrome

Micromedex Care Notes:

• Heart Block

Medical Encyclopedia:

• Arrhythmias

Drug List:

Adrenaclick-Auto-Injector

Adrenalin

Adrenalin-Chloride

Asthmahaler-Aerosol

Epipen-Auto-Injector

Epipen-2-Pak

Epipen-Auto-Injector

Epipen-Jr-Auto-Injector

Epipen-Jr-2-Pak

Epipen-Jr-Auto-Injector

Isuprel

Isuprel-Mistometer

Medihaler-Epi

Medihaler-Iso

Primatene-Mist-Aerosol

Twinject-Auto-Injector

Twinject-Auto-Injector

Twinject-Auto-Injector-Two-Pack

Todays Health Nasal Relief Extra Moisturizing

Generic Name: oxymetazoline hydrochloride

Dosage Form: nasal spray
Drug Facts

Active ingredient                                                                Purpose

Oxymetazoline hydrochloride 0.05% ...................................Nasal decongestant

Uses

• temporarily relieves nasal decongestant due to:


• common cold


• hay fever


• upper respiratory allergies


• sinusitis


• shrinks swollen nasal membranes so you can breathe more freely
  

Warnings

For external use only

Ask a doctor before use if you have

• heart disease


• high blood pressure


• thyroid disease


• diabetes


• trouble urinating due to an enlarged prostate gland
  

When using this product

• do not use more than directed


• do not use for more than 3 days.  Use only as directed.  Frequent or prolonged use may cause nasal congestion to recur or worsen


• temporary discomfort such as burning, stinging, sneezing or an increase in nasal discharge may occur


• use of this container by more than on person may spread infection.
  

Stop use and ask a doctor if symptoms persist

If pregnant or breast-feeding, ask a health professional before use.

Keep out of reach of children.  If swallowed, get medical help or contact a Poison Control Center right away.

Directions

• adults and children 6 to 12 years of age (with adult supervision): 2 or 3 sprays in each nostril not more often than every 10 to 12 hours.  Do not exceed 2 doses in any 24 hour period.


• children under 6 years of age: ask a doctor
  

To spray, squeeze bottle quickly and firmly.  Do not tilt head backward while spraying.  Wipe nozzle clean after use.

Other information

• store between 2o and 30oC (36o and 86oF)


• retain carton for future reference on full labeling
  

Inactive ingredients

benzalkonium chloride solution, edetate disodium, glycerin, polyethylene glycol, povidone, propylene glycol, sodium phosphate dibasic, sodium phosphate monobasic, water

Distributed by:

Today's Health, Inc.

4300 Sisk Road, #C

Modesto, CA 95356

Questions or comments

Call toll free 1-800-605-0236

TODAYS HEALTH NASAL RELIEF EXTRA MOISTURIZING  oxymetazoline hydrochloride  spray

Product Information Product Type HUMAN OTC DRUG NDC Product Code (Source) 68169-0014 Route of Administration NASAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength OXYMETAZOLINE HYDROCHLORIDE (OXYMETAZOLINE) OXYMETAZOLINE HYDROCHLORIDE 0.05 g  in 100 mL

Inactive Ingredients Ingredient Name Strength BENZALKONIUM CHLORIDE   EDETATE DISODIUM   GLYCERIN   POLYETHYLENE GLYCOL   POVIDONE   PROPYLENE GLYCOL   WATER

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 68169-0014-1 1 BOTTLE In 1 CARTON contains a BOTTLE 1 30 mL In 1 BOTTLE This package is contained within the CARTON (68169-0014-1)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
OTC monograph final	part341	11/11/2010

Labeler - TAI GUK PHARM. CO., LTD. (631101656)

Registrant - UNITED EXCHANGE CORP. (840130579)

Establishment
Name	Address	ID/FEI	Operations
TAI GUK PHARM. CO., LTD.		631101656	manufacture

Revised: 11/2010TAI GUK PHARM. CO., LTD.

More Todays Health Nasal Relief Extra Moisturizing resources

• Todays Health Nasal Relief Extra Moisturizing Side Effects (in more detail)
• Todays Health Nasal Relief Extra Moisturizing Dosage
• Todays Health Nasal Relief Extra Moisturizing Use in Pregnancy & Breastfeeding
• Todays Health Nasal Relief Extra Moisturizing Drug Interactions
• 1 Review for Todays Health Nasal Relief Extra Moisturizing - Add your own review/rating

Compare Todays Health Nasal Relief Extra Moisturizing with other medications

• Nasal Congestion

Lo Ovral

Dosage Form: Tablets

Rx only

Patients should be counseled that oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually transmitted diseases (STDs) such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.

