Hypnocalm may be available in the countries listed below.
Ingredient matches for Hypnocalm
Flunitrazepam
Flunitrazepam is reported as an ingredient of Hypnocalm in the following countries:
- Luxembourg
International Drug Name Search
Tuesday, October 25, 2016
Vistaril Suspension
Pronunciation: hye-DROX-i-zeen
Generic Name: Hydroxyzine
Brand Name: Vistaril
Vistaril Suspension is used for:
Treating anxiety, causing sedation before and after general anesthesia, and treating itching due to certain allergic conditions, including hives and contact dermatitis (eg, poison ivy). It also may be used for other conditions as determined by your doctor.
Vistaril Suspension is an antihistamine. It works by affecting the brain to reduce anxiety. It also has other activities, including opening breathing tubes, relieving pain or allergy symptoms, and preventing or treating nausea and vomiting caused by motion sickness.
Do NOT use Vistaril Suspension if:
- you are allergic to any ingredient in Vistaril Suspension
- you are taking sodium oxybate (GHB)
- you are in your first 3 months of pregnancy
Contact your doctor or health care provider right away if any of these apply to you.
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Before using Vistaril Suspension:
Some medical conditions may interact with Vistaril Suspension. 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 asthma, glaucoma, difficulty urinating, a urinary or intestinal blockage, a prostate disease, or a blood disease
- if you drink alcoholic beverages
Some MEDICINES MAY INTERACT with Vistaril Suspension. Tell your health care provider if you are taking any other medicines, especially any of the following:
- Sodium oxybate (GHB) because side effects, such as an increase in sleep duration and slowed breathing, may occur
This may not be a complete list of all interactions that may occur. Ask your health care provider if Vistaril Suspension 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 Vistaril Suspension:
Use Vistaril Suspension as directed by your doctor. Check the label on the medicine for exact dosing instructions.
- Take Vistaril Suspension by mouth with or without food. If stomach upset occurs, take with food to reduce stomach irritation.
- Shake well before each use.
- Use a measuring device marked for medicine dosing. Ask your pharmacist for help if you are unsure of how to measure your dose.
- If you miss a dose of Vistaril Suspension and you are using it regularly, take it as soon as possible. If it is almost time for you 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 Vistaril Suspension.
Important safety information:
- Vistaril Suspension may cause drowsiness. These effects may be worse if you take it with alcohol or certain medicines. Use Vistaril Suspension with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.
- Avoid drinking alcohol or using medicines that may cause drowsiness (eg, sleep aids, muscle relaxers) while you are using Vistaril Suspension; it may add to their effects. Ask your pharmacist if you have questions about which medicines may cause drowsiness.
- The effectiveness of Vistaril Suspension as anxiety treatment for longer than 4 months is not known.
- Use Vistaril Suspension with caution in the ELDERLY; they may be more sensitive to its effects.
- Vistaril Suspension should not be used in NEWBORNS; safety and effectiveness in newborns have not been confirmed.
- PREGNANCY and BREAST-FEEDING: Do not use Vistaril Suspension if you are in your first 3 months of pregnancy. If you think you may be pregnant, contact your doctor right away. It is not known if Vistaril Suspension is found in breast milk. Do not breast-feed while taking Vistaril Suspension.
Possible side effects of Vistaril Suspension:
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:
Drowsiness; dry mouth.
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); involuntary movements.
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: Vistaril 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 unusual drowsiness or dizziness.
Proper storage of Vistaril Suspension:
Store Vistaril Suspension at room temperature, between 59 and 86 degrees F (15 and 30 degrees C), in a tightly closed container. Do not freeze. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Vistaril Suspension out of the reach of children and away from pets.
General information:
- If you have any questions about Vistaril Suspension, please talk with your doctor, pharmacist, or other health care provider.
- Vistaril Suspension 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 Vistaril Suspension. 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 Vistaril resources
- Vistaril Side Effects (in more detail)
- Vistaril Use in Pregnancy & Breastfeeding
- Drug Images
- Vistaril Drug Interactions
- Vistaril Support Group
- 35 Reviews for Vistaril - Add your own review/rating
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VFEND
Generic Name: voriconazole (vor i KON a zole)
Brand Names: VFEND
What is voriconazole?
Voriconazole is an antifungal medication.
Voriconazole is used to treat infections caused by yeast or other types of fungus.
Voriconazole may also be used for purposes not listed in this medication guide.
What is the most important information I should know about voriconazole?
Do not use voriconazole if you are pregnant. It could harm the unborn baby.
There are many other medicines that can cause serious or life-threatening drug interactions with voriconazole. Tell your doctor about all the prescription and over-the-counter medications you use.
Before taking voriconazole, tell your doctor if you have heart rhythm problems, an electrolyte imbalance, liver or kidney disease, or a history of allergy to other antifungal medications such as fluconazole (Diflucan), ketoconazole (Nizoral), or itraconazole (Sporanox).
Take this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antibiotics. Voriconazole will not treat a viral infection such as the common cold or flu.
Voriconazole can cause problems with your vision. If you use this medicine for more than 28 days, you may need to have your eyes checked.
What should I discuss with my healthcare provider before taking voriconazole?
You should not take this medication if you are allergic to voriconazole, or if you are taking any of the following drugs:
carbamazepine (Carbatrol, Equetro, Tegretol);
cisapride (Propulsid);
pimozide (Orap);
quinidine (Quin-G);
sirolimus (Rapamune);
mephobarbital (Mebaral) or phenobarbital (Solfoton);
ritonavir (Norvir, Kaletra) in high doses;
rifabutin (Mycobutin) or rifampin (Rifadin, Rimactane, Rifater);
St. John's wort; or
an ergot medicine such as ergotamine (Ergomar, Cafergot, Ercaf, Wigraine, others) or dihydroergotamine (D.H.E., Migranal).
The drugs listed above can cause dangerous serious or life-threatening drug interactions with voriconazole. Tell your doctor about all other medicines you are using.
To make sure you can safely take voriconazole, tell your doctor if you have any of these other conditions:
heart rhythm problems;
a metabolic disorder such as high or low levels of calcium, potassium, or magnesium;
- liver disease;
- kidney disease; or
a history of allergy to other antifungal medications such as fluconazole (Diflucan), ketoconazole (Nizoral), or itraconazole (Sporanox).
Voriconazole tablets contain lactose. Before taking a voriconazole tablet, tell your doctor if you have a hereditary form of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
FDA pregnancy category D. Do not use voriconazole if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment. It is not known if voriconazole passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.
How should I take voriconazole?
Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
Take voriconazole at least one hour before or after eating a meal. Shake the oral suspension (liquid) well just before you measure a dose. Measure the liquid with a special dose-measuring spoon or medicine cup, not with a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one. Do not mix the oral suspension with any other medicine or liquid. Take this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antibiotics. Voriconazole will not treat a viral infection such as the common cold or flu.
To be sure voriconazole is helping your condition, your blood will need to be tested on a regular basis. Your kidney or liver function may also need to be tested. Visit your doctor regularly.
Voriconazole can cause problems with your vision. If you use this medicine for more than 28 days, you may need to have your eyes checked.
Store voriconazole tablets at room temperature away from moisture and heat. Store the oral liquid at room temperature for up to 14 days. Throw away any unused liquid after 14 days.
What happens if I miss a dose?
Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.
What happens if I overdose?
Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.
Overdose symptoms may include vision problems, excessive mouth watering, enlarged pupils, weakness, loss of balance, shortness of breath, or seizure (convulsions).
What should I avoid while taking voriconazole?
Voriconazole may cause changes in vision including blurred vision and sensitivity to light. Wear sunglasses during the day to protect your eyes from bright light. Be careful if you drive or do anything that requires you to have clear vision. Avoid exposure to sunlight or tanning beds. Voriconazole can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.
Voriconazole side effects
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have any of these serious side effects:
sudden behavior changes, problems with thinking or speech;
upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
urinating less than usual or not at all;
bone pain, swelling;
uneven heart rate, chest pain, general ill feeling; or
severe skin reaction -- fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.
