Losartan-ratiopharm may be available in the countries listed below.
Losartan potassium salt (a derivative of Losartan) is reported as an ingredient of Losartan-ratiopharm in the following countries:
International Drug Name Search
Daktarin Oral may be available in the countries listed below.
Miconazole is reported as an ingredient of Daktarin Oral in the following countries:
International Drug Name Search
Nastil may be available in the countries listed below.
Ketoconazole is reported as an ingredient of Nastil in the following countries:
International Drug Name Search
Niux may be available in the countries listed below.
Pefloxacin mesilate (a derivative of Pefloxacin) is reported as an ingredient of Niux in the following countries:
International Drug Name Search
Vitamine B12 Théa may be available in the countries listed below.
Cyanocobalamin is reported as an ingredient of Vitamine B12 Théa in the following countries:
International Drug Name Search
In the US, Novolog Mix 70/30 (insulin aspart/insulin aspart protamine systemic) is a member of the drug class insulin and is used to treat Diabetes - Type 1 and Diabetes - Type 2.
US matches:
Insulin Aspart is reported as an ingredient of Novolog Mix 70/30 in the following countries:
International Drug Name Search
Novofemme may be available in the countries listed below.
Estradiol hemihydrate (a derivative of Estradiol) is reported as an ingredient of Novofemme in the following countries:
Norethisterone 17ß-acetate (a derivative of Norethisterone) is reported as an ingredient of Novofemme in the following countries:
International Drug Name Search
Treating infections caused by certain bacteria. It may be used in combination with other medicines to treat certain amoeba infections. It may also be used to prevent or slow the progression of anthrax after exposure.
Doxy 100 is a tetracycline antibiotic. It works by slowing the growth of bacteria. Slowing bacteria's growth allows the body's immune system to destroy the bacteria.
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with Doxy 100. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
Some MEDICINES MAY INTERACT with Doxy 100. Tell your health care provider if you are taking any other medicines, especially any of the following:
This may not be a complete list of all interactions that may occur. Ask your health care provider if Doxy 100 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.
Use Doxy 100 as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Ask your health care provider any questions you may have about how to use Doxy 100.
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:
Loss of appetite; nausea; sensitivity to sunlight; vomiting.
Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); bloody stools; chest pain; dark urine; decreased urination; fever, chills, or sore throat; moderate to severe sunburn; red, swollen, blistered, or peeling skin; severe diarrhea; severe or persistent headache; stomach pain or cramps; throat irritation; trouble swallowing; unusual bruising or bleeding; unusual joint pain; unusual tiredness; vaginal irritation or discharge; vision changes; yellowing of the skin or eyes.
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: Doxy00 side effects (in more detail)
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.
Store mixed powder at 77 degrees F (25 degrees C) for up to 48 hours. Mixed solution is stable under fluorescent light for 48 hours, but must be protected from direct sunlight during storage and administration. Mixed solution may be stored up to 72 hours before administration if refrigerated and protected from sunlight and artificial light. Infusion must be completed within 12 hours of mixing. Throw away any unused portion. Keep Doxy 100 out of the reach of children and away from pets.
When frozen immediately after mixing in sterile water, the solution is stable for up to 8 weeks when stored at 68 degrees F (20 degrees C). If the product is warmed, avoid heating it after the thawing is complete. Do not refreeze the solution once it has been thawed.
This information is a summary only. It does not contain all information about Doxy 100. 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.
Novolin Flexpen 50R may be available in the countries listed below.
Insulin Injection, Biphasic Isophane human (a derivative of Insulin Injection, Biphasic Isophane) is reported as an ingredient of Novolin Flexpen 50R in the following countries:
International Drug Name Search
Sodium Ozagrel may be available in the countries listed below.
Ozagrel sodium (a derivative of Ozagrel) is reported as an ingredient of Sodium Ozagrel in the following countries:
International Drug Name Search
Novotossil may be available in the countries listed below.