DESCRIPTION

Each LO/OVRAL tablet, contains 0.3 mg of norgestrel (dl -13-beta-ethyl-17-alpha-ethinyl-17-beta-hydroxygon-4-en-3-one), a totally synthetic progestogen, and 0.03 mg of ethinyl estradiol, (19-nor-17α-pregna-1,3,5 (10)-trien-20-yne-3,17-diol). The inactive ingredients present are cellulose, lactose, magnesium stearate, and polacrilin potassium.

CLINICAL PHARMACOLOGY

Mode of Action

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).

INDICATIONS AND USAGE

Oral contraceptives are indicated for the prevention of pregnancy in women who elect to use this product 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, the IUD, and implants depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

Table I: Percentage Of Women Experiencing An Unintended Pregnancy During The First Year Of Typical Use And The First Year Of Perfect Use Of Contraception And The Percentage Continuing Use At The End Of The First Year. United States.

	% of Women Experiencing an Unintended Pregnancy within the First Year of Use		% of Women Continuing Use at One Year 3
Method (1)	Typical Use 1 (2)	Perfect Use 2 (3)	(4)
Lactation Amenorrhea Method: LAM is a highly effective, temporary method of contraception.9
Source: Trussell J. Contraceptive efficacy. In: Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowel D, Guest F. Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers; 1998.
1. Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.
2. Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.
3. Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year.
4. The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether.
5. Foams, creams, gels, vaginal suppositories, and vaginal film.
6. Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases.
7. With spermicidal cream or jelly.
8. Without spermicides.
9. However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches 6 months of age.
Chance 4	85	85
Spermicides 5	26	6	40
Periodic abstinence	25		63
Calendar		9
Ovulation Method		3
Sympto-Thermal 6		2
Post-Ovulation		1
Cap 7
Parous Women	40	26	42
Nulliparous Women	20	9	56
Sponge
Parous Women	40	20	42
Nulliparous Women	20	9	56
Diaphragm 7	20	6	56
Withdrawal	19	4
Condom 8
Female (Reality)	21	5	56
Male	14	3	61
Pill	5		71
Progestin only		0.5
Combined		0.1
IUD
Progesterone T	2.0	1.5	81
Copper T380A	0.8	0.6	78
LNg 20	0.1	0.1	81
Depo-Provera®	0.3	0.3	70
Levonorgestrel Implants (Norplant®)	0.05	0.05	88
Female Sterilization	0.5	0.5	100
Male Sterilization	0.15	0.10	100

CONTRAINDICATIONS

Combination oral contraceptives should not be used in women with any of the following conditions:

 

Thrombophlebitis or thromboembolic disorders

 

A past history of deep-vein thrombophlebitis or thromboembolic disorders

 

Cerebral-vascular or coronary-artery disease (current or history)

 

Thrombogenic valvulopathies

 

Thrombogenic rhythm disorders

 

Major surgery with prolonged immobilization

 

Diabetes with vascular involvement

 

Headaches with focal neurological symptoms

 

Uncontrolled hypertension

 

Known or suspected carcinoma of the breast or personal history of breast cancer

 

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, or active liver disease, as long as liver function has not returned to normal

 

Known or suspected pregnancy

 

Hypersensitivity to any of the components of Lo/Ovral

WARNINGS

Cigarette smoking increases the risk of serious cardiovascular side effects from oral-contraceptive use. This risk increases with age and with the extent of smoking (in epidemiologic studies, 15 or more cigarettes per day was associated with a significantly increased risk) 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 venous and arterial thrombotic and thromboembolic events (such as myocardial infarction, thromboembolism, and stroke), hepatic neoplasia, gallbladder disease, and hypertension, 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 certain inherited or acquired thrombophilias, hypertension, hyperlipidemias, obesity, diabetes, and surgery or trauma with increased risk of thrombosis.

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

The information contained in this package insert is based principally on studies carried out in patients who used oral contraceptives with higher doses of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower doses 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 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. 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. 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. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and nonsmokers over the age of 40 (Table II) among women who use oral contraceptives.

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

TABLE II. (Adapted from P.M. Layde and V. Beral, Lancet, 1:541-546, 1981.)

Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age, and obesity. In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. Oral contraceptives have been shown to increase blood pressure among users (see section 9 inWARNINGS). 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. Venous thrombosis and thromboembolism

An increased risk of venous 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 nonusers 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. 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. The approximate incidence of deep-vein thrombosis and pulmonary embolism in users of low dose (<50 mcg ethinyl estradiol) combination oral contraceptives is up to 4 per 10,000 woman-years compared to 0.5-3 per 10,000 woman-years for non-users. However, the incidence is substantially less than that associated with pregnancy (6 per 10,000 woman-years). The excess risk is highest during the first year a woman ever uses a combined oral contraceptive. Venous thromboembolism may be fatal. The risk of venous thrombotic and thromboembolic events is further increased in women with conditions predisposing for venous thrombosis and thromboembolism. The risk of thromboembolic disease due to oral contraceptives is not related to length of use and gradually disappears after pill use is stopped.

A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. 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 weeks after delivery in women who elect not to breast-feed, or a midtrimester pregnancy termination.

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.

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. The relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers 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. The attributable risk is also greater in older women. Oral contraceptives also increase the risk for stroke in women with other underlying risk factors such as certain inherited or acquired thrombophilias, hyperlipidemias, and obesity.

Women with migraine (particularly migraine/headaches with focal neurological symptoms, see CONTRAINDICATIONS) who take combination oral contraceptives may be at an increased risk of stroke.

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. A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents. 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 progestogen and the nature and absolute amount of progestogen used in the contraceptive. The amount 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 estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral-contraceptive agents should be started on preparations containing the lowest estrogen content which is judged appropriate for the individual 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 five or more years, but this increased risk was not demonstrated in other age groups. 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. However, both studies were performed with oral-contraceptive formulations containing 50 mcg or higher of estrogen.

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 less than 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. 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, 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 nonsmoking 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 nonsmoking 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 NONSTERILE WOMEN, BY FERTILITY-CONTROL METHOD AND ACCORDING TO AGE

*Deaths are birth related
**Deaths are method related
Adapted from H.W. Ory, Family Planning Perspectives, 15:57-63, 1983.
Method of control and outcome	15-19	20-24	25-29	30-34	35-39	40-44
No fertility-control    methods*	7.0	7.4	9.1	14.8	25.7	28.2
Oral contraceptives    nonsmoker**	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

3. Carcinoma of the Reproductive Organs and Breasts

Numerous epidemiological studies have examined the association between the use of oral contraceptives and the incidence of breast and cervical cancer.

The risk of having breast cancer diagnosed may be slightly increased among current and recent users of COCs. However, this excess risk appears to decrease over time after COC discontinuation and by 10 years after cessation the increased risk disappears. Some studies report an increased risk with duration of use while other studies do not and no consistent relationships have been found with dose or type of steroid. Some studies have reported a small increase in risk for women who first use COCs at a younger age. Most studies show a similar pattern of risk with COC use regardless of a woman's reproductive history or her family breast cancer history.

Breast cancers diagnosed in current or previous OC users tend to be less clinically advanced than in nonusers.

Women with known or suspected carcinoma of the breast or personal history of breast cancer should not use oral contraceptives because breast cancer is usually a hormonally-sensitive tumor.

Some studies suggest that oral-contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia or invasive cervical cancer in some populations of women. 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 combination 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. Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.

Studies from Britain have shown an increased risk of developing hepatocellular carcinoma 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 that may lead to partial or complete loss of vision. 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 or During Early Pregnancy

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

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

Combination oral contraceptives may worsen existing gallbladder disease and may accelerate the development of this disease in previously asymptomatic women. Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens. More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral-contraceptive users may be minimal. 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 been shown to cause glucose intolerance in a significant percentage of users. Oral contraceptives containing greater than 75 mcg of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance. Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents. However, in the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. 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.; PRECAUTIONS, 3.), changes in serum triglycerides and lipoprotein levels have been reported in oral-contraceptive users.

9. Elevated Blood Pressure

Women with uncontrolled hypertension should not be started on hormonal contraception. An increase in blood pressure has been reported in women taking oral contraceptives, and this increase is more likely in older oral-contraceptive users and with continued use. Data from the Royal College of General Practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing quantities of progestogens.

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

10. Headache

The onset or exacerbation of migraine or development of headache with a new pattern that is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause. (See WARNINGS, 1c. and CONTRAINDICATIONS.)

11. Bleeding Irregularities

Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. The type and dose of progestogen may be important. If bleeding persists or recurs, nonhormonal 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 some women withdrawal bleeding may not occur during the “tablet-free” or “inactive-tablet” interval. If the COC has not been taken according to directions prior to the first missed withdrawal bleed, or if two consecutive withdrawal bleeds are missed, tablet-taking should be discontinued and a nonhormonal method of contraception should be used until the possibility of pregnancy is excluded.