Less serious side effects may include:
vision problems such as blurred vision, eyes being more sensitive to light;
fever;
mild nausea, vomiting, or diarrhea;
headache; or
swelling in your hands, ankles, or feet.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
What other drugs will affect voriconazole?
Many drugs can interact with voriconazole. Below is just a partial list. Tell your doctor if you are using:
clopidogrel (Plavix);
cyclosporine (Sandimmune, Neoral);
phenytoin (Dilantin);
prednisolone (Orapred, Pediapred, Predalone, Veripred, and others);
tacrolimus (Prograf);
warfarin (Coumadin, Jantoven);
birth control pills;
medication to treat HIV or AIDS, especially efavirenz (Atripla, Sustiva);
alfentanil (Alfenta) or fentanyl (Abstral, Actiq, Fentora, Duragesic, Lazanda, Onsolis);
omeprazole (Prilosec) and other stomach acid reducers;
cancer medicine such as vinblastine (Velban), vincristine (Oncovin), or vinorelbine (Navelbine);
methadone (Diskets, Methadose, Dolophine) or oxycodone (OxyContin, Combunox, Roxicodone, Percocet);
non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn, Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Arthrotec, Cambia, Cataflam, Voltaren, Flector Patch, Pennsaid, Solareze), indomethacin (Indocin), meloxicam (Mobic), and others;
tranquilizers or sedatives such as alprazolam (Xanax), midazolam (Versed), triazolam (Halcion), and others;
cholesterol-lowering medicines such as atorvastatin (Lipitor, Caduet), lovastatin (Mevacor), pravastatin (Pravachol), or simvastatin (Zocor, Simcor, Vytorin);
heart or blood pressure medicine such as amlodipine (Norvasc, Caduet, Exforge, Lotrel, Tekamlo, Tribenzor, Twynsta, Amturnide), felodipine (Plendil), nicardipine (Cardene), nifedipine (Nifedical, Procardia), and others; or
an oral diabetes medicine such as glipizide (Glucotrol, Metaglip), glyburide (DiaBeta, Micronase, Glucovance), or tolbutamide (Orinase).
This list is not complete and there are many other drugs that can interact with voriconazole. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.
More VFEND resources
- VFEND Side Effects (in more detail)
- VFEND Use in Pregnancy & Breastfeeding
- Drug Images
- VFEND Drug Interactions
- VFEND Support Group
- 1 Review for VFEND - Add your own review/rating
- Voriconazole Prescribing Information (FDA)
- Voriconazole Professional Patient Advice (Wolters Kluwer)
- voriconazole Advanced Consumer (Micromedex) - Includes Dosage Information
- Vfend MedFacts Consumer Leaflet (Wolters Kluwer)
- Vfend Prescribing Information (FDA)
- Vfend Advanced Consumer (Micromedex) - Includes Dosage Information
- Vfend Monograph (AHFS DI)
- Vfend Consumer Overview
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- Aspergillosis, Invasive
- Blastomycosis
- Candida Infections, Systemic
- Coccidioidomycosis, Meningitis
- Cutaneous Fungal Infection
- Esophageal Candidiasis
- Eumycetoma
- Fungal Infection, Internal and Disseminated
- Fungal Meningitis
- Fungal Pneumonia
- Fusariosis
- Ocular Fungal Infection
- Pseudoallescheriosis
- Systemic Fungal Infection
Where can I get more information?
- Your pharmacist can provide more information about voriconazole.
See also: VFEND side effects (in more detail)
Ferrum
Ferrum may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Ingredient matches for Ferrum
Ferrous Fumarate
Ferrous Fumarate is reported as an ingredient of Ferrum in the following countries:
- Japan
Iron Dextran
Iron Dextran is reported as an ingredient of Ferrum in the following countries:
- Germany
Iron Polymaltose
Iron Polymaltose is reported as an ingredient of Ferrum in the following countries:
- Ireland
International Drug Name Search
Monday, October 24, 2016
Integra Plus
Generic Name: ferrous fumarate, ferrous asparto glycinate, folic acid, ascorbic acid, niacin, thiamine mononitrate, riboflavin, calcium pantothenate, pyridoxine hydrochloride and biotin
Dosage Form: capsule
see all prescribing information for Integra Plus
DESCRIPTION: Each capsule contains: Ferrous Fumarate (anhydrous) ......191.1 mg Polysaccharide Iron Complex... 135.9 mg (Equivalent to about 125 mg of elemental iron) Vitamin C (from ProAscorb C‡)....210 mg Folic Acid .....1 mg Thiamine Mononitrate (B1)...5 mg Riboflavin (B2)....5 mg Niacin (B3) . 20 mg d-Calcium Pantothenate (B5)..7 mg Pyridoxine HCl (B6) ...25 mg Biotin (B7)......300 mcg Cyanocobalamin (B12) .. 10 mcg
CLINICAL PHARMACOLOGY: Integra PlusTM is unique in that it utilizes two (2) different forms of iron, i.e., Ferrous Fumarate and Polysaccharide Iron Complex (as cell-contracted akaganèite), making available a total of 125 mg of elemental iron per capsule as follows:
Ferrous Fumarate (anhydrous) 191.1 mg Polysaccharide iron complex (PIC) 135.9 mg
Subclinical B-Group vitamin deficiencies have greatly increased in recent years, due to changes in dietetic habits, increase in the use of sugar, and the excessive milling of flour and cereals. With thiamine deficiencies in a healthy populous, it is self-evident that the unwell person is particularly prone to thiamine avitaminosis. This is true of the anemic individual with his/her poor appetite and disturbed digestive functions. Folic acid is best known for its role in megaloblastic anemias. Zinc has been recognized in the nutrition of animals and humans, even though the evidence for an uncomplicated zinc deficiency in humans is limited.
Ferrous Fumarate: Provides about 62.5 mg of elemental iron per dose. Ferrous Fumarate is an anhydrous salt of a combination of ferrous iron and fumaric acid, containing 33% of iron per weight. The acute toxicity in experimental animals is low and Ferrous Fumarate is well tolerated clinically. As a ferrous salt, it is more efficiently absorbed in the duodenum. Ferrous Fumarate contrasts very favorably with the availability of the 20% of elemental iron of ferrous sulfate, and the 13% of elemental iron of ferrous gluconate.
Polysaccharide Iron Complex: Provides about 62.5 mg elemental iron, as a cell-contracted akaganèite. It is a product of ferric iron complexed to a low molecular weight polysaccharide. This polysaccharide is produced by the extensive hydrolysis of starch and is a dark brown powder that dissolves in water to form a very dark brown solution, which is virtually odorless and tasteless.
Folic Acid: Folic Acid is one of the important hematopoetic agents necessary for proper regeneration of the blood-forming elements and their function. Folic acid is a precursor of a large family of compounds which serve as coenzymes in carbon transfer reactions. These reactions are required for the synthesis of purine and pyrimidine bases, inter-conversion of glycine and serine, biosynthesis of methionine methyl groups and degradation of histidine. Additionally, folic acid increases jejunal glycolytic enzymes and is involved in the desaturation and hydroxylation of long-chain fatty acids in the brain. A deficiency in folic acid results in megaloblastic anemia.
All IntegraTM products include a unique patented source of iron, e.g. Ferrous Fumarate and Polysaccharide Iron Complex (U.S. Patent No: 11/243,043 Pending). "An increase in tolerability is observed with the (patented formulation) and is believed to occur as the result of distributing the total iron content in the composition among compounds that provide iron to the patient's blood stream via two different mechanisms. The ferrous salts are readily absorbed in the upper gut, by direct dissolution and absorption of the ferrous iron by the bloodstream. However, the iron available from PIC is absorbed in the lower gut, via an active protein transport mechanism".