Cloperastine hydrochloride (a derivative of Cloperastine) is reported as an ingredient of Novotossil in the following countries:
International Drug Name Search
Claritromicina Tarbis may be available in the countries listed below.
Clarithromycin is reported as an ingredient of Claritromicina Tarbis in the following countries:
International Drug Name Search
Merbentyl Syrup
Dicycloverine Hydrochloride 10mg
Syrup
Merbentyl is a smooth muscle antispasmodic primarily indicated for treatment of functional conditions involving smooth muscle spasm of the gastrointestinal tract. The commonest of these are irritable colon (mucous colitis, spastic colon).
Adults
One to two 5ml spoonfuls (10 - 20mg) three times daily before or after meals.
Children (2-12 years):
One 5ml spoonful (10mg) three times daily.
Children (6 months - 2 years)
5 - 10mg three or four times daily, 15 minutes before feeds. Do not exceed a daily dose of 40mg. If it is necessary to dilute Merbentyl Syrup this may be done using Syrup or if diluted immediately prior to use with water.
Known idiosyncrasy to dicycloverine hydrochloride. Infants under 6 months of age.
Patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Products containing dicycloverine hydrochloride should be used with caution in any patient with or suspected of having glaucoma or prostatic hypertrophy. Use with care in patients with hiatus hernia associated with reflux oesophagitis because anticholinergic drugs may aggravate the condition. There are reports of infants, 3 months of age and under, administered dicycloverine hydrochloride syrup who have evidenced respiratory symptoms (breathing difficulty, shortness of breath, breathlessness, respiratory collapse, apnoea) as well as seizures, syncope, asphyxia, pulse rate fluctuations, muscular hypotonia and coma. The above symptoms have occurred within minutes of ingestion and lasted 20-30 minutes. The symptoms were reported in association with dicycloverine hydrochloride syrup therapy but the cause and effect relationship has neither been disproved or proved. The timing and nature of the reactions suggest that they were a consequence of local irritation and/or aspiration, rather than to a direct pharmacological effect. Although no causal relationship between these effects, observed in infants and dicycloverine administration has been established, dicycloverine hydrochloride is contra-indicated in infants under 6 months of age.
None stated.
Epidemiological studies in pregnant women with products containing dicycloverine hydrochloride (at doses up to 40mg/day) have not shown that dicycloverine hydrochloride increases the risk of foetal abnormalities if administered during the first trimester of pregnancy. Reproduction studies have been performed in rats and rabbits at doses of up to 100 times the maximum recommended dose (based on 60mg per day for an adult person) and have revealed no evidence of impaired fertility or harm to the foetus due to dicycloverine. Since the risk of teratogenicity cannot be excluded with absolute certainty for any product, the drug should be used during pregnancy only if clearly needed.
It is not known whether dicycloverine is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when dicycloverine is administered to a nursing mother.
None stated.
Side-effects seldom occur with Merbentyl. However, in susceptible individuals, dry mouth, thirst and dizziness may occur. On rare occasions, fatigue, sedation, blurred vision, rash, constipation, anorexia, nausea and vomiting, headache and dysuria have also been reported.
Symptoms of Merbentyl overdosage are headache, dizziness, nausea, dry mouth, difficulty in swallowing, dilated pupils and hot dry skin. Treatment may include emetics, gastric lavage and symptomatic therapy if indicated.
Dicycloverine hydrochloride relieves smooth muscle spasm of the gastrointestinal tract.
Animal studies indicate that this action is achieved via a dual mechanism;
(1) a specific anticholinergic effect (antimuscarinic at the ACh-receptor sites) and
(2) a direct effect upon smooth muscle (musculotropic).
After a single oral 20mg dose of dicycloverine hydrochloride in volunteers, peak plasma concentration reached a mean value of 58ng/ml in 1 to 1.5 hours. 14C labelled studies demonstrated comparable bioavailability from oral and intravenous administration. The principal route of elimination is via the urine.
None stated.