Some women may encounter post-pill amenorrhea or oligomenorrhea (possibly with anovulation), especially when such a condition was pre-existent.

12. Ectopic Pregnancy

Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.

PRECAUTIONS

1. General

Patients should be counseled that oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually transmitted diseases (STDs) such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.

2. Physical Examination and Follow-Up

A periodic personal and family medical history and complete physical examination are appropriate for all women, 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 diagnostic 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 hyperlipidemias 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. (See WARNINGS, 1a., 1d., and 8.)

In patients with defects of lipoprotein metabolism, estrogen-containing preparations may be associated with rare but significant elevations of plasma triglycerides which may lead to pancreatitis.

4. Liver Function

If jaundice develops in any woman receiving hormonal contraceptives, 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

Patients becoming significantly depressed while taking oral contraceptives should stop the medication and use an alternate method of contraception in an attempt to determine whether the symptom is drug related. Women with a history of depression should be carefully observed and the drug discontinued if significant depression occurs.

7. Contact Lenses

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

8. Gastrointestinal

Diarrhea and/or vomiting may reduce hormone absorption resulting in decreased serum concentrations.

9. Drug Interactions

Changes in contraceptive effectiveness associated with coadministration of other products:

Contraceptive effectiveness may be reduced when hormonal contraceptives are coadministered with antibiotics, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. This could result in unintended pregnancy or breakthrough bleeding. Examples include rifampin, rifabutin, barbiturates, primidone, phenylbutazone, phenytoin, dexamethasone, carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin, and modafinil.

Several cases of contraceptive failure and breakthrough bleeding have been reported in the literature with concomitant administration of antibiotics such as ampicillin and other penicillins, and tetracyclines, possibly due to a decrease of enterohepatic recirculation of estrogens. However, clinical pharmacology studies investigating drug interactions between combined oral contraceptives and these antibiotics have reported inconsistent results. Enterohepatic recirculation of estrogens may also be decreased by substances that reduce gut transit time.

Several of the anti-HIV protease inhibitors have been studied with coadministration of oral combination hormonal contraceptives; significant changes (increase and decrease) in the plasma levels of the estrogen and progestin have been noted in some cases. The safety and efficacy of oral contraceptive products may be affected with coadministration of anti-HIV protease inhibitors. Health-care professionals should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information.

Herbal products containing St. John's Wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding.

During concomitant use of ethinyl estradiol containing products and substances that may lead to decreased plasma steroid hormone concentrations, it is recommended that a nonhormonal back-up method of birth control be used in addition to the regular intake of Lo/Ovral. If the use of a substance which leads to decreased ethinyl estradiol plasma concentrations is required for a prolonged period of time, combination oral contraceptives should not be considered the primary contraceptive.

After discontinuation of substances that may lead to decreased ethinyl estradiol plasma concentrations, use of a nonhormonal back-up method of birth control is recommended for 7 days. Longer use of a back-up method is advisable after discontinuation of substances that have led to induction of hepatic microsomal enzymes, resulting in decreased ethinyl estradiol concentrations. It may take several weeks until enzyme induction has completely subsided, depending on dosage, duration of use, and rate of elimination of the inducing substance.

Increase in plasma levels associated with coadministered drugs:

Coadministration of atorvastatin and certain oral contraceptives containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. The mechanism of this interaction is unknown. Ascorbic acid and acetaminophen increase the bioavailability of ethinyl estradiol since these drugs act as competitive inhibitors for sulfation of ethinyl estradiol in the gastrointestinal wall, a known pathway of elimination for ethinyl estradiol. CYP 3A4 inhibitors such as indinavir, itraconazole, ketoconazole, fluconazole, and troleandomycin may increase plasma hormone levels. Troleandomycin may also increase the risk of intrahepatic cholestasis during coadministration with combination oral contraceptives.

Changes in plasma levels of coadministered drugs:

Combination hormonal contraceptives containing some synthetic estrogens (eg, ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporin, prednisolone and other corticosteroids, and theophylline have been reported with concomitant administration of oral contraceptives. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine, and clofibric acid, due to induction of conjugation (particularly glucuronidation), have been noted when these drugs were administered with oral contraceptives.

The prescribing information of concomitant medications should be consulted to identify potential interactions.

10. 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 ie, corticosteroid binding globulin (CBG), sex hormone-binding globulins (SHBG) leading to increased levels of total circulating corticosteroids and sex steroids respectively. Free or biologically active hormone concentrations are unchanged.


4. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected.


5. Glucose tolerance may