Betadona

Betadona may be available in the countries listed below.

Ingredient matches for Betadona

Povidone Iodine

Povidone-Iodine is reported as an ingredient of Betadona in the following countries:

• Austria

International Drug Name Search

Fucil

Fucil may be available in the countries listed below.

Ingredient matches for Fucil

Flucloxacillin

Flucloxacillin sodium salt (a derivative of Flucloxacillin) is reported as an ingredient of Fucil in the following countries:

• Bangladesh

International Drug Name Search

Dallergy

Pronunciation: KLOR-fen-IR-a-meen/FEN-il-EF-rin/METH-skoe-POL-a-meen
Generic Name: Chlorpheniramine/Phenylephrine/Methscopolamine
Brand Name: Dallergy

Dallergy is used for:

Relieving congestion, sneezing, runny nose, and itchy, watery eyes due to colds, flu, or hay fever. It may also be used for other conditions as determined by your doctor.

Dallergy is an antihistamine, decongestant, and anticholinergic combination. It works by blocking histamine, a substance in the body that causes sneezing, runny nose, and watery eyes. It also relieves nasal congestion by shrinking the nasal mucous membranes, which promotes nasal drainage, and dries the chest by decreasing lung secretions.

Do NOT use Dallergy if:

• you are allergic to any ingredient in Dallergy


• you are pregnant or breast-feeding


• you take sodium oxybate (GHB) or you have taken furazolidone or a monoamine oxidase inhibitor (MAOI) (eg, phenelzine) within the last 14 days


• you are taking or have taken medicine for high blood pressure or depression in the last 14 days


• you have a history of narrow-angle glaucoma, blockage in the stomach or intestines, peptic ulcer disease, intestinal or bowel problems, difficulty urinating, inflammation of the esophagus from reflux disease, difficulty swallowing, or uncontrolled bleeding


• you have severe heart disease or severe high blood pressure

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

Before using Dallergy:

Some medical conditions may interact with Dallergy. 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 have diabetes, an enlarged prostate, a history of bladder or kidney problems, high blood pressure, diarrhea, asthma, nerve problems, heart problems, blood clots, a hiatal hernia, an adrenal gland tumor, glaucoma, breathing problems during sleep, myasthenia gravis (muscle weakness), or an overactive thyroid

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

• Alpha-blockers (eg, guanethidine, methyldopa, prazosin), beta-blockers (eg, atenolol), diuretics (eg, furosemide, hydrochlorothiazide), furazolidone, or MAOIs (eg, phenelzine) because the risk of high or low blood pressure may be increased


• Alkalizers (eg, calcium or magnesium antacids), anticholinergics (eg, atropine, benztropine, dicyclomine), carbonic anhydrase inhibitors (eg, acetazolamide), ergotamine, sodium bicarbonate, or tricyclic antidepressants (eg, amitriptyline) because they may increase the risk of Dallergy's side effects


• Bromocriptine, catechol-O-methyltransferase (COMT) inhibitors (eg, entacapone), certain stimulants (eg, doxapram, pseudoephedrine), cocaine, digoxin, droxidopa, potassium chloride, or sodium oxybate (GHB) because the risk of their side effects may be increased by Dallergy


• Guanadrel, guanethidine, mecamylamine, methyldopa, or reserpine because their effectiveness may be decreased by Dallergy

This may not be a complete list of all interactions that may occur. Ask your health care provider if Dallergy 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 Dallergy:

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

• Take Dallergy by mouth with or without food. If stomach upset occurs, take with food to reduce stomach irritation.


• Do not take Dallergy at the same time as antacids, certain medicines for diarrhea (eg, attapulgite, bismuth, kaolin, pectin), or ketoconazole. Take these medicines 2 or 3 hours before or after you take Dallergy.


• If you miss a dose of Dallergy and you are taking it regularly, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

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

Important safety information:

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


• Do not drink alcohol or use medicines that may cause drowsiness (eg, sleep aids, muscle relaxers) while you are using Dallergy; it may add to their effects. Ask your pharmacist if you have questions about which medicines may cause drowsiness.


• If your symptoms do not get better within 7 days or if they get worse or you develop a high fever or persistent headache, check with your doctor.


• Dallergy may interfere with certain lab tests. Be sure your doctor and lab personnel know that you are taking Dallergy.


• Dallergy may cause dry mouth. To relieve dry mouth, suck on sugarless hard candy or ice chips, chew sugarless gum, drink water, or use a saliva substitute.


• Dallergy may make your eyes more sensitive to sunlight. It may help to wear sunglasses.


• Dallergy may reduce sweating. Do not become overheated in hot weather or while you are being active; heatstroke may occur.


• Do not take diet or appetite control medicines while you are taking Dallergy without checking with your doctor.


• If you have trouble sleeping, ask your doctor or pharmacist about the best time of day to take Dallergy.


• Diabetes patients - Dallergy may affect your blood sugar. Check blood sugar levels closely. Ask your doctor before you change the dose of your diabetes medicine.


• Use Dallergy with caution in the ELDERLY; they may be more sensitive to its effects.


• Dallergy should be used with extreme caution in CHILDREN younger than 6 years old; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: Do not use Dallergy if you are pregnant. If you think you may be pregnant, contact your doctor right away. Do not use Dallergy during labor or delivery because it could cause harm to the fetus. Dallergy is found in breast milk. Do not breast-feed while taking Dallergy.

Possible side effects of Dallergy:

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:

Blurred vision; clumsiness; constipation; dizziness; drowsiness; dry mouth, nose, or throat; excitability or irritability (especially in children); flushing; giddiness; headache; lack of energy; nausea; nervousness; tearing; trouble sleeping; unusual tiredness or weakness.

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); difficulty swallowing; mental or mood changes; pounding in the chest; unusual bleeding or bruising; urinary retention; vomiting.

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: Dallergy 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. Symptoms may include convulsions; deep sleep or loss of consciousness; hot or cool skin; irregular heartbeat; irritability, anxiety, or panic; large pupils; numbness or tingling in the arms or legs; seizures; slowed or shallow breathing; vomiting.

Proper storage of Dallergy:

Store Dallergy in a tightly closed container between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Dallergy out of the reach of children and away from pets.

General information:

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


• Dallergy 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 Dallergy. 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 Dallergy resources

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

• Dallergy Concise Consumer Information (Cerner Multum)

Compare Dallergy with other medications

• Nasal Congestion
• Rhinitis

Loperamid dura

Loperamid dura may be available in the countries listed below.

Ingredient matches for Loperamid dura

Loperamide

Loperamide hydrochloride (a derivative of Loperamide) is reported as an ingredient of Loperamid dura in the following countries:

• Germany

International Drug Name Search

Paracetamol for Chlidren

Paracetamol for Chlidren may be available in the countries listed below.

Ingredient matches for Paracetamol for Chlidren

Paracetamol

Paracetamol is reported as an ingredient of Paracetamol for Chlidren in the following countries:

• Georgia

International Drug Name Search

Bontril

Ingredient matches for Bontril

Phendimetrazine

Phendimetrazine tartrate (a derivative of Phendimetrazine) is reported as an ingredient of Bontril in the following countries:

• United States

International Drug Name Search

Sim Drop

Sim Drop may be available in the countries listed below.

Ingredient matches for Sim Drop

Simeticone

Simeticone is reported as an ingredient of Sim Drop in the following countries:

• Bangladesh

International Drug Name Search

Reumatrex

Reumatrex may be available in the countries listed below.

Ingredient matches for Reumatrex

Methotrexate

Methotrexate is reported as an ingredient of Reumatrex in the following countries:

• Peru

International Drug Name Search

Ravonal

Ravonal may be available in the countries listed below.