Clinical Studies: Because Ferrous Fumarate is an organic complex, it contains no free ions, either ferric or ferrous. Polysaccharide Iron Complex is clinically non-toxic. Prior studies in rats demonstrated that Polysaccharide Iron Complex (PIC), administered as a single oral dose to Sprague Dawley rats did not produce evidence of toxicity at a dosage level of 5000 mg Iron/kg: (An Acute Oral Toxicity Study in Rats with Polysaccharide-Iron Complex. T.N.Merriman, M. Aikman and R.E. Rush, Springborn Laboratories. Inc. Spencerville, Ohio Study No. 3340.1 March - April 1994). Other clinical studies had demonstrated that Polysaccharide Iron gives a good hematopoietic response with an almost complete absence of the side effects usually associated with oral iron therapy. Picinni and Ricciotti suggested in 1982, that "the therapeutic effectiveness of Polysaccharide Iron Complex when compared with iron fumarate in the treatment of iron deficiency anemia, appears to be as active as the iron fumarate and as well tolerated, however, it exerted a greater influence on the level of hemoglobin and on the number of red cells..." and that, "it has been exceptionally well tolerated by all patients" (Picinni, L.-Ricciotti, M. 1982. Therapeutic effectiveness of an iron-polysaccharide complex in comparison with iron fumarate in the treatment of iron deficiency anemias): PANMINERVA MEDICA-EUROPA MEDICA, Vol. 24, No. 3, pp. 213-220 (July-September 1982).
As mentioned above, the patented source of iron used in Integra PlusTM (Ferrous Fumarate and Polysaccharide Iron Complex) provides a high level of elemental iron with a low incidence of gastric distress.
CONCLUSION: Based on the results of this study, the oral combination of Ferrous Fumarate and Polysaccharide Iron Complex was better tolerated and safer than the oral administration of Ferrous Fumarate alone. The conclusion of this research stated, that the addition of PIC to Ferrous Fumarate surprisingly allows the same concentration of Ferrous Fumarate to be better tolerated than the Ferrous Fumarate alone.
CONTRAINDICATIONS: Integra PlusTM is contraindicated in patients with a known hypersensitivity to any of its ingredients; also, all iron compounds are contraindicated in patients with hemosiderosis, hemochromatosis, or hemolytic anemias. Pernicious anemia is a contraindication, as folic acid may obscure its signs and symptoms.
WARNING: Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6. Keep this product out of reach of children. In case of accidental overdose, call a doctor or poison control center immediately.
WARNING: Folic acid alone is improper therapy in the treatment of pernicious anemia and other megaloblastic anemias where Vitamin B12 is deficient.
PRECAUTIONS: General: Folic acid in doses above 0.1 mg - 0.4 mg daily may obscure pernicious anemia, in that hematological remission can occur while neurological manifestations remain progressive. Pediatric Use: Safety and effectiveness of this product have not been established in pediatric patients. Geriatric Use: No clinical studies have been performed in patients age 65 and over to determine whether older persons respond differently from younger persons. Dosage should always begin at the low end of the dosage scale and should consider that elderly persons may have decreased hepatic, renal, or cardiac function and or concomitant diseases.
Adverse Reactions: Folic Acid: Allergic sensitizations have been reported following both oral and parenteral administration of folic acid. Ferrous Fumarate: Gastrointestinal disturbances (anorexia, nausea, diarrhea, constipation) occur occasionally, but are usually mild and may subside with continuation of therapy. Although the absorption of iron is best when taken between meals, giving Integra PlusTM after meals may control occasional G.I. disturbances. Integra PlusTM is best absorbed when taken at bedtime.
OVERDOSE: Iron: Signs and Symptoms: Iron is toxic. Acute overdosage of iron may cause nausea and vomiting and, in severe cases, cardiovascular collapse and death. Other symptoms include pallor and cyanosis, melena, shock, drowsiness and coma. The estimated overdose of orally ingested iron is 300-mg/kg body weight. When overdoses are ingested by children, severe reactions, including fatalities, have resulted. Integra PlusTM should be stored beyond the reach of children to prevent against accidental iron poisoning. Keep this and all other drugs out of the reach of children.
Treatment: For specific therapy, exchange transfusion and chelating agents should be used. For general management, perform gastric lavage with sodium bicarbonate solution or milk. Administer intravenous fluids and electrolytes and use oxygen.
DOSAGE AND ADMINISTRATION: Adults (persons over 12 years of age), One (1) capsule daily, between meals, or as prescribed by a physician. Do not exceed recommended dosage. Do not administer to children under the age of 12.
Pediatric Use: Safety and effectiveness of this product have not been established in pediatric patients.
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HOW SUPPLIED: Integra PlusTM are bright yellow (body) and maroon (cap) capsules imprinted "US" logo in maroon and "Integra Plus" in bright yellow. Child resistant bottles of 90 capsules NDC# 52747-712-60. Dispense in a tight, light-resistant container as defined in the USP/NF with a child resistant closure. Store at controlled room temperature 15 ̊ to 30 ̊C (59 ̊ to 86 ̊ F). Keep in a cool, dry place. Capsules are not USP.
CAUTION: Rx only.
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| unapproved drug other | 04/27/2009 | ||
| Labeler - US Pharmaceutical Corporation (048318224) |
| Registrant - US Pharmaceutical Corporation (048318224) |
More Integra Plus resources
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Vimovo
Dosage Form: tablet, delayed release
FULL PRESCRIBING INFORMATION
Cardiovascular Risk
• Non-Steroidal Anti-inflammatory Drugs (NSAIDs), a component of Vimovo, may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk [see Warnings and Precautions (5.1)].
• Vimovo is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4), and Warnings and Precautions (5.1)].
Gastrointestinal Risk
• NSAIDs, including naproxen, a component of Vimovo, cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events [see Warnings and Precautions (5.4)].
Indications and Usage for Vimovo
Vimovo is a combination product that contains naproxen and esomeprazole. It is indicated for the relief of signs and symptoms of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis and to decrease the risk of developing gastric ulcers in patients at risk of developing NSAID-associated gastric ulcers. Vimovo is not recommended for initial treatment of acute pain because the absorption of naproxen is delayed compared to absorption from other naproxen-containing products. Controlled studies do not extend beyond 6 months.
Vimovo Dosage and Administration
Carefully consider the potential benefits and risks of Vimovo and other treatment options before deciding to use Vimovo. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. Vimovo does not allow for administration of a lower daily dose of esomeprazole. If a dose of esomeprazole lower than a total daily dose of 40 mg is more appropriate, a different treatment should be considered.
Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis
The dosage is one tablet twice daily of Vimovo 375 mg naproxen and 20 mg of esomeprazole or 500 mg naproxen and 20 mg of esomeprazole.
The tablets are to be swallowed whole with liquid. Do not split, chew, crush or dissolve the tablet. Vimovo is to be taken at least 30 minutes before meals.
Geriatric Patients
Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Use caution when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly use the lowest effective dose [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].
Patients With Moderate to Severe Renal Impairment
Naproxen-containing products are not recommended for use in patients with moderate to severe or severe renal impairment (creatinine clearance <30 mL/min) [see Warnings and Precautions (5.6, 5.7) and Use in Specific Populations (8.7)].
Hepatic Insufficiency
Monitor patients with mild to moderate hepatic impairment closely and consider a possible dose reduction based on the naproxen component of Vimovo.
Vimovo should be avoided in patients with severe hepatic impairment [see Warnings and Precautions (5.11), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
Pediatric Patients
The safety and efficacy of Vimovo in children younger than 18 years has not been established. Vimovo is therefore not recommended for use in children.
Dosage Forms and Strengths
Oval, yellow, delayed release tablets for oral administration containing either:
• 375 mg enteric coated naproxen and 20 mg esomeprazole (as magnesium trihydrate) tablets printed with 375/20 in black, or
• 500 mg enteric coated naproxen and 20 mg esomeprazole (as magnesium trihydrate) tablets printed with 500/20 in black.