Invert Syrup Medium
Citric Acid Monohydrate
Sodium Benzoate
Raspberry Flavour
Wild Cherry Bark Flavour
Blackcurrant Essence
Vanilla Essence
Purified water
None stated.
3 years.
Do not store above 25'C. Should be stored and dispensed in amber glass bottles.
Type III, EP amber glass bottles sealed with a polyethylene screw cap equiped with a polyethylene seal and pilferproof closure.
Pack size: 1 bottle containing 120ml syrup.
None stated.
Sanofi-aventis
One Onslow Street
Guildford
Surrey, GU1 4YS, UK
PL 04425/0047
Date of first authorisation: 13th July 1983
Date of renewal: 31 July 2001
December 2006
Legal category: POM
Atenolol Gador may be available in the countries listed below.
Atenolol is reported as an ingredient of Atenolol Gador in the following countries:
International Drug Name Search
Novolizer Budesonide may be available in the countries listed below.
Budesonide is reported as an ingredient of Novolizer Budesonide in the following countries:
International Drug Name Search
Bactroban 2% Ointment
mupirocin
Bactroban 2% Ointment (called ‘Bactroban’ in this leaflet) contains a medicine called mupirocin.
Bactroban is an antibiotic ointment.
It is used:
Do not use if the above applies to you. If you are not sure do not use this medicine. Talk to your doctor, nurse or pharmacist before using Bactroban.
Thrush (a yeast infection) may develop if Bactroban is used for a long time. If this occurs, tell your doctor, pharmacist or nurse.
Keep the ointment away from your eyes.
There is a different preparation of Bactroban that is used to prevent or treat infections inside your nose.
Please tell your doctor, pharmacist or nurse if you are taking or have recently taken any other medicines. This includes medicines obtained without a prescription, including herbal medicines.
Do not use Bactroban if you are pregnant, might become pregnant or are breast-feeding. Talk to your doctor, nurse or pharmacist for advice before using any medicine, if you are pregnant or breast-feeding. If a cracked nipple is being treated, the ointment must be thoroughly washed off prior to breast-feeding.
Always use Bactroban exactly as your doctor has told you. You should check with your doctor, nurse or pharmacist if you are not sure.
Do not mix Bactroban with any other external cream or ointment medicines on the infected area of your skin as this may reduce the effectiveness of Bactroban.
You usually apply Bactroban on your skin up to 3 times a day.
Use Bactroban for as long as your doctor has told you. If you are not sure, ask your doctor, nurse or pharmacist. The bacteria are normally cleared from your skin within 10 days of starting treatment.
Do not use for more than 10 days.
If you use more Bactroban than you should, speak to your doctor, nurse or pharmacist for advice.
If you stop using Bactroban too early, not all the bacteria may have been killed or they may continue to grow. Ask your doctor, nurse or pharmacist when to stop using the ointment.
If you have any further questions on the use of this product, ask your doctor, nurse or pharmacist.
Like all medicines, Bactroban can cause side effects, although not everybody gets them.
Severe skin reactions or allergies
The following side effects may happen with this medicine:
Common (these may affect between 1 in 10 and 1 in 100 people)
Uncommon (these may affect between 1 in 100 and 1 in 1,000 people)
Very rare (these may affect up to 1 in 10,000 people)
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor, nurse or pharmacist.
Marketing authorisation holder
Manufacturer
Other formats:
To listen to or request a copy of this leaflet in Braille, large print or audio please call, free of charge:
0800 198 5000 (UK Only)
Please be ready to give the following information:
Product Name: Bactroban 2% Ointment
Reference number: 00038/0319
This is a service provided by the Royal National Institute for the Blind.
Leaflet date: January 2010
Bactroban is a registered trademark of the GlaxoSmithKline group of companies.
© 2010 GlaxoSmithKline group of companies.
10000000078208
Novo-Spirozine may be available in the countries listed below.