Ingredient matches for Ravonal

Thiopental

Thiopental Sodium is reported as an ingredient of Ravonal in the following countries:

• Japan

International Drug Name Search

Clinagel

Clinagel may be available in the countries listed below.

In some countries, this medicine may only be approved for veterinary use.

Ingredient matches for Clinagel

Gentamicin

Gentamicin sulfate (a derivative of Gentamicin) is reported as an ingredient of Clinagel in the following countries:

• United Kingdom

International Drug Name Search

Altadol

Altadol may be available in the countries listed below.

In some countries, this medicine may only be approved for veterinary use.

Ingredient matches for Altadol

Tramadol

Tramadol hydrochloride (a derivative of Tramadol) is reported as an ingredient of Altadol in the following countries:

• Italy

International Drug Name Search

DHC Continus prolonged release tablets 60mg, 90mg and 120 mg

DHC Continus 60 mg, 90 mg and 120 mg prolonged-release tablets

Dihydrocodeine tartrate

Read all of this leaflet carefully before you start taking this medicine.

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


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


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


• If any of the side effects become serious, or if you notice any side effects not listed in this leaflet, please
  tell your doctor or pharmacist.

In this leaflet:

1. What DHC Continus tablets are and what they are used for

2. Before you take DHC Continus tablets

3. How to take DHC Continus tablets

4. Possible side effects

5. How to store DHC Continus tablets

6. Further information

What DHC Continus tablets are and what they are used for

These tablets have been prescribed for you to relieve severe pain over a period of 12 hours. They contain the active ingredient dihydrocodeine which belongs to a group of medicines called strong analgesics or ‘painkillers’.

Before you take DHC Continus tablets

Do not take DHC Continus tablets if you:

• are allergic (hypersensitive) to dihydrocodeine or any of the other ingredients of the tablets (see section 6
  ‘Further Information’);


• have breathing problems, such as obstructive airways disease or respiratory depression. Your doctor will have told you if you have these conditions. Symptoms may include breathlessness, coughing or breathing more slowly or weakly than expected;


• are having an asthma attack;


• have a condition where the small bowel (part of your gut) does not work properly (paralytic ileus);


• have a severe headache or feel sick due to a head injury or increased pressure in your skull (for instance due to brain disease). This is because the tablets may make these symptoms worse or hide the extent of a head injury;


• are addicted to alcohol;


• have an intolerance to some sugars;


• are under 12 years of age.

Take special care with DHC Continus tablets

Before treatment with these tablets tell your doctor or pharmacist if you:

• have asthma;


• have an under-active thyroid gland (hypothyroidism);


• have kidney or long-term liver problems;


• have constipation or obstructive bowel disorders;


• have inflammation of the pancreas (which causes severe pain in the abdomen and back);


• have problems with your gall bladder;


• have prostate problems;


• have a severe heart problem after long-term lung disease (severe cor pulmonale);


• are or have ever been addicted to drugs.

Taking other medicines

Tell your doctor or pharmacist if you are taking:

• medicines to help you sleep (for example tranquillisers, hypnotics or sedatives);


• medicines to treat psychiatric or mental disorders (such as phenothiazines);


• a type of medicine known as a monoamine oxidase inhibitor (examples include tranylcypromide, phenelzine, isocarboxazid, moclobemide and linezolid), or you have taken this type of medicine in the last two weeks.

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. If you take these tablets with some other medicines, the effect of these tablets or the other medicine may be changed.

Taking DHC Continus tablets with alcohol

Drinking alcohol during your treatment with these tablets may make you sleepy. If you are affected you should avoid drinking alcohol.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding do not take these tablets until you have spoken to your doctor.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

These tablets may cause a number of side effects such as drowsiness which could affect your ability to drive or use machinery (see section 4 for a full list of side effects). These are usually most noticeable when you first start taking the tablets or when changing to a higher dose. If you are affected you should not drive or use machinery.

Important information about some of the ingredients of DHC Continus tablets

These tablets contain lactose which is a form of sugar. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking these tablets.

How to take DHC Continus tablets

Always take these tablets exactly as your doctor has told you. The label on your medicine will tell you how many tablets to take and how often. Do not take for longer than directed by your doctor.

Swallow your tablets whole with a glass of water. Do not break, crush or chew them.

DHC Continus tablets are designed to work properly over 12 hours when swallowed whole. If a tablet is broken, crushed or chewed, the entire 12-hour dose may be absorbed rapidly into your body. This can be dangerous, causing serious problems such as an overdose, which may be fatal.

You should take your tablets every 12 hours. For instance, if you take a tablet at 8 o’clock in the morning, you should take your next tablet at 8 o’clock in the evening.

Adults and children over 12 years of age

The usual starting dose is 60 mg to 120 mg every 12 hours. If you are elderly your doctor may suggest a lower starting dose. Your doctor will prescribe the dose required to treat your pain. If you find that you are still in pain whilst taking these tablets discuss this with your doctor.

Children under 12 years of age

Children under 12 years of age should not take the tablets.

If you take more DHC Continus tablets than you should or if someone accidentally swallows your tablets

Call your doctor or hospital straight away. People who have taken an overdose may feel very sleepy, sick or dizzy. They may also have breathing difficulties leading to unconsciousness or even death and may need emergency treatment in hospital. When seeking medical attention make sure that you take this leaflet and any remaining tablets with you to show the doctor.

If you forget to take DHC Continus tablets

If you remember within 4 hours of the time your tablet was due, take your tablet straight away. Take your next tablet at your normal time. If you are more than 4 hours late, please call your doctor or pharmacist for advice. Do not take a double dose to make up for a forgotten tablet.

If you stop taking DHC Continus tablets

You should not stop taking these tablets unless your doctor tells you to. If you want to stop taking your tablets, discuss this with your doctor first. Withdrawal symptoms such as agitation, anxiety, shaking or sweating may occur if you suddenly stop taking these tablets.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Possible side effects

Like all medicines, these tablets can cause side effects, although not everybody gets them.

The most serious side effect is a condition where you breathe more slowly or weakly than expected (respiratory depression).

As with all strong painkillers, there is a risk you may become addicted or reliant on these tablets.

Taking a painkiller for headaches too often or for too long can make your headaches worse.

Common side effects (Probably affecting more than 1 in 100 people taking these tablets)

• Constipation (your doctor can prescribe a laxative to overcome this problem).


• Feeling or being sick (this should normally wear off after a few days, however your doctor can prescribe an anti-sickness medicine if it continues to be a problem).


• Drowsiness (this is most likely when you start taking your tablets or when your dose is increased, but it should wear off after a few days).


• Headache.


• Rash or itchy skin.

Uncommon side effects (Probably affecting fewer than 1 in 100 people taking these tablets)

• Dry mouth.


• Abdominal pain or discomfort.


• A condition where the small bowel (part of your gut) does not work properly (paralytic ileus).


• Mood changes.


• Confusion.


• Hallucinations.


• Blurred vision.


• Dizziness.


• Tingling or numbness.


• Low blood pressure.


• Decreased sexual drive.


• Difficulty in passing urine.


• Flushing of the skin.


• Sweating.


• A need to take increasingly higher doses to obtain the same level of pain relief (tolerance).

If any of the side effects become serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How to store DHC Continus tablets

Keep out of the reach and sight of children.

Do not use any tablets after the expiry date which is stated on the label and carton. EXP 08 2010 means that you should not take the tablets after the last day of that month i.e. August 2010.