Contraindications
Vimovo is contraindicated in patients with known hypersensitivity to naproxen, esomeprazole magnesium, substituted benzimidazoles, or to any of the excipients.
Vimovo is contraindicated in patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.8, 5.13)]. Hypersensitivity reactions, eg, angioedema and anaphylactic reaction/shock, have been reported with esomeprazole use.
Vimovo is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)].
Vimovo is contraindicated in patients in the late stages of pregnancy [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1)].
Warnings and Precautions
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDS, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use.
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke [see Contraindications (4)].
Hypertension
NSAIDs, including naproxen, a component of Vimovo, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy [see Drug Interactions (7.1, 7.4)].
Congestive Heart Failure and Edema
Fluid retention, edema, and peripheral edema have been observed in some patients taking NSAIDs and should be used with caution in patients with fluid retention or heart failure.
Gastrointestinal Effects — Risk of Ulceration, Bleeding, and Perforation
NSAIDs, including naproxen, a component of Vimovo, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. While Vimovo has been shown to significantly decrease the occurrence of gastric ulcers compared to naproxen alone, ulceration and associated complications can still occur.
These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3–6 months, and in about 2–4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed.
Vimovo should be prescribed with caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk of developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants or antiplatelets (including low-dose aspirin), longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients, and therefore special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an NSAID or NSAID-containing product, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
Epidemiological studies of the case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of an NSAID, COX-2 inhibitor, or aspirin potentiated the risk of bleeding [see Drug Interactions (7.2, 7.8)]. Although these studies focused on upper gastrointestinal bleeding, bleeding at other sites cannot be ruled out.
NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated.
Gastrointestinal symptomatic response to therapy with Vimovo does not preclude the presence of gastric malignancy.
Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole, of which esomeprazole is an enantiomer and a component of Vimovo.
Active Bleeding
When active and clinically significant bleeding from any source occurs in patients receiving Vimovo, the treatment should be withdrawn.
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, hypovolemia, heart failure, liver dysfunction, salt depletion, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of Vimovo in patients with advanced renal disease. Therefore, treatment with Vimovo is not recommended in these patients with advanced renal disease. If Vimovo therapy must be initiated, close monitoring of the patient’s renal function is advisable [see Dosage and Administration (2), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
Anaphylactic Reactions
Anaphylactic reactions may occur in patients without known prior exposure to either component of Vimovo. NSAIDs should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs [see Contraindications (4)]. Emergency help should be sought in cases where an anaphylactic reaction occurs. Anaphylactic reactions, like anaphylaxis, may have a fatal outcome.
Skin Reactions
NSAIDs can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
Pregnancy
Pregnancy Category C
In late pregnancy, as with other NSAIDs, naproxen, a component of Vimovo, should be avoided because it may cause premature closure of the ductus arteriosus [see Contraindications (4), and Use in Specific Populations (8.1)].
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including naproxen, a component of Vimovo. Hepatic abnormalities may be the result of hypersensitivity rather than direct toxicity. These laboratory abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver dysfunction. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes, have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with Vimovo.
If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (eg, eosinophilia, rash, etc.), Vimovo should be discontinued.
Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. Caution is advised when high doses are required and some adjustment of dosage may be required in these patients. It is prudent to use the lowest effective dose for the shortest possible duration of adequate treatment.
Vimovo should be avoided in patients with severe hepatic impairment [see Dosage and Administration (2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving Vimovo who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants or antiplatelets, should be carefully monitored.
Pre-existing Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, Vimovo should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with pre-existing asthma.
Concomitant NSAID Use
Vimovo contains naproxen as one of its active ingredients. It should not be used with other naproxen-containing products since they all circulate in the plasma as the naproxen anion.
The concomitant use of Vimovo with any dose of a non-aspirin NSAID should be avoided due to the potential for increased risk of adverse reactions.
Corticosteroid Treatment
Vimovo cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids and the patient should be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis.
Bone Fracture
Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to the established treatment guidelines. [see Dosage and Administration (2) and Adverse Reactions (6.2)].
Vimovo (a combination PPI/NSAID) is approved for use twice a day and does not allow for administration of a lower daily dose of the PPI. [see Dosage and Administration (2)].
Masking of Inflammation and Fever
The pharmacological activity of Vimovo in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, noninflammatory painful conditions.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (eg, eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, Vimovo should be discontinued.
Patients with initial hemoglobin values of 10 g or less who are to receive long-term therapy should have hemoglobin values determined periodically.
Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Providers should temporarily stop esomeprazole treatment before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary [see Pharmacodynamics (12.2)].
Hypomagnesemia
Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically. [see Adverse Reactions (6.2)].
Concomitant use of St John's Wort or Rifampin with Vimovo
Drugs that induce CYP2C19 or CYP3A4 (such as St John’s Wort or rifampin) can substantially decrease esomeprazole concentrations. Avoid concomitant use of Vimovo with St John’s Wort or rifampin [see Drug Interactions (7.15)].
Concomitant use of Vimovo with Methotrexate
Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration a temporary withdrawal of the PPI may be considered in some patients. [see Drug Interactions (7.8)]
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.
The adverse reactions reported below are specific to the clinical trials with Vimovo. See also the full prescribing information for naproxen and esomeprazole magnesium products.
The safety of Vimovo was evaluated in clinical studies involving 2317 patients (aged 27 to 90 years) and ranging from 3-12 months. Patients received either 500 mg/20 mg of Vimovo twice daily (n=1157), 500 mg of enteric-coated naproxen twice daily (n=426), or placebo (n=246). The average number of Vimovo doses taken over 12 months was 696+44.
The table below lists all adverse reactions, regardless of causality, occurring in >2% of patients receiving Vimovo from two clinical studies (Study 1 and Study 2). Both of these studies were randomized, multi-center, double-blind, parallel studies. The majority of patients were female (67%), white (86%). The majority of patients were 50-69 years of age (83%). Approximately one quarter were on low-dose aspirin.
Preferred term (sorted by SOC) | Vimovo 500 mg/20 mg twice daily (n=428) % | EC-Naproxen 500 mg twice daily (n=426) % |
Gastrointestinal Disorders | ||
Gastritis Erosive | 19 | 38 |
Dyspepsia | 18 | 27 |
Gastritis | 17 | 14 |
Diarrhea | 6 | 5 |
Gastric Ulcer | 6 | 24 |
Abdominal Pain Upper | 6 | 9 |
Nausea | 5 | 5 |
Hiatus Hernia | 4 | 6 |
Abdominal Distension | 4 | 4 |
Flatulence | 4 | 3 |
Esophagitis | 4 | 8 |
Constipation | 3 | 3 |
Abdominal pain | 2 | 2 |
Erosive Duodenitis | 2 | 12 |
Abdominal pain lower | 2 | 3 |
Duodenitis | 1 | 7 |
Gastritis hemorrhagic | 1 | 2 |
Gastroesophageal reflux disease | <1 | 4 |
Duodenal ulcer | <1 | 5 |
Erosive esophagitis | <1 | 6 |
Infections and infestations | ||
Upper respiratory tract infection | 5 | 4 |
Bronchitis | 2 | 2 |
Urinary tract infection | 2 | 1 |
Sinusitis | 2 | 2 |
Nasopharyngitis | <1 | 2 |
Musculoskeletal and connective tissue disorders | ||
Arthralgia | 1 | 2 |
Nervous system disorders | ||
Headache | 3 | 1 |
Dysgeusia | 2 | 1 |
Respiratory, thoracic and mediastinal disorders | ||
Cough | 2 | 3 |
In Study 1 and Study 2, patients taking Vimovo had fewer premature discontinuations due to adverse reactions compared to patients taking enteric-coated naproxen alone (7.9% vs. 12.5% respectively). The most common reasons for discontinuations due to adverse events in the Vimovo treatment group were upper abdominal pain (1.2%, n=5), duodenal ulcer (0.7%, n=3) and erosive gastritis (0.7%, n=3). Among patients receiving enteric-coated naproxen, the most common reasons for discontinuations due to adverse events were duodenal ulcer 5.4% (n=23), dyspepsia 2.8% (n=12) and upper abdominal pain 1.2% (n=5). The proportion of patients discontinuing treatment due to any upper gastrointestinal adverse events (including duodenal ulcers) in patients treated with Vimovo was 4% compared to 12% for patients taking enteric-coated naproxen.