Hydrochlorothiazide is reported as an ingredient of Novo-Spirozine in the following countries:
Spironolactone is reported as an ingredient of Novo-Spirozine in the following countries:
International Drug Name Search
Novolin ge 50/50 may be available in the countries listed below.
Insulin, Isophane human (a derivative of Insulin, Isophane) is reported as an ingredient of Novolin ge 50/50 in the following countries:
International Drug Name Search
Novogyn may be available in the countries listed below.
Ethinylestradiol is reported as an ingredient of Novogyn in the following countries:
Levonorgestrel is reported as an ingredient of Novogyn in the following countries:
International Drug Name Search
Flumirex may be available in the countries listed below.
Fluoxetine hydrochloride (a derivative of Fluoxetine) is reported as an ingredient of Flumirex in the following countries:
International Drug Name Search
Laremid may be available in the countries listed below.
Loperamide is reported as an ingredient of Laremid in the following countries:
International Drug Name Search
NifeHexal may be available in the countries listed below.
Nifedipine is reported as an ingredient of NifeHexal in the following countries:
International Drug Name Search
Generic Name: acetaminophen and dextromethorphan (a SEET a MIN oh fen and DEX troe me THOR fan)
Brand Names: Children's Triacting, Triaminic Cough & Sore Throat Softchews, Tylenol Cough and Sore Throat Daytime
Acetaminophen is a pain reliever and fever reducer.
Dextromethorphan is a cough suppressant. It affects the signals in the brain that trigger cough reflex.
The combination of acetaminophen and dextromethorphan is used to treat cough and pain or fever caused by the common cold or flu.
Acetaminophen and dextromethorphan may also be used for other purposes not listed in this medication guide.
Ask a doctor or pharmacist about taking this medication if you have:
liver disease;
alcoholism or cirrhosis of the liver; or
emphysema or chronic bronchitis.
Artificially-sweetened liquid forms of cough medicine may contain phenylalanine. This would be important to know if you have phenylketonuria (PKU). Check the ingredients and warnings on the medication label if you are concerned about phenylalanine.
Use this medication exactly as directed on the label, or as it has been prescribed by your doctor. Do not use the medication in larger amounts, or use it for longer than recommended. Cough medicine is usually taken only for a short time until your symptoms clear up.
Measure the liquid form of this medication with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.
If you need to have any type of surgery, tell the surgeon ahead of time if you have taken a cough medicine within the past few days.
Take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at your next regularly scheduled time. Do not take extra medicine to make up the missed dose.
The first signs of an acetaminophen overdose include loss of appetite, nausea, vomiting, stomach pain, sweating, and confusion or weakness. Later symptoms may include pain in your upper stomach, dark urine, and yellowing of your skin or the whites of your eyes.
Overdose symptoms may also include dizziness, drowsiness, feeling restless or nervous, diarrhea, loss of appetite, seizure (convulsions), or coma.
Avoid taking diet pills, caffeine pills, or other stimulants (such as ADHD medications) without your doctor's advice. Taking a stimulant together with cough medicine can increase your risk of unpleasant side effects.
severe dizziness, anxiety, restless feeling, or nervousness;
confusion, hallucinations;
slow, shallow breathing;
easy bruising or bleeding, unusual weakness, fever, chills, body aches, flu symptoms; or
nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).
Less serious side effects may include:
mild loss of appetite, upset stomach.
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.
Before taking this medication, tell your doctor if you are using any of the following drugs:
celecoxib (Celebrex);
cinacalcet (Sensipar);
darifenacin (Enablex);
imatinib (Gleevec);
isoniazid;
quinidine (Quinaglute, Quinidex);
ranolazine (Ranexa);
ritonavir (Norvir);
sibutramine (Meridia);
terbinafine (Lamisil);
zidovudine (Retrovir, AZT);
gout medication such as probenecid (Benemid);
medicines to treat high blood pressure;
seizure medication such as phenytoin (Dilantin) or phenobarbital (Luminal, Solfoton); or
an antidepressant such as amitriptyline (Elavil, Etrafon), bupropion (Wellbutrin, Zyban), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), imipramine (Janimine, Tofranil), paroxetine (Paxil), sertraline (Zoloft), and others.