Do not store your tablets above 25°C.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further information

What DHC Continus tablets contain

The active ingredient is dihydrocodeine tartrate. Each tablet contains 60 mg, 90 mg or 120 mg of dihydrocodeine tartrate.

The other ingredients are:

• Lactose


• Hydroxyethylcellulose


• Cetostearyl alcohol


• Magnesium stearate


• Talc

What DHC Continus tablets look like and the contents of the pack

The tablets are white, capsule shaped and marked DHC followed by the strength (e.g. 60, 90 etc.).

In each bottle there are 56 tablets.

Marketing Authorisation Holder and Manufacturer

The tablets are made by

Bard Pharmaceuticals Limited

Cambridge Science Park

Milton Road

Cambridge

CB4 0GW

UK

for the marketing authorisation holder

Napp Pharmaceuticals Limited

Cambridge Science Park

Milton Road

Cambridge

CB4 0GW

UK

This leaflet is also available in large print, Braille or as an audio CD. To request a copy, please call the RNIB Medicine Information line (free of charge) on:

0800 198 5000

You will need to give details of the product name and reference number.

These are as follows:

Product name: DHC Continus prolonged-release tablets

Reference number: 16950/0019

This leaflet was last revised in May 2009

DHC, Continus, DHC Continus and the NAPP device (logo) are Registered Trade Marks.

© 2009 Napp Pharmaceuticals Limited

DHC P0083-A R1V6 UK AW 05-02-09 (Approved)

Gemzar

gemcitabine hydrochloride

Dosage Form: injection, powder, lyophilized, for solution
FULL PRESCRIBING INFORMATION

Indications and Usage for Gemzar

Ovarian Cancer

Gemzar in combination with carboplatin is indicated for the treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy.

Breast Cancer

Gemzar in combination with paclitaxel is indicated for the first-line treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated.

Non-Small Cell Lung Cancer

Gemzar is indicated in combination with cisplatin for the first-line treatment of patients with inoperable, locally advanced (Stage IIIA or IIIB), or metastatic (Stage IV) non-small cell lung cancer.

Pancreatic Cancer

Gemzar is indicated as first-line treatment for patients with locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas. Gemzar is indicated for patients previously treated with 5-FU.

Gemzar Dosage and Administration

Gemzar is for intravenous use only. Gemzar may be administered on an outpatient basis.

Ovarian Cancer

Gemzar should be administered intravenously at a dose of 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Carboplatin AUC 4 should be administered intravenously on Day 1 after Gemzar administration. Patients should be monitored prior to each dose with a complete blood count, including differential counts. Patients should have an absolute granulocyte count ≥1500 x 106/L and a platelet count ≥100,000 x 106/L prior to each cycle.

Dose Modifications

Gemzar dosage adjustment for hematological toxicity within a cycle of treatment is based on the granulocyte and platelet counts taken on Day 8 of therapy. If marrow suppression is detected, Gemzar dosage should be modified according to guidelines in Table 1.

Table 1: Day 8 Dosage Reduction Guidelines for Gemzar in Combination with Carboplatin

Absolute granulocyte count (x 106/L)		Platelet count (x 106/L)	% of full dose
≥1500	And	≥100,000	100
1000-1499	And/or	75,000-99,999	50
<1000	And/or	<75,000	Hold

In general, for severe (Grade 3 or 4) non-hematological toxicity, except nausea/vomiting, therapy with Gemzar should be held or decreased by 50% depending on the judgment of the treating physician. For carboplatin dosage adjustment, see manufacturer's prescribing information.

Dose adjustment for Gemzar in combination with carboplatin for subsequent cycles is based upon observed toxicity. The dose of Gemzar in subsequent cycles should be reduced to 800 mg/m2 on Days 1 and 8 in case of any of the following hematologic toxicities:

• Absolute granulocyte count <500 x 106/L for more than 5 days


• Absolute granulocyte count <100 x 106/L for more than 3 days


• Febrile neutropenia


• Platelets <25,000 x 106/L


• Cycle delay of more than one week due to toxicity

If any of the above toxicities recur after the initial dose reduction, for the subsequent cycle, Gemzar should be given on Day 1 only at 800 mg/m2.

Breast Cancer

Gemzar should be administered intravenously at a dose of 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Paclitaxel should be administered at 175 mg/m2 on Day 1 as a 3-hour intravenous infusion before Gemzar administration. Patients should be monitored prior to each dose with a complete blood count, including differential counts. Patients should have an absolute granulocyte count ≥1500 x 106/L and a platelet count ≥100,000 x 106/L prior to each cycle.

Dose Modifications

Gemzar dosage adjustment for hematological toxicity is based on the granulocyte and platelet counts taken on Day 8 of therapy. If marrow suppression is detected, Gemzar dosage should be modified according to the guidelines in Table 2.

Table 2: Day 8 Dosage Reduction Guidelines for Gemzar in Combination with Paclitaxel

Absolute granulocyte count (x 106/L)		Platelet count (x 106/L)	% of full dose
≥1200	And	>75,000	100
1000-1199	Or	50,000-75,000	75
700-999	And	≥50,000	50
<700	Or	<50,000	Hold

In general, for severe (Grade 3 or 4) non-hematological toxicity, except alopecia and nausea/vomiting, therapy with Gemzar should be held or decreased by 50% depending on the judgment of the treating physician. For paclitaxel dosage adjustment, see manufacturer's prescribing information.

Non-Small Cell Lung Cancer

Two schedules have been investigated and the optimum schedule has not been determined [see Clinical Studies (14.3)]. With the 4-week schedule, Gemzar should be administered intravenously at 1000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle. Cisplatin should be administered intravenously at 100 mg/m2 on Day 1 after the infusion of Gemzar. With the 3-week schedule, Gemzar should be administered intravenously at 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Cisplatin at a dose of 100 mg/m2 should be administered intravenously after the infusion of Gemzar on Day 1. See prescribing information for cisplatin administration and hydration guidelines.

Dose Modifications

Dosage adjustments for hematologic toxicity may be required for Gemzar and for cisplatin. Gemzar dosage adjustment for hematological toxicity is based on the granulocyte and platelet counts taken on the day of therapy. Patients receiving Gemzar should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet counts. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 3. For cisplatin dosage adjustment, see manufacturer's prescribing information.

In general, for severe (Grade 3 or 4) non-hematological toxicity, except alopecia and nausea/vomiting, therapy with Gemzar plus cisplatin should be held or decreased by 50% depending on the judgment of the treating physician. During combination therapy with cisplatin, serum creatinine, serum potassium, serum calcium, and serum magnesium should be carefully monitored (Grade 3/4 serum creatinine toxicity for Gemzar plus cisplatin was 5% versus 2% for cisplatin alone).

Pancreatic Cancer

Gemzar should be administered by intravenous infusion at a dose of 1000 mg/m2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing or holding a dose), followed by a week of rest from treatment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks.

Dose Modifications

Dosage adjustment is based upon the degree of hematologic toxicity experienced by the patient [see Warnings and Precautions (5.2)]. Clearance in women and the elderly is reduced and women were somewhat less able to progress to subsequent cycles [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

Patients receiving Gemzar should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 3.

Table 3: Dosage Reduction Guidelines

Absolute granulocyte count (x 106/L)		Platelet count (x 106/L)	% of full dose
≥1000	And	≥100,000	100
500-999	Or	50,000-99,999	75
<500	Or	<50,000	Hold

Laboratory evaluation of renal and hepatic function, including transaminases and serum creatinine, should be performed prior to initiation of therapy and periodically thereafter. Gemzar should be administered with caution in patients with evidence of significant renal or hepatic impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations.