The table below lists all adverse reactions, regardless of causality, occurring in >2% of patients from 2 clinical studies conducted in patients with osteoarthritis of the knee (Study 3 and Study 4).
Preferred term (sorted by SOC) | Vimovo 500 mg/20 mg twice daily (n=490) % | Placebo (n=246) % |
Gastrointestinal Disorders | ||
Dyspepsia | 8 | 12 |
Diarrhea | 6 | 4 |
Abdominal Pain Upper | 4 | 3 |
Constipation | 4 | 1 |
Nausea | 4 | 4 |
Nervous System Disorders | ||
Dizziness | 3 | 2 |
Headache | 3 | 5 |
General disorders and administration site conditions | ||
Peripheral edema | 3 | 1 |
Respiratory, thoracic and mediastinal disorders | ||
Cough | 1 | 3 |
Infections and infestations | ||
Sinusitis | 1 | 2 |
The percentage of subjects who withdrew from the Vimovo treatment group in these studies due to treatment-emergent adverse events was 7%. There were no preferred terms in which more than 1% of subjects withdrew from any treatment group.
The long-term safety of Vimovo was evaluated in an open-label clinical trial of 239 patients, of which 135 patients received 500 mg/20 mg of Vimovo for 12 months. There were no differences in frequency or types of adverse reactions seen in the long-term safety study compared to shorter-term treatment in the randomized controlled studies.
Postmarketing Experience
Naproxen
The following adverse reactions have been identified during post-approval use of naproxen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reports are listed below by body system:
Body as a Whole: anaphylactic reactions, angioneurotic edema, menstrual disorders, pyrexia (chills and fever)
Cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary edema
Gastrointestinal: gastrointestinal bleeding and/or perforation, hematemesis, pancreatitis, vomiting, colitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn’s disease), nonpeptic gastrointestinal ulceration, ulcerative stomatitis, esophagitis, peptic ulceration
Hepatobiliary: jaundice, abnormal liver function tests, hepatitis (some cases have been fatal)
Hemic and Lymphatic: eosinophilia, leukopenia, melena, thrombocytopenia, agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia
Metabolic and Nutritional: hyperglycemia, hypoglycemia
Nervous System: inability to concentrate, depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction, convulsions
Respiratory: eosinophilic pneumonitis, asthma
Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis, erythema multiforme, erythema nodosum, fixed drug eruption, lichen planus, pustular reaction, systemic lupus erythematoses, bullous reactions, including Stevens-Johnson syndrome, photosensitive dermatitis, photosensitivity reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored.
Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar optic neuritis, papilledema
Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis, raised serum creatinine
Reproduction (female): infertility
Esomeprazole
The following adverse reactions have been identified during post-approval use of esomeprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reports are listed below by body system:
Blood and Lymphatic: agranulocytosis, pancytopenia;
Eye: blurred vision;
Gastrointestinal: pancreatitis; stomatitis; microscopic colitis
Hepatobiliary: hepatic failure, hepatitis with or without jaundice;
Immune System: anaphylactic reaction/shock;
Infections and Infestations: GI candidiasis;
Metabolism and Nutritional Disorders: hypomagnesemia
Musculoskeletal and Connective Tissue: muscular weakness, myalgia, bone fracture;
Nervous System: hepatic encephalopathy, taste disturbance;
Psychiatric: aggression, agitation, depression, hallucination;
Renal and Urinary: interstitial nephritis;
Reproductive System and Breast: gynecomastia;
Respiratory, Thoracic, and Mediastinal: bronchospasm;
Skin and Subcutaneous Tissue: alopecia, erythema multiforme, hyperhidrosis, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal).
Drug Interactions
Several studies conducted with Vimovo have shown no interaction between the two components, naproxen and esomeprazole.
ACE-inhibitors
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking Vimovo concomitantly with ACE-inhibitors.
Aspirin
Vimovo can be administered with low-dose aspirin (≤325 mg/day) therapy. The concurrent use of aspirin and Vimovo may increase the risk of serious adverse events [see Warnings and Precautions (5.1, 5.4), Adverse Reactions (6), and Clinical Studies (14)].
When naproxen is administered with doses of aspirin (>1 gram/day), its protein binding is reduced. The clinical significance of this interaction is not known. However, as with other NSAIDs, concomitant administration of naproxen and aspirin is not generally recommended because of the potential of increased adverse effects.
Cholestyramine
As with other NSAIDs, concomitant administration of cholestyramine can delay the absorption of naproxen.
Cyclosporin
As with all NSAIDs caution is advised when cyclosporin is co-administered because of the increased risk of nephrotoxicity.
Tacrolimus
Concomitant administration of esomeprazole, a component of Vimovo, and tacrolimus may increase the serum levels of tacrolimus.
Diuretics
Clinical studies, as well as postmarketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely both for signs of renal failure, as well as to monitor to assure diuretic efficacy [see Warnings and Precautions (5.6, 5.7)].
Lithium
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.
Methotrexate
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. NSAIDs have been reported to reduce the tubular secretion of methotrexate in an animal model. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.
Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted [see Warnings and Precautions (5.21)].
Anticoagulants
Naproxen decreases platelet aggregation and may prolong bleeding time. In addition, because warfarin and NSAIDs are highly protein bound, the free fraction of warfarin and naproxen may increase substantially in some patients.
Concomitant use of Vimovo and anticoagulants (such as warfarin, dicumarol and heparin) may result in increased risk of bleeding complications.
The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.
Post-marketing reports of changes in prothrombin measures have been reported among patients on concomitant warfarin and esomeprazole therapy. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.
Selective Serotonin Reuptake Inhibitors (SSRIs)
There is an increased risk of gastrointestinal bleeding when selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs including COX-2 selective inhibitors. Caution should be used when NSAIDs are administered concomitantly with SSRIs [see Warnings and Precautions (5.4)].
Other Information Concerning Drug Interactions
Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as sulphonylureas, hydantoins, and other NSAIDs. Patients simultaneously receiving Vimovo and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.
Naproxen and other NSAIDs can reduce the antihypertensive effect of propranolol and other beta-blockers.
Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Interactions With Investigations of Neuroendocrine Tumors
Drug-induced decrease in gastric acidity results in enterochromaffin-like cell hyperplasia and increased Chromogranin A levels which may interfere with investigations for neuroendocrine tumors [see Warnings and Precautions (5.18) and Pharmacodynamics (12.2)].
Drug/Laboratory Test Interaction
Naproxen may decrease platelet aggregation and prolong bleeding time. This effect should be kept in mind when bleeding times are determined.
The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay. Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Interactions Related to Absorption
Esomeprazole inhibits gastric acid secretion. Therefore, esomeprazole may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability. Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, iron salts and erlotinib can decrease, while the absorption of drugs such as digoxin can increase during treatment with esomeprazole. Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects). Esomeprazole is an enantiomer of omeprazole. Coadministration of digoxin with esomeprazole is expected to increase the systemic exposure of digoxin. Therefore, patients may need to be monitored for increases in digoxin toxicity when digoxin is taken concomitantly with esomeprazole.
Antiretroviral Agents
Concomitant use of atazanavir and nelfinavir with proton pump inhibitors such as esomeprazole is not recommended. Co-administration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and thereby reduce its therapeutic effect.