This list is not complete and there may be other drugs that can interact with acetaminophen and dextromethorphan. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.
Doxil (doxorubicin HCl liposome injection) is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy.
Doxil is indicated for the treatment of AIDS-related Kaposi's sarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy.
Doxil in combination with bortezomib is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy.
Liposomal encapsulation can substantially affect a drug's functional properties relative to those of the unencapsulated drug. Therefore DO NOT SUBSTITUTE one drug for the other.
Do not administer as a bolus injection or an undiluted solution. Rapid infusion may increase the risk of infusion-related reactions [see Warnings and Precautions (5.2)]. Doxil must not be given by the intramuscular or subcutaneous route.
Until specific compatibility data are available, it is not recommended that Doxil be mixed with other drugs.
Doxil should be considered an irritant and precautions should be taken to avoid extravasation. With intravenous administration of Doxil, extravasation may occur with or without an accompanying stinging or burning sensation, even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the infusion should be immediately terminated and restarted in another vein. The application of ice over the site of extravasation for approximately 30 minutes may be helpful in alleviating the local reaction.
Doxil (doxorubicin HCl liposome injection) should be administered intravenously at a dose of 50 mg/m2 (doxorubicin HCl equivalent) at an initial rate of 1 mg/min to minimize the risk of infusion reactions. If no infusion-related adverse reactions are observed, the rate of infusion can be increased to complete administration of the drug over one hour. The patient should be dosed once every 4 weeks, for as long as the patient does not progress, shows no evidence of cardiotoxicity [see Warnings and Precautions (5.1)], and continues to tolerate treatment. A minimum of 4 courses is recommended because median time to response in clinical trials was 4 months. To manage adverse reactions such as hand-foot syndrome (HFS), stomatitis, or hematologic toxicity the doses may be delayed or reduced [see Dosage and Administration (2.5)]. Pretreatment with or concomitant use of antiemetics should be considered.
Doxil (doxorubicin HCl liposome injection) should be administered intravenously at a dose of 20 mg/m2 (doxorubicin HCl equivalent). An initial rate of 1 mg/min should be used to minimize the risk of infusion-related reactions. If no infusion-related adverse reactions are observed, the infusion rate should be increased to complete the administration of the drug over one hour. The dose should be repeated once every three weeks, for as long as patients respond satisfactorily and tolerate treatment.
Bortezomib is administered at a dose of 1.3 mg/m2 as intravenous bolus on days 1, 4 , 8 and 11, every three weeks. Doxil 30 mg/m2 should be administered as a 1-hr intravenous infusion on day 4 following bortezomib. With the first Doxil dose, an initial rate of 1 mg/min should be used to minimize the risk of infusion-related reactions. If no infusion-related adverse reactions are observed, the infusion rate should be increased to complete the administration of the drug over one hour. Patients may be treated for up to 8 cycles until disease progression or the occurrence of unacceptable toxicity.
Doxil exhibits nonlinear pharmacokinetics at 50 mg/m2; therefore, dose adjustments may result in a non-proportional greater change in plasma concentration and exposure to the drug [see Clinical Pharmacology (12.3)].
Patients should be carefully monitored for toxicity. Adverse reactions, such as HFS, hematologic toxicities, and stomatitis may be managed by dose delays and adjustments. Following the first appearance of a Grade 2 or higher adverse reactions, the dosing should be adjusted or delayed as described in the following tables. Once the dose has been reduced, it should not be increased at a later time.