Patients treated with Gemzar who complete an entire cycle of therapy may have the dose for subsequent cycles increased by 25%, provided that the absolute granulocyte count (AGC) and platelet nadirs exceed 1500 x 106/L and 100,000 x 106/L, respectively, and if non-hematologic toxicity has not been greater than WHO Grade 1. If patients tolerate the subsequent course of Gemzar at the increased dose, the dose for the next cycle can be further increased by 20%, provided again that the AGC and platelet nadirs exceed 1500 x 106/L and 100,000 x 106/L, respectively, and that non-hematologic toxicity has not been greater than WHO Grade 1.

Preparation and Administration Precautions

Caution should be exercised in handling and preparing Gemzar solutions. The use of gloves is recommended. If Gemzar solution contacts the skin or mucosa, immediately wash the skin thoroughly with soap and water or rinse the mucosa with copious amounts of water. Although acute dermal irritation has not been observed in animal studies, 2 of 3 rabbits exhibited drug-related systemic toxicities (death, hypoactivity, nasal discharge, shallow breathing) due to dermal absorption.

Procedures for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines on this subject have been published [see References (15)].

Preparation for Intravenous Infusion Administration

The recommended diluent for reconstitution of Gemzar is 0.9% Sodium Chloride Injection without preservatives. Due to solubility considerations, the maximum concentration for Gemzar upon reconstitution is 40 mg/mL. Reconstitution at concentrations greater than 40 mg/mL may result in incomplete dissolution, and should be avoided.

To reconstitute, add 5 mL of 0.9% Sodium Chloride Injection to the 200-mg vial or 25 mL of 0.9% Sodium Chloride Injection to the 1-g vial. Shake to dissolve. These dilutions each yield a gemcitabine concentration of 38 mg/mL which includes accounting for the displacement volume of the lyophilized powder (0.26 mL for the 200-mg vial or 1.3 mL for the 1-g vial). The total volume upon reconstitution will be 5.26 mL or 26.3 mL, respectively. Complete withdrawal of the vial contents will provide 200 mg or 1 g of gemcitabine, respectively. Prior to administration the appropriate amount of drug must be diluted with 0.9% Sodium Chloride Injection. Final concentrations may be as low as 0.1 mg/mL.

Reconstituted Gemzar is a clear, colorless to light straw-colored solution. After reconstitution with 0.9% Sodium Chloride Injection, the pH of the resulting solution lies in the range of 2.7 to 3.3. The solution should be inspected visually for particulate matter and discoloration prior to administration, whenever solution or container permit. If particulate matter or discoloration is found, do not administer.

When prepared as directed, Gemzar solutions are stable for 24 hours at controlled room temperature 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Discard unused portion. Solutions of reconstituted Gemzar should not be refrigerated, as crystallization may occur.

The compatibility of Gemzar with other drugs has not been studied. No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.

Dosage Forms and Strengths

Gemzar (gemcitabine for injection, USP) is a white to off-white lyophilized powder available in sterile single-use vials containing 200 mg or 1 g gemcitabine.

Contraindications

Gemzar is contraindicated in those patients with a known hypersensitivity to the drug.

Warnings and Precautions

Patients receiving therapy with Gemzar should be monitored closely by a physician experienced in the use of cancer chemotherapeutic agents.

Infusion Time

Caution — Prolongation of the infusion time beyond 60 minutes and more frequent than weekly dosing have been shown to increase toxicity [see Clinical Studies (14.5)].

Hematology

Gemzar can suppress bone marrow function as manifested by leukopenia, thrombocytopenia, and anemia [see Adverse Reactions (6.1)], and myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)].

Pulmonary

Pulmonary toxicity has been reported with the use of Gemzar. In cases of severe lung toxicity, Gemzar therapy should be discontinued immediately and appropriate supportive care measures instituted [see Adverse Reactions (6.1 and 6.2)].

Renal

Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of Gemzar. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been reported. The majority of the cases of renal failure leading to death were due to HUS [see Adverse Reactions (6.1 and 6.2)].

Gemzar should be used with caution in patients with preexisting renal impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations [see Use in Specific Populations (8.6)].

Hepatic

Serious hepatotoxicity, including liver failure and death, has been reported in patients receiving Gemzar alone or in combination with other potentially hepatotoxic drugs [see Adverse Reactions (6.1 and 6.2)].

Gemzar should be used with caution in patients with preexisting hepatic insufficiency as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations. Administration of Gemzar in patients with concurrent liver metastases or a preexisting medical history of hepatitis, alcoholism, or liver cirrhosis may lead to exacerbation of the underlying hepatic insufficiency [see Use in Specific Populations (8.7)].

Pregnancy

Gemzar can cause fetal harm when administered to a pregnant woman. In pre-clinical studies in mice and rabbits, gemcitabine was teratogenic, embryotoxic, and fetotoxic. There are no adequate and well-controlled studies of Gemzar in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

Laboratory Tests

Patients receiving Gemzar should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. Suspension or modification of therapy should be considered when marrow suppression is detected [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)].

Laboratory evaluation of renal and hepatic function should be performed prior to initiation of therapy and periodically thereafter [see Dosage and Administration (2.4)].

Radiation Therapy

A pattern of tissue injury typically associated with radiation toxicity has been reported in association with concurrent and non-concurrent use of Gemzar.

Non-concurrent (given >7 days apart) — Analysis of the data does not indicate enhanced toxicity when Gemzar is administered more than 7 days before or after radiation, other than radiation recall. Data suggest that Gemzar can be started after the acute effects of radiation have resolved or at least one week after radiation.

Concurrent (given together or ≤7 days apart) — Preclinical and clinical studies have shown that Gemzar has radiosensitizing activity. Toxicity associated with this multimodality therapy is dependent on many different factors, including dose of Gemzar, frequency of Gemzar administration, dose of radiation, radiotherapy planning technique, the target tissue, and target volume. In a single trial, where Gemzar at a dose of 1000 mg/m2 was administered concurrently for up to 6 consecutive weeks with therapeutic thoracic radiation to patients with non-small cell lung cancer, significant toxicity in the form of severe, and potentially life-threatening mucositis, especially esophagitis and pneumonitis was observed, particularly in patients receiving large volumes of radiotherapy [median treatment volumes 4795 cm3]. Subsequent studies have been reported and suggest that Gemzar administered at lower doses with concurrent radiotherapy has predictable and less severe toxicity. However, the optimum regimen for safe administration of Gemzar with therapeutic doses of radiation has not yet been determined in all tumor types.

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Most adverse reactions are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced.

Gemzar has been used in a wide variety of malignancies, both as a single-agent and in combination with other cytotoxic drugs.

Single-Agent Use:

Myelosuppression is the principal dose-limiting toxicity with Gemzar therapy. Dosage adjustments for hematologic toxicity are frequently needed [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)].

The data in Table 4 are based on 979 patients receiving Gemzar as a single-agent administered weekly as a 30-minute infusion for treatment of a wide variety of malignancies. The Gemzar starting doses ranged from 800 to 1250 mg/m2. Data are also shown for the subset of patients with pancreatic cancer treated in 5 clinical studies. The frequency of all grades and severe (WHO Grade 3 or 4) adverse reactions were generally similar in the single-agent safety database of 979 patients and the subset of patients with pancreatic cancer. Adverse reactions reported in the single-agent safety database resulted in discontinuation of Gemzar therapy in about 10% of patients. In the comparative trial in pancreatic cancer, the discontinuation rate for adverse reactions was 14.3% for the Gemzar arm and 4.8% for the 5-FU arm. All WHO-graded laboratory adverse reactions are listed in Table 4, regardless of causality. Non-laboratory adverse reactions listed in Table 4 or discussed below were those reported, regardless of causality, for at least 10% of all patients, except the categories of Extravasation, Allergic, and Cardiovascular and certain specific adverse reactions under the Renal, Pulmonary, and Infection categories.