Omeprazole, the racemate of esomeprazole, has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP2C19. For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole. Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg once a day), AUC was decreased by 36% and 92%, Cmax by 37% and 89% and Cmin by 39% and 75% respectively for nelfinavir and main oxidative metabolite, hydroxy-t-butylamide (M8). Following multiple doses of atazanavir (400 mg, once a day) and omeprazole (40 mg, once a day, 2 hr before atazanavir), AUC was decreased by 94%, Cmax by 96%, and Cmin by 95%. Concomitant administration with omeprazole and drugs such as atazanavir and nelfinavir is therefore not recommended. For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported with an increase in AUC by 82% in Cmax by 75% and in Cmin by 106% following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice a day for 15 days with omeprazole 40 mg once a day co-administered on days 11 to 15. Therefore, clinical and laboratory monitoring for saquinavir toxicity is recommended during concurrent use with esomeprazole. Dose reduction of saquinavir should be considered from the safety perspective for individual patients. There are also some antiretroviral drugs of which unchanged serum levels have been reported when given with omeprazole.
Effects on Hepatic Metabolism/Cytochrome P-450 pathways
Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4.
In vitro and in vivo studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1 and 3A4. No clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with phenytoin, warfarin, quinidine, clarithromycin or amoxicillin.
However, post-marketing reports of changes in prothrombin measures have been received among patients on concomitant warfarin and esomeprazole therapy. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.
Esomeprazole may potentially interfere with CYP2C19, the major esomeprazole metabolizing enzyme. Co-administration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam.
Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP3A4, such as voriconazole, may result in more than doubling of the esomeprazole exposure. Dose adjustment of esomeprazole is not normally required. Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased Cmax and AUC of cilostazol by 18% and 26% respectively. Cmax and AUC of one of its active metabolites, 3,4-dihydrocilostazol, which has 4-7 times the activity of cilostazol, were increased by 29% and 69% respectively. Co-administration of cilostazol with esomeprazole is expected to increase concentrations of cilostazol and its above mentioned active metabolite. Therefore a dose reduction of cilostazol from 100 mg twice daily to 50 mg twice daily should be consid
Epirubicin hydrochloride 2mg / ml solution for injection or infusion (hameln)
1. Name Of The Medicinal Product
Epirubicin hydrochloride 2 mg/ml solution for injection or infusion
2. Qualitative And Quantitative Composition
1 ml contains 2 mg epirubicin hydrochloride
Each 5 ml vial contains 10 mg epirubicin hydrochloride
Each 10 ml vial contains 20 mg epirubicin hydrochloride
Each 25 ml vial contains 50 mg epirubicin hydrochloride
Each 50 ml vial contains 100 mg epirubicin hydrochloride
Each 100 ml vial contains 200 mg epirubicin hydrochloride
For a full list of excipients, see section 6.1.
1 ml contains 3.5 mg sodium
3. Pharmaceutical Form
Solution for injection or infusion
Red, clear solution
4. Clinical Particulars
4.1 Therapeutic Indications
Intravenous use:
• Breast carcinoma
• Gastric carcinoma
Intravesical use:
• Prophylaxis of recurrences after transurethral resection
4.2 Posology And Method Of Administration
Epirubicin is not active when given orally and is not for intrathecal or intramuscular injection. For instructions on dilution of the product before administration, see section 6.6.
The safety and efficacy of epirubicin in children has not been established.
Intravenous use
It is advisable to give the drug via the tubing of a freely running intravenous infusion after checking that the needle is well placed in the vein. This method minimises the risk of drug extravasation and makes sure that the vein is flushed with infusion solution after the administration of the drug. Extravasation of epirubicin from the vein during injection may give rise to severe tissue lesions, even necrosis. In case of extravasation, administration should be stopped immediately. Venous sclerosis may result from injection into small vessels or repeated injections into the same vein.
Discard any unused solution.
Conventional doses
When epirubicin is used as a single agent, the recommended dose in adults is generally 60-90 mg/ m2 body area; the drug should be injected intravenously over 3
Alternatively, 20-30 mg/ m2 may be given weekly during palliative care in order to reduce frequency of adverse reactions or in patients who do not tolerate higher doses in a range as mentioned above.
Dose modification (reduction) following signs of toxicity (specifically severe neutropenia /neutropenic fever and thrombocytopenia, which could persist on day 21 after the first dose) could be required or the following dose could be delayed, as the case of liver impairment.
High doses
Breast cancer
In the adjuvant treatment of early breast cancer patients with positive lymph nodes, intravenous doses of epirubicin ranging from 100 mg/ m2 (as a single dose on day 1) to 120 mg/m²(in two divided doses on days 1 and 8) every 3 - 4 weeks, in combination with intravenous cyclophosphamide and 5-fluorouracil and oral tamoxifen, are recommended.
The most commonly used dosage schedule of epirubicin in metastatic breast cancer, when employed as a single agent for adults, is up to 135 mg/m2 administered at 212 has been used and has been reported to produce less clinical toxicity than higher doses given every three weeks.
In metastatic breast cancer, epirubicin usually can be used in combination with cyclophosphamide and 5-fluorouracil (FEC), at a dose of up to 120 mg/m2 every 3 weeks.
Epirubicin should be given as an intravenous bolus over 3 2 for conventional dose and 105 2 for high dose schedules) are recommended for patients whose bone marrow function has already been impaired by previous chemotherapy or radiotherapy, by age, or neoplastic bone-marrow infiltration. The total dose per cycle may be divided over 2 - 3 successive days.
When epirubicin is used in combination with other antitumour agents, the doses need to be adequately reduced.
Impaired liver function
Since the major route of elimination of epirubicin is the hepatobiliary system, the doses should be reduced in patients with impaired liver function, in order to avoid an increase of overall toxicity. Moderate liver impairment (bilirubin: 20 - 50 µmol/l) requires a 50 % reduction of dose, while severe impairment (bilirubin > 50 µmol/l) necessitates a dose reduction of 75 %.
Impaired renal function
Moderate renal impairment does not appear to require a dose reduction in view of the limited amount of epirubicin excreted by this route. Lower starting doses should be considered in patients with severe renal impairment (serum creatinine > 450 µmol/l).
Intravesical use
Epirubicin may be given by intravesical administration for the treatment of superficial bladder carcinoma and carcinoma-in-situ. It should not be used in this way for the treatment of invasive tumours which have penetrated the bladder wall where systemic therapy or surgery is more appropriate. Epirubicin has also been successfully used intravesically as a prophylactic agent after transurethral resection of superficial tumours in order to prevent recurrences.
While many regimens have been used, the following may be helpful as a guide: for therapy 8 x weekly instillations of 50 mg/25-50 ml (diluted with 0.9 % sodium chloride injection). In the case of local toxicity (chemical cystitis), a dose reduction to 30 mg is advised. For carcinoma-in-situ, depending on the individual tolerability of the patient, the dose may be increased up to 80 mg. For prophylaxis, 4 x weekly administrations of 50 mg/25
For the preparation of the solution for intravesical use see section 6.6.
The solution should be retained intravesically for 1-2 hours. To avoid undue dilution with urine, the patient should be instructed not to drink any fluid in the 12 hours prior to instillation. During the instillation, the patient should be rotated occasionally and should be instructed to void urine at the end of the instillation time.
4.3 Contraindications
Epirubicin is contraindicated in patients with marked myelosuppression induced by previous treatment with other antitumour agents or by radiotherapy and in patients already treated with maximal cumulative doses of other anthracyclines such as Doxorubicin or Daunorubicin.
The drug is contraindicated in patients with current or previous history of cardiac impairment (including 4th degree muscular heart failure, acute heart attack and previous heart attack which led to 3rd and 4th degree muscular heart failure, acute inflammatory heart diseases, arrhythmia with serious heamodynamic consequences).
The drug is contraindicated in patients with acute systemic infections.
Epirubicin is contraindicated in patients with hypersensitivity to epirubicin, other antracyclines and/or anthracenediones or to any of the excipients.
Epirubicin is contraindicated in lactating women.