Recommended Dose Modification Guidelines
| Toxicity Grade | Dose Adjustment |
|---|---|
| 1 (mild erythema, swelling, or desquamation not interfering with daily activities) | Redose unless patient has experienced previous Grade 3 or 4 HFS. If so, delay up to 2 weeks and decrease dose by 25%. Return to original dose interval. |
| 2 (erythema, desquamation, or swelling interfering with, but not precluding normal physical activities; small blisters or ulcerations less than 2 cm in diameter) | Delay dosing up to 2 weeks or until resolved to Grade 0–1. If after 2 weeks there is no resolution, Doxil should be discontinued. If resolved to Grade 0–1 within 2 weeks, and there are no prior Grade 3–4 HFS, continue treatment at previous dose and return to original dose interval. If patient experienced previous Grade 3–4 toxicity, continue treatment with a 25% dose reduction and return to original dose interval. |
| 3 (blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothing) | Delay dosing up to 2 weeks or until resolved to Grade 0–1. Decrease dose by 25% and return to original dose interval. If after 2 weeks there is no resolution, Doxil should be discontinued. |
| 4 (diffuse or local process causing infectious complications, or a bed ridden state or hospitalization) | Delay dosing up to 2 weeks or until resolved to Grade 0–1. Decrease dose by 25% and return to original dose interval. If after 2 weeks there is no resolution, Doxil should be discontinued. |
| Grade | ANC | Platelets | Modification |
|---|---|---|---|
| 1 | 1,500 – 1,900 | 75,000 – 150,000 | Resume treatment with no dose reduction |
| 2 | 1,000 – <1,500 | 50,000 – <75,000 | Wait until ANC ≥ 1,500 and platelets ≥ 75,000; redose with no dose reduction |
| 3 | 500 – 999 | 25,000 – <50,000 | Wait until ANC ≥ 1,500 and platelets ≥ 75,000; redose with no dose reduction |
| 4 | <500 | <25,000 | Wait until ANC ≥ 1,500 and platelets ≥ 75,000; redose at 25% dose reduction or continue full dose with cytokine support |
| Toxicity Grade | Dose Adjustment |
|---|---|
| 1 (painless ulcers, erythema, or mild soreness) | Redose unless patient has experienced previous Grade 3 or 4 toxicity. If so, delay up to 2 weeks and decrease dose by 25%. Return to original dose interval. |
| 2 (painful erythema, edema, or ulcers, but can eat) | Delay dosing up to 2 weeks or until resolved to Grade 0–1. If after 2 weeks there is no resolution, Doxil should be discontinued. If resolved to Grade 0–1 within 2 weeks and there was no prior Grade 3–4 stomatitis, continue treatment at previous dose and return to original dose interval. If patient experienced previous Grade 3–4 toxicity, continue treatment with a 25% dose reduction and return to original dose interval. |
| 3 (painful erythema, edema, or ulcers, and cannot eat) | Delay dosing up to 2 weeks or until resolved to Grade 0–1. Decrease dose by 25% and return to original dose interval. If after 2 weeks there is no resolution, Doxil should be discontinued. |
| 4 (requires parenteral or enteral support) | Delay dosing up to 2 weeks or until resolved to Grade 0–1. Decrease dose by 25% and return to Doxil original dose interval. If after 2 weeks there is no resolution, Doxil should be discontinued. |
Multiple Myeloma
For patients treated with Doxil in combination with bortezomib who experience hand-foot syndrome or stomatitis, the Doxil dose should be modified as described in Tables 1 and 3 above. Table 4 describes dosage adjustments for Doxil and bortezomib combination therapy. For bortezomib dosing and dosage adjustments, see manufacturer's prescribing information.