Table 4: Selected WHO-Graded Adverse Reactions in Patients Receiving Single-Agent Gemzar WHO Grades (% incidence)a

a Grade based on criteria from the World Health Organization (WHO).
b N=699-974; all patients with laboratory or non-laboratory data.
c N=161-241; all pancreatic cancer patients with laboratory or non-laboratory data.
d N=979.
e Regardless of causality.
f Table includes non-laboratory data with incidence for all patients ≥10%. For approximately 60% of the patients, non-laboratory adverse reactions were graded only if assessed to be possibly drug-related.
	All Patientsb			Pancreatic Cancer Patientsc			Discontinuations (%)d
	All Grades	Grade 3	Grade 4	All Grades	Grade 3	Grade 4	All Patients
Laboratorye
Hematologic
Anemia	68	7	1	73	8	2	<1
Leukopenia	62	9	<1	64	8	1	<1
Neutropenia	63	19	6	61	17	7	-
Thrombocytopenia	24	4	1	36	7	<1	<1
Hepatic							<1
ALT	68	8	2	72	10	1
AST	67	6	2	78	12	5
Alkaline Phosphatase	55	7	2	77	16	4
Bilirubin	13	2	<1	26	6	2
Renal							<1
Proteinuria	45	<1	0	32	<1	0
Hematuria	35	<1	0	23	0	0
BUN	16	0	0	15	0	0
Creatinine	8	<1	0	6	0	0
Non-laboratoryf
Nausea and Vomiting	69	13	1	71	10	2	<1
Fever	41	2	0	38	2	0	<1
Rash	30	<1	0	28	<1	0	<1
Dyspnea	23	3	<1	10	0	<1	<1
Diarrhea	19	1	0	30	3	0	0
Hemorrhage	17	<1	<1	4	2	<1	<1
Infection	16	1	<1	10	2	<1	<1
Alopecia	15	<1	0	16	0	0	0
Stomatitis	11	<1	0	10	<1	0	<1
Somnolence	11	<1	<1	11	2	<1	<1
Paresthesias	10	<1	0	10	<1	0	0

Hematologic — In studies in pancreatic cancer myelosuppression is the dose-limiting toxicity with Gemzar, but <1% of patients discontinued therapy for either anemia, leukopenia, or thrombocytopenia. Red blood cell transfusions were required by 19% of patients. The incidence of sepsis was less than 1%. Petechiae or mild blood loss (hemorrhage), from any cause, was reported in 16% of patients; less than 1% of patients required platelet transfusions. Patients should be monitored for myelosuppression during Gemzar therapy and dosage modified or suspended according to the degree of hematologic toxicity [see Dosage and Administration (2.1, 2.2, 2.3, and 2.4)].

Gastrointestinal — Nausea and vomiting were commonly reported (69%) but were usually of mild to moderate severity. Severe nausea and vomiting (WHO Grade 3/4) occurred in <15% of patients. Diarrhea was reported by 19% of patients, and stomatitis by 11% of patients.

Hepatic — In clinical trials, Gemzar was associated with transient elevations of one or both serum transaminases in approximately 70% of patients, but there was no evidence of increasing hepatic toxicity with either longer duration of exposure to Gemzar or with greater total cumulative dose. Serious hepatotoxicity, including liver failure and death, has been reported very rarely in patients receiving Gemzar alone or in combination with other potentially hepatotoxic drugs [see Adverse Reactions (6.2)].

Renal — In clinical trials, mild proteinuria and hematuria were commonly reported. Clinical findings consistent with the Hemolytic Uremic Syndrome (HUS) were reported in 6 of 2429 patients (0.25%) receiving Gemzar in clinical trials. Four patients developed HUS on Gemzar therapy, 2 immediately posttherapy. The diagnosis of HUS should be considered if the patient develops anemia with evidence of microangiopathic hemolysis, elevation of bilirubin or LDH, reticulocytosis, severe thrombocytopenia, and/or evidence of renal failure (elevation of serum creatinine or BUN). Gemzar therapy should be discontinued immediately. Renal failure may not be reversible even with discontinuation of therapy and dialysis may be required [see Adverse Reactions (6.2)].

Fever — The overall incidence of fever was 41%. This is in contrast to the incidence of infection (16%) and indicates that Gemzar may cause fever in the absence of clinical infection. Fever was frequently associated with other flu-like symptoms and was usually mild and clinically manageable.

Rash — Rash was reported in 30% of patients. The rash was typically a macular or finely granular maculopapular pruritic eruption of mild to moderate severity involving the trunk and extremities. Pruritus was reported for 13% of patients.

Pulmonary — In clinical trials, dyspnea, unrelated to underlying disease, has been reported in association with Gemzar therapy. Dyspnea was occasionally accompanied by bronchospasm. Pulmonary toxicity has been reported with the use of Gemzar [see Adverse Reactions (6.2)]. The etiology of these effects is unknown. If such effects develop, Gemzar should be discontinued. Early use of supportive care measures may help ameliorate these conditions.

Edema — Edema (13%), peripheral edema (20%), and generalized edema (<1%) were reported. Less than 1% of patients discontinued due to edema.

Flu-like Symptoms — “Flu syndrome” was reported for 19% of patients. Individual symptoms of fever, asthenia, anorexia, headache, cough, chills, and myalgia were commonly reported. Fever and asthenia were also reported frequently as isolated symptoms. Insomnia, rhinitis, sweating, and malaise were reported infrequently. Less than 1% of patients discontinued due to flu-like symptoms.

Infection — Infections were reported for 16% of patients. Sepsis was rarely reported (<1%).

Alopecia — Hair loss, usually minimal, was reported by 15% of patients.

Neurotoxicity — There was a 10% incidence of mild paresthesias and a <1% rate of severe paresthesias.

Extravasation — Injection-site related events were reported for 4% of patients. There were no reports of injection site necrosis. Gemzar is not a vesicant.

Allergic — Bronchospasm was reported for less than 2% of patients. Anaphylactoid reaction has been reported rarely. Gemzar should not be administered to patients with a known hypersensitivity to this drug [see Contraindications (4)].

Cardiovascular — During clinical trials, 2% of patients discontinued therapy with Gemzar due to cardiovascular events such as myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension. Many of these patients had a prior history of cardiovascular disease [see Adverse Reactions (6.2)].

Combination Use in Non-Small Cell Lung Cancer:

In the Gemzar plus cisplatin versus cisplatin study, dose adjustments occurred with 35% of Gemzar injections and 17% of cisplatin injections on the combination arm, versus 6% on the cisplatin-only arm. Dose adjustments were required in greater than 90% of patients on the combination, versus 16% on cisplatin. Study discontinuations for possibly drug-related adverse reactions occurred in 15% of patients on the combination arm and 8% of patients on the cisplatin arm. With a median of 4 cycles of Gemzar plus cisplatin treatment, 94 of 262 patients (36%) experienced a total of 149 hospitalizations due to possibly treatment-related adverse reactions. With a median of 2 cycles of cisplatin treatment, 61 of 260 patients (23%) experienced 78 hospitalizations due to possibly treatment-related adverse reactions.