Additional contraindications to the intravesical use are:
invasive tumors that had penetrated the vesical wall; urinary infections; inflammation of the bladder; catheterization problems; contracted bladder; big volume of residual urine
4.4 Special Warnings And Precautions For Use
Epirubicin therapy should be administered only under the supervision of a qualified physician experienced in antiblastic and cytotoxic therapy. Treatment with high dose epirubicin in particular requires the availability of facilities for the care of possible clinical complications due to myelosuppression.
Initial treatment calls for a careful baseline monitoring of various laboratory parameters and cardiac function.
During each cycle of treatment with epirubicin, patients must be carefully and frequently monitored. Red and white blood cells, neutrophils and platelet counts should be carefully assessed both before and during each cycle of therapy. Leukopenia and neutropenia are usually transient with conventional and high-dose schedules, reaching a nadir between the 10thand 14th day and returning to normal values by the 21st day; they are more severe with high dose schedules. Very few patients, even receiving high doses, experience thrombocytopenia (< 100,000 platelets/mm3).
Patients must have adequately recovered from severe stomatitis or mucositis before starting treatment with epirubicin.
Epirubicin is mainly eliminated via the liver. Therefore it is necessary to evaluate liver function (AST, ALT, alkaline phosphatase, bilirubin) prior to initiating treatment and during treatment. In patients with increased bilirubin levels or AST epirubicin clearance can be reduced, which may lead to increased toxicity. For these patients a dose reduction is recommended (see section 4.2). For patients with reduced renal function serum creatinine levels should be checked regularly prior to and during treatment. For patients with increased serum creatinine (>450µmol/l) a dose reduction is proposed (see section 4.2).
A cumulative dose of 900 2 should only be exceeded with extreme caution with both conventional and high doses.
Above this level the risk of irreversible congestive cardiac failure increases greatly. There is objective evidence that cardiac toxicity may occur rarely below this range. However, cardiac function must be carefully monitored during treatment to minimise the risk of cardiac failure of the type described for other anthracyclines.
Heart failure can appear even several weeks after discontinuing treatment and may prove unresponsive to specific medical treatment. The potential risk of cardiotoxicity may increase in patients who have received concomitant, or prior, radiotherapy to the mediastinal pericardial area.
In establishing the maximal cumulative doses of epirubicin, any concomitant therapy with potential cardiotoxic drugs should be taken into account.
It is recommended that an ECG before and after each treatment cycle should be carried out. Alterations in the ECG tracing, such as flattening or inversion of the T
Cardiomyopathy induced by anthracyclines, is associated with a persistent reduction of the QRS voltage, prolongation beyond normal limits of the systolic interval (PEP/LVET) and a reduction of the ejection fraction. Cardiac monitoring of patients receiving epirubicin treatment is highly important and it is advisable to assess cardiac function by non-invasive techniques such as ECG, echocardiography and, if necessary, measurement of ejection fraction by radionuclide angiography.
Like other cytotoxic agents, epirubicin may induce hyperuricaemia as a result of rapid lysis of neoplastic ells. Blood uric acid levels should therefore be carefully checked so that this phenomenon may be controlled pharmacologically.
Epirubicin may impart a red colour to the urine for 1
This medicinal product contains 3.5 mg sodium per ml. To be taken into consideration by patients on a controlled sodium diet.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Epirubicin hydrochloride 2 mg/ml Solution for injection or infusion can be used in combination with other anticancer drugs but patients should be monitored for additive toxicity. Concomitant use of other medicinal products that may be cardiotoxic or affect cardiac function should be monitored throughout treatment.
Drug interactions with epirubicin have been observed with cimetidine, verapamil/dexverapamil, dexrazoxane, docetaxel, interferon α2b, paclitaxel and quinine.Cimetidine 400 mg b.i.d given prior to epirubicin 100 mg/m2 every 3 weeks led to a 50% increase in epirubicin AUC and a 41% increase in epirubicinol AUC (latter p<0.05). The AUC of the 7-deoxy-doxorubicinol aglycone and liver blood flow were not reduced, so results are not explained by reduced cytochrome P-450 activity.
Verapamil/Dexverapamil may alter the pharmacokinetics of epirubicin and possibly increase its bone marrow depressant effects.
Prior administration of higher doses (900 mg/m2 and 1200 mg/m2) of dexrazoxane may increase the systemic clearance of epirubicin and result in a decrease in AUC.
One study found that docetaxel may increase the plasma concentrations of epirubicin metabolites when administered immediately after epirubicin.
The co-administration of interferon α2b may cause a reduction in both the terminal elimination half-life and the total clearance of epirubicin.
Paclitaxel may affect the pharmacokinetics of epirubicin and its metabolite, epirubicinol. In one study, haematological toxicity was greater when paclitaxel was administered before epirubicin compared with after epirubicin.
One study has shown that paclitaxel clearance is reduced by epirubicin.
Quinine may accelerate the initial distribution of epirubicin from blood into the tissues and may have an influence on the red blood cell partitioning of epirubicin.
The possibility of a marked disturbance of the haematopoiesis needs to be kept in mind with a (pre-) treatment with medications which influence the bone marrow (i.e. cytostatic agents, sulfonamide, chloramphenicol, diphenylhydantoin, amidopyrine-derivate, antiretroviral agents).
Cardiotoxicity of epirubicin is enhanced by certain radiotherapeutic treatments and by previous or concomitant use of other anthracycline derivates like mitomycin-c, dacarbazine, dactinomycin and possibly cyclophosphamide. Epirubicin can potentate the effect of radiation. Medicinal products that induce the cytochrome P450 system (e.g., rifampicin and barbiturates) can enhance epirubicin metabolism, with consequently reduced efficacy.
4.6 Pregnancy And Lactation
Epirubicin is a potential teratogen and if administered to pregnant women may cause miscarriage, embryotoxicity and foetal death. During pregnancy, particularly the first trimester, cytostatic drugs should only be used on strict indication and when the potential benefits to the mother have been weighed against possible risks to the foetus. Both men and women receiving epirubicin 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 epirubicin therapy, and use effective contraception during treatment with epirubicin.
It is unknown whether epirubicin is excreted in human breast milk. A risk to the breast-feeding infant cannot be excluded. Breast-feeding must be discontinued during treatment with epirubicin.
Fertility
Epirubicin can have genotoxic effects. Therefore, male patients treated with epirubicin are advised not to father a child during and up to 6 months after treatment and to seek advice on conservation of sperm prior to treatment because of the possibility of infertility due to therapy with epirubicin.
Women should not become pregnant during treatment with epirubicin. Men and women should use an effective method of contraception during treatment and for six months thereafter.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed with Epirubicin.
Epirubicin may cause episodes of nausea and vomiting, which can temporarily lead to an impairment of ability to drive or operate machines.
4.8 Undesirable Effects
Adverse event frequencies have been categorised as follows:
Very common (
Common (
Uncommon (
Rare (
Infections and infestations:
Common: Fever, infections, pneumonia, sepsis and septic shock may occur as a result of myelosuppression.
Neoplasms benign, malignant and unspecified (including cysts and polyps):
Rare: Secondary acute myeloid leukaemia with or without a pre-leukaemic phase, in patients treated with epirubicin in combination with DNA-damaging antineoplastic agents. These leukaemias have a short (1-3 year) latency.
Blood and lymphatic system disorders:
Common: Myelosuppression (leucopenia, granulocytopenia, neutropenia, febrile neutropenia, thrombo-cytopenia, anaemia). Haemorrhage and tissue hypoxia (as a result of myelosuppression) may occur.
High doses of epirubicin have been safely administered in a large number of untreated patients having various solid tumours and have caused adverse effects which are no different from those seen at conventional doses with the exception of reversible severe neutropenia (<500 neutrophils/mm3 for < 7 days) which occurred in the majority of patients. Only a few patients required hospitalisation and supportive therapy for severe infectious complications at high doses.
Immune system disorders:
Common: Allergic reactions following intravesical administration.
Uncommon: Sensitivity to light or hypersensitivity in the case of radiotherapy ("recall phenomenon").