| Patient status | Doxil | bortezomib |
|---|---|---|
| Fever ≥38°C and ANC <1,000/mm3 | Do not dose this cycle if before Day 4; if after Day 4, reduce next dose by 25%. | Reduce next dose by 25% |
| On any day of drug administration after Day 1 of each cycle: Platelet count <25,000/mm3 Hemoglobin <8g/dL ANC <500/mm3 | Do not dose this cycle if before Day 4; if after Day 4 reduce next dose by 25% in the following cycles if bortezomib is reduced for hematologic toxicity. | Do not dose; if 2 or more doses are not given in a cycle, reduce dose by 25% in following cycles. |
| Grade 3 or 4 non-hematologic drug related toxicity | Do not dose until recovered to Grade <2 and reduce dose by 25% for all subsequent doses. | Do not dose until recovered to Grade <2 and reduce dose by 25% for all subsequent doses. |
| Neuropathic pain or peripheral neuropathy | No dosage adjustments. | See bortezomib manufacturer's prescribing information for dosage adjustments in patients with neuropathic pain. |
Limited clinical experience exists in treating patients with hepatic impairment with Doxil. Based on experience with doxorubicin HCl, it is recommended that the Doxil dosage be reduced if the bilirubin is elevated as follows: serum bilirubin 1.2 to 3.0 mg/dL - give ½ normal dose; serum bilirubin > 3 mg/dL - give ¼ normal dose.
No information, including dosage adjustments, is available for patients with multiple myeloma with hepatic impairment.
Each 10-mL vial contains 20 mg doxorubicin HCl at a concentration of 2 mg/mL.
Each 30-mL vial contains 50 mg doxorubicin HCl at a concentration of 2 mg/mL.
Doxil doses up to 90 mg must be diluted in 250 mL of 5% Dextrose Injection, USP prior to administration. Doses exceeding 90 mg should be diluted in 500 mL of 5% Dextrose Injection, USP prior to administration. Aseptic technique must be strictly observed since no preservative or bacteriostatic agent is present in Doxil. Diluted Doxil should be refrigerated at 2°C to 8°C (36°F to 46°F) and administered within 24 hours.
Do not use with in-line filters.
Do not mix with other drugs.
Do not use with any diluent other than 5% Dextrose Injection.
Do not use any bacteriostatic agent, such as benzyl alcohol.
Doxil is not a clear solution but a translucent, red liposomal dispersion.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if a precipitate or foreign matter is present.
Rapid flushing of the infusion line should be avoided.
Caution should be exercised in the handling and preparation of Doxil.
The use of gloves is required.
If Doxil comes into contact with skin or mucosa, immediately wash thoroughly with soap and water.
Doxil should be considered an irritant and precautions should be taken to avoid extravasation. With intravenous administration of Doxil, extravasation may occur with or without an accompanying stinging or burning sensation, even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the infusion should be immediately terminated and restarted in another vein. Doxil must not be given by the intramuscular or subcutaneous route.
Doxil should be handled and disposed of in a manner consistent with other anticancer drugs. Several guidelines on this subject exist [see References (15)].
Doxil (doxorubicin HCl liposome injection) is contraindicated in patients who have a history of hypersensitivity reactions to a conventional formulation of doxorubicin HCl or the components of Doxil [see Warnings and Precautions (5.2)].
Doxil is contraindicated in nursing mothers [see Use in Specific Populations (8.3)].
Special attention must be given to the risk of myocardial damage from cumulative doses of doxorubicin HCl. Acute left ventricular failure may occur with doxorubicin, particularly in patients who have received a total cumulative dosage of doxorubicin exceeding the currently recommended limit of 550 mg/m2. Lower (400 mg/m2) doses appear to cause heart failure in patients who have received radiotherapy to the mediastinal area or concomitant therapy with other potentially cardiotoxic agents such as cyclophosphamide.
Prior use of other anthracyclines or anthracenodiones should be included in calculations of total cumulative dosage. Congestive heart failure or cardiomyopathy may be encountered after discontinuation of anthracycline therapy. Patients with a history of cardiovascular disease should be administered Doxil only when the potential benefit of treatment outweighs the risk.
Cardiac function should be carefully monitored in patients treated with Doxil. The most definitive test for anthracycline myocardial injury is endomyocardial biopsy. Other methods, such as echocardiography or multigated radionuclide scans, have been used to monitor cardiac function during anthracycline therapy. Any of these methods should be employed to monitor potential cardiac toxicity in patients treated with Doxil. If these test results indicate possible cardiac injury associated with Doxil therapy, the benefit of continued therapy must be carefully weighed against the risk of myocardial injury.