In the Gemzar plus cisplatin versus etoposide plus cisplatin study, dose adjustments occurred with 20% of Gemzar injections and 16% of cisplatin injections in the Gemzar plus cisplatin arm compared with 20% of etoposide injections and 15% of cisplatin injections in the etoposide plus cisplatin arm. With a median of 5 cycles of Gemzar plus cisplatin treatment, 15 of 69 patients (22%) experienced 15 hospitalizations due to possibly treatment-related adverse reactions. With a median of 4 cycles of etoposide plus cisplatin treatment, 18 of 66 patients (27%) experienced 22 hospitalizations due to possibly treatment-related adverse reactions. In patients who completed more than one cycle, dose adjustments were reported in 81% of the Gemzar plus cisplatin patients, compared with 68% on the etoposide plus cisplatin arm. Study discontinuations for possibly drug-related adverse reactions occurred in 14% of patients on the Gemzar plus cisplatin arm and in 8% of patients on the etoposide plus cisplatin arm. The incidence of myelosuppression was increased in frequency with Gemzar plus cisplatin treatment (~90%) compared to that with the Gemzar monotherapy (~60%). With combination therapy Gemzar dosage adjustments for hematologic toxicity were required more often while cisplatin dose adjustments were less frequently required.

Table 5 presents the safety data from the Gemzar plus cisplatin versus cisplatin study in non-small cell lung cancer. The NCI Common Toxicity Criteria (CTC) were used. The two-drug combination was more myelosuppressive with 4 (1.5%) possibly treatment-related deaths, including 3 resulting from myelosuppression with infection and one case of renal failure associated with pancytopenia and infection. No deaths due to treatment were reported on the cisplatin arm. Nine cases of febrile neutropenia were reported on the combination therapy arm compared to 2 on the cisplatin arm. More patients required RBC and platelet transfusions on the Gemzar plus cisplatin arm.

Cervidil

dinoprostone

Dosage Form: vaginal insert
Cervidil®

Brand of dinoprostone vaginal insert

Rev. 04/10     Rx only    RMC 226

Cervidil Description

Dinoprostone vaginal insert is a thin, flat, polymeric slab which is rectangular in shape with rounded corners contained within the pouch of an off-white knitted polyester retrieval system. Each slab is buff colored, semitransparent and contains 10 mg of dinoprostone in a hydrogel insert. An integral part of the knitted polyester retrieval system is a long tape designed to aid retrieval at the end of the dosing interval or earlier if clinically indicated. The finished product is a controlled release formulation which has been found to release dinoprostone in vivo at a rate of approximately 0.3 mg/hr.

The chemical name for dinoprostone (commonly known as prostaglandin E2 or PGE2) is 11α, 15S-dihydroxy-9-oxo-prosta-5Z,13E-dien-1-oic acid and the structural formula is represented below:

The molecular formula is C20H32O5 and its molecular weight is 352.5. Dinoprostone occurs as a white to off-white crystalline powder. It has a melting point within the range of 65° to 69°C. Dinoprostone is soluble in ethanol and in 25% ethanol in water. Each insert contains 10 mg of dinoprostone in 241 mg of a cross-linked polyethylene oxide/urethane polymer which is a semi-opaque, beige colored, flat rectangular slab measuring 29 mm by 9.5 mm and 0.8 mm in thickness. The insert and its retrieval system, made of polyester yarn, are non-toxic and when placed in a moist environment, absorb water, swell, and release dinoprostone.

Cervidil - Clinical Pharmacology

Dinoprostone (PGE2) is a naturally-occurring biomolecule. It is found in low concentrations in most tissues of the body and functions as a local hormone (1-3). As with any local hormone, it is very rapidly metabolized in the tissues of synthesis (the half-life estimated to be 2.5-5 minutes). The rate limiting step for inactivation is regulated by the enzyme 15-hydroxyprostaglandin dehydrogenase (PGDH) (1,4). Any PGE2 that escapes local inactivation is rapidly cleared to the extent of 95% on the first pass through the pulmonary circulation (1,2).

In pregnancy, PGE2 is secreted continuously by the fetal membranes and placenta and plays an important role in the final events leading to the initiation of labor (1,2). It is known that PGE2 stimulates the production of PGF2α which in turn sensitizes the myometrium to endogenous or exogenously administered oxytocin. Although PGE2 is capable of initiating uterine contractions and may interact with oxytocin to increase uterine contractility, the available evidence indicates that, in the concentrations found during the early part of labor, PGE2 plays an important role in cervical ripening without affecting uterine contractions (5-7). This distinction serves as the basis for considering cervical ripening and induction of labor, usually by the use of oxytocin (8-10), as two separate processes.

PGE2 plays an important role in the complex set of biochemical and structural alterations involved in cervical ripening. Cervical ripening involves a marked relaxation of the cervical smooth muscle fibers of the uterine cervix which must be transformed from a rigid structure to a softened, yielding and dilated configuration to allow passage of the fetus through the birth canal (11-13). This process involves activation of the enzyme collagenase which is responsible for digestion of some of the structural collagen network of the cervix (1, 14). This is associated with a concomitant increase in the amount of hydrophilic glycosaminoglycan, hyaluronic acid and a decrease in dermatan sulfate (1). Failure of the cervix to undergo these natural physiologic changes, usually assessed by the method described by Bishop (15,16), prior to the onset of effective uterine contractions, results in an unfavourable outcome for successful vaginal delivery and may result in fetal compromise. It is estimated that in approximately 5% of pregnancies the cervix does not ripen normally (17). In an additional 10-11% of pregnancies, labor must be induced for medical or obstetric reasons prior to the time of cervical ripening (17).

The delivery rate of PGE2in vivo is about 0.3 mg/hour over a period of 12 hours. The controlled release of PGE2 from the hydrogel insert is an attempt to provide sufficient quantities of PGE2 to the local receptors to satisfy hormonal requirements. In the majority of patients, these local effects are manifested by changes in the consistency, dilatation and effacement of the cervix as measured by the Bishop score. Although some patients experience uterine hyperstimulation as a result of direct PGE2- or PGF2α-, mediated sensitization of the myometrium to oxytocin, systemic effects of PGE2 are rarely encountered. The insert is fitted with a biocompatible retrieval system which facilitates removal at the conclusion of therapy or in the event of an adverse reaction.

No correlation could be established between PGE2 release and plasma concentrations of PGEm. The relative contributions of endogenously and exogenously released PGE2 to the plasma levels of the metabolite PGEm could not be determined. Moreover, it is uncertain as to whether the measured concentrations of PGEm reflect the natural progression of PGEm concentrations in blood as birth approaches or to what extent the measured concentrations following PGE2 administration represent an increase over basal levels that might be measured in control patients.

Indications and Usage for Cervidil

Cervidil Vaginal Insert (dinoprostone, 10 mg) is indicated for the initiation and/or continuation of cervical ripening in patients at or near term in whom there is a medical or obstetrical indication for the induction of labor.

Contraindications

Cervidil is contraindicated in:

*

Patients with known hypersensitivity to prostaglandins.

*

Patients in whom there is clinical suspicion or definite evidence of fetal distress where delivery is not imminent.

*

Patients with unexplained vaginal bleeding during this pregnancy.

*

Patients in whom there is evidence or strong suspicion of marked cephalopelvic disproportion.

*

Patients in whom oxytocic drugs are contraindicated or when prolonged contraction of the uterus may be detrimental to fetal safety or uterine integrity, such as previous cesarean section or major uterine surgery (seePRECAUTIONSandADVERSE REACTIONS).

*

Patients already receiving intravenous oxytocic drugs.

*

Multipara with 6 or more previous term pregnancies.

Warnings

For hospital use only

Cervidil should be administered only by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.