Rare: Anaphylaxis (anaphylactic/anaphylactoid reactions with or without shock including skin rash, pruritus, fever and chills).
Cardiac disorders:
Rare: Cardiotoxicity (ECG changes, tachycardia, arrhythmia, cardiomyopathy, congestive heart failure (dyspnoea, oedema, enlargement of the liver, ascites, pulmonary oedema, pleural effusions, gallop rhythm), ventricular tachycardia, bradycardia, AV block, bundle-branch block (see Section 4.4).
Vascular disorders:
Uncommon: Thrombophlebitis
Coincidental cases of thromboembolic events (including pulmonary embolism [in isolated cases with fatal outcome]) have occurred.
Gastrointestinal disorders:
Common: Nausea, vomiting, diarrhoea, which can result in dehydration, loss of appetite and abdominal pain. Oesophagitis and hyperpigmentation of the oral mucosa may also occur.
Skin and subcutaneous tissue disorders:
Very common: Alopecia, normally reversible, appears in 60-90 % of treated cases; it is accompanied by lack of beard growth in males.
Common: Hot flushes
Uncommon: Hyperpigmentation of skin and nails. Skin reddening.
Rare: Urticaria.
General disorders and administration site conditions:
Common: Mucositis - may appear 5-10 days after the start of treatment, and usually involves stomatitis with areas of painful erosions, ulceration and bleeding, mainly along the side of the tongue and the sublingual mucosa.
Common: Redness along the infusion vein, local phlebitis, phlebosclerosis, local pain and tissue necrosis (following accidental paravenous injection) may occur.
Uncommon: Headache
Rare: Fever, chills, dizziness, amenorrhea, azoospermia, hyperuricaemia (as a result of rapid lysis of neoplastic cells). Hyperpyrexia, malaise, weakness and increased transaminase levels have also been reported.
Injury, poisoning and procedural complications:
Common: Chemical cystitis, sometimes haemorrhagic, has been observed following intravesical administration.
4.9 Overdose
Very high single doses of epirubicin may be expected to cause acute myocardial degeneration within 24 hours and severe myelosuppression within 10
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: cytotoxic antibiotics and related substances, anthracyclines. ATC code: L01D B03
The mechanism of action of epirubicin is related to its ability to bind to DNA. Cell culture studies have shown rapid cell penetration, localisation in the nucleus and inhibition of nucleic acid synthesis and mitosis. Epirubicin has proved to be active on a wide spectrum of experimental tumours including L1210 and P388 leukemias, sarcomas SA180 (solid and ascitic forms), B16 melanoma, mammary carcinoma, Lewis lung carcinoma and colon carcinoma 38. It has also shown activity against human tumours transplanted into athymic nude mice (melanoma, mammary, lung, prostatic and ovarian carcinomas).
5.2 Pharmacokinetic Properties
In patients with normal hepatic and renal function, plasma levels after i.v. injection of 60 2 of the drug follow a tri-exponential decreasing pattern with a very fast first phase and a slow terminal phase with a mean half-life of about 40 hours.
These doses are within the limits of pharmacokinetic linearity both in terms of plasma clearance values and metabolic pathway. The major metabolites that have been identified are epirubicinol (13-OH-epirubicin) and glucuronides of epirubicin and epirubicinol.
The 4′-O-glucuronidation distinguishes epirubicin from doxorubicin and may account for the faster elimination of epirubicin and its reduced toxicity. Plasma levels of the main metabolite, the 13-OH derivative (epirubicinol) are constantly lower and virtually parallel those of the unchanged drug.
Epirubicin is eliminated mainly through the liver. High plasma clearance values (0.9 l/min) indicate that this slow elimination is due to extensive tissue distribution.
Urinary excretion accounts for approximately 9
The drug does not cross the blood-brain-barrier. When epirubicin is administered intravesically the systemic absorption is minimal.
5.3 Preclinical Safety Data
Following repeated dosing with epirubicin, the target organs in rat, rabbit and dog were the haemolymphopoietic system, GI tract, kidney, liver and reproductive organs. Epirubicin was also cardiotoxic in the rat, rabbit and dog.
Epirubicin, like other anthracyclines, was mutagenic, genotoxic, embryotoxic and carcinogenic in rats.
No malformations were seen in rats or rabbits, but like other anthracyclines and cytotoxic drugs, epirubicin must be considered potentially teratogenic.
A local tolerance study in rats and mice showed extravasation of epirubicin causes tissue necrosis.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Water for injections
Hydrochloric acid (for pH-adjustment)
Sodium chloride
6.2 Incompatibilities
Prolonged contact with any solution of an alkaline pH should be avoided as it will result in hydrolysis of the drug. Epirubicin hydrochloride 2 mg/ml Solution for injection or infusion should not be mixed with heparin due to chemical incompatibility which may lead to precipitation when the drugs are in certain proportions.
Epirubicin hydrochloride 2 mg/ml Solution for injection or infusion can be used in combination with other antitumour agents, but it is not recommended that it be mixed with other drugs. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf Life
Unopened container: 2 years
After dilution:
Epirubicin hydrochloride 2 mg/ml Solution for injection or infusion may be further diluted, under aseptic conditions, in Glucose 5 % or Sodium chloride 0.9 %, and administered as an intravenous infusion. The infusion solution is chemically stable when stored in PE infusion bags, prepared under full aseptic conditions:
Sodium chloride 0.9 %: for 2 days at 25°C ± 2°C or for 4 days at 2-8°C protected from light.
Glucose 5 %: for 1 day at 25°C ± 2°C or for 2 days at 2-8°C protected from light.
From the microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.
6.4 Special Precautions For Storage
Store in a refrigerator (2°C - 8°C)
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
For 'in use' storage conditions, see section 6.3.
6.5 Nature And Contents Of Container
6 ml, 10 ml, 25 ml, 50 ml, 100 ml colourless glass vial (type I) with a rubber (chlorobutyl) stopper.
Package quantities:
Packs of | 1, 5 vials containing | 5 ml |
1, 5 vials containing | 10 ml | |
1, 5 vials containing | 25 ml | |
1, 5 vials containing | 50 ml | |
1, 5 vials containing | 100 ml |
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
The product should be brought to room temperature prior to use.
Epirubicin 2 mg/ml may be further diluted in Glucose 5% or Sodium Chloride 0.9%.
The injection solution contains no preservative and any unused portion of the vial should be disposed of immediately in accordance with local requirements
The following protective recommendations are given due to the toxic nature of this substance:
Personnel should be trained in good technique for reconstitution and handling.
Pregnant staff should be excluded from working with this drug.
Personnel handling Epirubicin hydrochloride 2 mg/ml Solution for injection or infusion should wear protective clothing: goggles, gowns and disposable gloves and masks.
A designated area should be defined for reconstitution (preferably under laminar flow system). The work surface should be protected by disposable, plastic-backed, absorbent paper.
All items used for reconstitution, administration or cleaning including gloves should be placed in high-risk, waste disposal bags for high temperature incineration. Spillage or leakage should be treated with dilute sodium hypochlorite (1 % available chlorine) solution, preferably by soaking, and then water.
All cleaning materials should be disposed of as indicated previously.
In case of skin contact thoroughly wash the affected area with soap and water or sodium bicarbonate solution. However, do not abrade the skin by using a scrub brush. In case of contact with the eye(s), hold back the eyelid of the affected eye(s), and flush with copious amounts of water for at least 15 minutes. Then seek medical evaluation by a physician.
Always wash hands after removing gloves.
7. Marketing Authorisation Holder
hameln pharma plus gmbh
Langes Feld 13
31789 Hameln
Germany
8. Marketing Authorisation Number(S)
PL 25215/0017
9. Date Of First Authorisation/Renewal Of The Authorisation
01/08/2008
10. Date Of Revision Of The Text
01/08/2008
11 DOSIMETRY (IF APPLICABLE)
12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)
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