Women aged 30 years or older, those with complications during pregnancy and those with a gestational age over 40 weeks have been shown to have an increased risk of postpartum disseminated intravascular coagulation. In addition, these factors may further increase the risk associated with labor induction (See ADVERSE REACTIONS, Post-marketing surveillance). Therefore, in these women, use of dinoprostone should be undertaken with caution. Measures should be applied to detect as soon as possible an evolving fibrinolysis in the immediate post-partum period.

The Clinician should be alert that use of dinoprostone may result in inadvertent disruption and subsequent embolization of antigenic tissue causing in rare circumstances the development of Anaphylactoid Syndrome of Pregnancy (Amniotic Fluid Embolism).

Precautions

1. General Precautions: Since prostaglandins potentiate the effect of oxytocin, Cervidil must be removed before oxytocin administration is initiated and the patient's uterine activity carefully monitored for uterine hyperstimulation. If uterine hyperstimulation is encountered or if labor commences, the vaginal insert should be removed. Cervidil should also be removed prior to amniotomy.

Cervidil is contraindicated when prolonged contraction of the uterus may be detrimental to fetal safety and uterine integrity. Therefore, Cervidil should not be administered to patients with a history of previous cesarean section or uterine surgery given the potential risk for uterine rupture and associated obstetrical complications, including the need for hysterectomy and the occurrence of fetal or neonatal death.

Caution should be exercised in the administration of Cervidil for cervical ripening in patients with ruptured membranes, in cases of non-vertex or non-singleton presentation, and in patients with a history of previous uterine hypertony, glaucoma, or a history of childhood asthma, even though there have been no asthma attacks in adulthood.

Uterine activity, fetal status and the progression of cervical dilatation and effacement should be carefully monitored whenever the dinoprostone vaginal insert is in place. With any evidence of uterine hyperstimulation, sustained uterine contractions, fetal distress, or other fetal or maternal adverse reactions, the vaginal insert should be removed.

An increased risk of post-partum disseminated intravascular coagulation has been described in patients whose labor was induced by physiologic means, either with dinoprostone or oxytocin.

2. Drug Interactions: Cervidil may augment the activity of oxytocic agents and their concomitant use is not recommended. A dosing interval of at least 30 minutes is recommended for the sequential use of oxytocin following the removal of the dinoprostone vaginal insert. No other drug interactions have been identified.

3. Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term carcinogenicity and fertility studies have not been conducted with Cervidil (dinoprostone) Vaginal Insert. No evidence of mutagenicity has been observed with prostaglandin E2 in the Unscheduled DNA Synthesis Assay, the Micronucleus Test, or Ames Assay.

4. Pregnancy, Teratogenic Effects:

Pregnancy Category C.

Prostaglandin E2 has produced an increase in skeletal anomalies in rats and rabbits. No effect would be expected clinically, when used as indicated, since Cervidil (dinoprostone) Vaginal Insert is administered after the period of organogenesis. Prostaglandin E2 has been shown to be embryotoxic in rats and rabbits, and any dose that produces sustained increased uterine tone could put the embryo or fetus at risk.

5. Pediatric Use: The safety and efficacy of Cervidil has been established in women of a reproductive age and women who are pregnant. Although safety and efficacy has not been established in pediatric patients, safety and efficacy are expected to be the same for adolescents.

Adverse Reactions

Cervidil is well tolerated. In placebo-controlled trials in which 658 women were entered and 320 received active therapy (218 without retrieval system, 102 with retrieval system), the following events were reported.

Table 1 Total Cervidil – Treated Drug Related Adverse Events

1Controlled Studies (with and without retrieval system)
2Controlled Study (with retrieval system)
	Controlled Studies1
	Active	Placebo
Uterine hyperstimulation with fetal distress	2.8%	0.3%
Uterine hyperstimulation without fetal distress	4.7%	0%
Fetal Distress without uterine hyperstimulation	3.8%	1.2%
N	320	338
	STUDY 101-8012
	Active	Placebo
Uterine hyperstimulation with fetal distress	2.9%	0%
Uterine hyperstimulation without fetal distress	2.0%	0%
Fetal Distress without uterine hyperstimulation	2.9%	1.0%
N	102	104

Drug related fever, nausea, vomiting, diarrhea, and abdominal pain were noted in less than 1% of patients who received Cervidil.

In study 101-801 (with the retrieval system) cases of hyperstimulation reversed within 2 to 13 minutes of removal of the product. Tocolytics were required in one of the five cases.

In cases of fetal distress, when product removal was thought advisable there was a return to normal rhythm and no neonatal sequelae.

Five minute Apgar scores were 7 or above in 98.2% (646/658) of studied neonates whose mothers received Cervidil. In a report of a 3 year pediatric follow-up study in 121 infants, 51 of whose mothers received Cervidil, there were no deleterious effects on physical examination or psychomotor evaluation (18).

Post-marketing surveillance:

Immune System Disorders: Hypersensitivity

Blood and lymphatic system disorders: Disseminated Intravascular Coagulation (See Warnings Section)

Reproductive system: Reports of uterine rupture have been reported in association with use of Cervidil some required a hysterectomy and some resulted in subsequent fetal or neonatal death.

Vascular Disorders: Hypotension

Pregnancy, Puerperium and Perinatal Conditions: Amniotic fluid embolism

Drug Abuse and Dependence

No drug abuse or dependence has been seen with the use of Cervidil.

Overdosage

Cervidil is used as a single dosage in a single application. Overdosage is usually manifested by uterine hyperstimulation which may be accompanied by fetal distress, and is usually responsive to removal of the insert. Other treatment must be symptomatic since, to date, clinical experience with prostaglandin antagonists is insufficient.

The use of beta-adrenergic agents should be considered in the event of undesirable increased uterine activity.

Cervidil Dosage and Administration

The dosage of dinoprostone in the vaginal insert is 10 mg designed to be released at approximately 0.3 mg/hour over a 12 hour period. Cervidil should be removed upon onset of active labor or 12 hours after insertion.

Cervidil is supplied in an individually wrapped aluminium/polyethylene package with a "tear mark" on one side of the package. The package should only be opened by tearing the aluminium package along the tear mark. The package should never be opened with scissors or other sharp objects which may compromise or cut the knitted polyester pouch that serves as the retrieval system for the polymeric slab.

Cervidil must be kept frozen until use, and is administered by placing one unit transversely in the posterior fornix of the vagina immediately after removal from its foil package. The insertion of the vaginal insert does not require sterile conditions. The vaginal insert must not be used without its retrieval system. There is no need for previous warming of the product. A minimal amount of water-miscible lubricant may be used to assist insertion of Cervidil. Care should be taken not to permit excess contact or coating with the lubricant which could prevent optimal swelling and release of dinoprostone from the vaginal insert. Patients should remain in the recumbent position for 2 hours following insertion, but thereafter may be ambulatory. If the patient is ambulatory, care should be taken to ensure the vaginal insert remains in place. If uterine hyperstimulation is encountered or if labor commences, the vaginal insert should be removed. Cervidil should also be removed prior to amniotomy.

Upon removal of Cervidil, it is essential to ensure that the slab has been removed, as it will continue delivering the active ingredient. This is accomplished by visualizing the knitted polyester retrieval system and confirming that it contains the slab. In the rare instance that the slab is not contained within the polyester retrieval system, a vaginal exam should be performed to remove the slab.

How is Cervidil Supplied

Cervidil (NDC 0456-4123-63) contains 10 mg dinoprostone. The product is wound and enclosed in an aluminium/polyethylene pack.

Store in a freezer: between -20°C and -10°C (-4°F and 14°F). Cervidil is packed in foil and is stable when stored in a freezer for a period of three years. Vaginal inserts exposed to high humidity will absorb moisture from the air and thereby alter the release characteristics of dinoprostone. Once used, the vaginal insert should be discarded.

Clinical Studies

Table 2 Efficacy of Cervidil in Double Blind Studies

		Primip/Nullip		Multip
Parameter	Study #	Cervidil	Placebo	Cervidil	Placebo	P-Value
*Treatment success was defined as Bishop score increase at 12 hours of≥ 3, vaginal delivery within 12 hours or Bishop score at 12 hours≥ 6. These studies were not designed with the power to show differences in cesarean section rates between Cervidil and placebo groups and none were noted.
Treatment Success*	101-103 (N=81)	65%	28%	87%	29%	<0.001
	101-003 (N=371)	68%	24%	77%	24%	<0.001
	101-801 (N=206)	72%	48%	55%	41%	0.003
Time to Delivery (hours)
Average Median	101-103 (N=81)	33.7 25.7	48.6 34.5	14.0 12.3	28.6 24.6	0.001
Average Median	101-801 (N=206)	31.1 25.5	51.8 37.2	52.3 20.8	45.9 27.4	<0.001
Time to Onset of Labor (hrs)
Average Median	101-103 (N=81)	19.9 12.0	39.4 19.2	6.8 6.9	22.4 18.3	<0.001

References

1. Physiology of Labor In: Williams Obstetrics. Eds. Pritchard, J. A., MacDonald, P. C., and Gant, N.F. Appleton-Century-Crofts, Conn, Pp 295-321, (1985).


2. Rall, T. W. and Schliefer, L. S. Oxytocin, prostaglandin, ergot alkaloids, and other drugs; tocolytics agents, In: The Pharmacological Basis of Therapeutics. Eds. Gilman, A.G., Goodman, L.S., Rall, T.W., and Murad, F. MacMillan, Publ. Co., New York, Pp. 926-945, (1985).


3. Casey, M.L. and MacDonald, P.C. The initiation of labor in women: Regulation of phospholipid and arachidonic acid metabolism and of prostaglandin production. Semin. Perinat. 10:270-275, (1986).


4. Casey, M.L., MacDonald, P.C. and Mitchell, M.D. Stimulation of Prostaglandin E2 production in amnion cells in culture by a substance(s) in human fetal urine. Biochem. Biophys. Res. Comm. 114:1056, (1983).


5. Olson, C.M., Lye, S.J., Skinner, K. and Challis, J.R.G. Prostanoid concentrations in maternal/fetal plasma and amniotic fluid and intrauterine tissue prostanoid output in relation to myometrial contractility during the onset of Endocrinology, 116: 389-397, (1985).


6. Ledger, W.L., Ellwood, D.A., and Taylor, M.J. Cervical softening in late pregnant sheep by infusion of Prostaglandin E2 into cervical artery. J. Reprod. Fert. 69, 511-515, (1983).


7. Olson, D.M., Lye, S.J., Skinner, K. and Challis, J.R.G. Early changes in prostaglandin concentrations in ovine maternal and fetal plasma, amniotic fluid and from dispersed cells of intrauterine tissues before the onset of ACTH-induced pre-term labor. J. Reprod. Fert., 71: 45-55, (1984).


8. Caldero-Garcia, R. and Posiero, J. Oxytocin and the contractility of the human uterus, Ann, N. Y. Acad. Sci. 75:813, (1959).


9. Posiero, J. and Noriega-Guerra, L. Dose-response relationships in uterine effects of oxytocin infusion. Oxytocin. Eds., Caldero-Garcia, R. and Heller, J. Pergamon Press, New York, (1961).


10. Cibils, L. Enhancement of induction of labor. In: Risks in the Practice of Modern Obstetrics. Aldjem, S. Ed. Mosby Publishing, St. Louis, (1972).


11. Bryman, I., Lindblom, B., and Norstrom, A. Extreme sensitivity of cervical musculature to prostaglandin E2 in early pregnancy. Lancet, 2:1471, (1982).


12. Thiery, M. Induction of labor with prostaglandins. In: Human Parturition. Eds. Keirse, M.J.N.C., Anderson, A.B.M., and Gravenhorst, J.B. Martinus Nijhoff Publ., Boston, 155-164, (1979).


13. Thiery, M. and Amy, J.J. Induction of labor with prostaglandins. In:Advances in Prostaglandin Research. Prostaglandin and Reproduction, Karim, S.M.M., Ed., MTP, Lancaster, Pp. 149-228, (1975).


14. MacLennan, A.H., Katz, M., and Creasey, R. The morphologic characteristics of cervical ripening induced by the hormones relaxin and prostaglandin F2 in a rabbit model. Am. J. Obstet. Gynecol, 152:910696, (1985).


15. Bishop, E. Elective induction of labor. Obstet & Gynecol, 5: 519-527, (1955).


16. Bishop, E. Pelvic scoring for elective induction. Obstet & Gynecol. 24: 266-268, (1969).


17. Thiery, M. Preinduction cervical ripening. In: Obstetrics and Gynecology Annual, Vol. 12, Ed. Wynn, R. M. Appleton-Century-Crofts, New York, Pp. 103-146, (1983).


18. MacKenzie, I.; Information on File: Controlled Therapeutics (Scotland).


19. De Abajo FJ et al. Labor induction with dinoprostone or oxytocin and postpartum disseminated intravascular coagulation: a hospital-based case-control study. Am J Obs Gynecol, 2004, 191: 1637-1643.

Mfg by:

Controlled Therapeutics

East Kilbride, Scotland, G74 5PB

Made in the U.K.

Distributed by:

FOREST PHARMACEUTICALS, INC.

Subsidiary of Forest Laboratories, Inc.

St. Louis, MO 63045 USA

Rev. 04/10             RMC 226

Principal Display Panel

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - PACKAGE CARTON

Cervidil®

DINOPROSTONE 10 mg

vaginal insert

KEEP FROZEN

Made in the U.K.

Distributed by:

FOREST PHARMACEUTICALS, INC.

Subsidiary of Forest Laboratories, Inc.

St. Louis, MO 63045

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Unit Carton

NDC 0456-4123-63

Cervidil®

DINOPROSTONE 10 mg

vaginal insert

Contains: One Cervidil® Vaginal Insert containing

10 mg Dinoprostone in 241 mg hydrogel polymer

(cross-linked polyethylene oxide/urethane)

With polyester retrieval system.

Store in freezer: between -20C and -10C (-4F and 14F)

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Packet

Bar Code 04564 12363

Cervidil®

DINOPROSTONE 10 mg

vaginal insert

FOREST PHARMACEUTICALS, INC.

St. Louis, MO 63045, Made in the UK.

Cervidil  dinoprostone  insert

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0456-4123 Route of Administration VAGINAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Dinoprostone (Dinoprostone) Dinoprostone 10 mg

Inactive Ingredients Ingredient Name Strength polyethylene glycol

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0456-4123-63 1 INSERT In 1 PACKET None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA020411	05/19/1995

Labeler - Forest Laboratories, Inc. (001288281)

Establishment
Name	Address	ID/FEI	Operations
Chinoin Pharmaceutical and Chemical Works Private		643939754	API MANUFACTURE

Establishment
Name	Address	ID/FEI	Operations
DAIICHI FINE CHEMICAL CO LTD		690852371	API MANUFACTURE

Establishment
Name	Address	ID/FEI	Operations
CONTROLLED THERAPEUTICS (SCOTLAND) LTD		298229634	MANUFACTURE

Establishment
Name	Address	ID/FEI	Operations
Forest Pharmaceuticals, Inc.		139419675	MANUFACTURE

Revised: 04/2010Forest Laboratories, Inc.

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