In a clinical study in patients with advanced breast cancer, 250 patients received Doxil at starting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450–500 mg/m2, or between 500–550 mg/m2, the risk of cardiac toxicity for patients treated with Doxil was 11%. In this study, cardiotoxicity was defined as a decrease of >20% from baseline if the resting left ventricular ejection fraction (LVEF) remained in the normal range, or a decrease of >10% if the resting LVEF became abnormal (less than the institutional lower limit of normal). The data on left ventricular ejection fraction (LVEF) defined cardiotoxicity and congestive heart failure (CHF) are in the table below.
| Doxil (n=250) | |
|---|---|
| Patients who Developed Cardiotoxicity (LVEF Defined) | 10 |
| Cardiotoxicity (With Signs & Symptoms of CHF) | 0 |
| Cardiotoxicity (no Signs & Symptoms of CHF) | 10 |
| Patients With Signs and Symptoms of CHF Only | 2 |
In the randomized multiple myeloma study, the incidence of heart failure events (ventricular dysfunction, cardiac failure, right ventricular failure, congestive cardiac failure, chronic cardiac failure, acute pulmonary edema and pulmonary edema) was similar in the Doxil+bortezomib group and the bortezomib monotherapy group, 3% in each group. LVEF decrease was defined as an absolute decrease of ≥15% over baseline or a ≥5% decrease below the institutional lower limit of normal. Based on this definition, 25 patients in the bortezomib arm (8%) and 42 patients in the Doxil + bortezomib arm (13%) experienced a reduction in LVEF.
Acute infusion-related reactions were reported in 7.1% of patients treated with Doxil in the randomized ovarian cancer study. These reactions were characterized by one or more of the following symptoms: flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients, the reaction resolved when the rate of infusion was slowed. In this study, two patients treated with Doxil (0.8%) discontinued due to infusion-related reactions. In clinical studies, six patients with AIDS-related Kaposi's sarcoma (0.9%) and 13 (1.7%) solid tumor patients discontinued Doxil therapy because of infusion-related reactions.
Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use.
The majority of infusion-related events occurred during the first infusion. Similar reactions have not been reported with conventional doxorubicin and they presumably represent a reaction to the Doxil liposomes or one of its surface components.
The initial rate of infusion should be 1 mg/min to help minimize the risk of infusion reactions [see Dosage and Administration (2)].
Because of the potential for bone marrow suppression, careful hematologic monitoring is required during use of Doxil, including white blood cell, neutrophil, platelet counts, and Hgb/Hct. With the recommended dosage schedule, leukopenia is usually transient. Hematologic toxicity may require dose reduction or delay or suspension of Doxil therapy. Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage. Development of sepsis in the setting of neutropenia has resulted in discontinuation of treatment and, in rare cases, death.
Doxil may potentiate the toxicity of other anticancer therapies. In particular, hematologic toxicity may be more severe when Doxil is administered in combination with other agents that cause bone marrow suppression.
In patients with relapsed ovarian cancer, myelosuppression was generally moderate and reversible. In the three single-arm studies, anemia was the most common hematologic adverse reaction (52.6%), followed by leukopenia (WBC< 4,000 mm3; 42.2%), thrombocytopenia (24.2%), and neutropenia (ANC <1,000; 19.0%). In the randomized study, anemia was the most common hematologic adverse reaction (40.2%), followed by leukopenia (WBC <4,000 mm3; 36.8%), neutropenia (ANC <1,000; 35.1%), and thrombocytopenia (13.0%) [see Adverse Reactions (6.2)].
In patients with relapsed ovarian cancer, 4.6% received G-CSF (or GM-CSF) to support their blood counts [see Dosage and Administrations (2.5)].
For patients with AIDS-related Kaposi's sarcoma who often present with baseline myelosuppression due to such factors as their HIV disease or concomitant medications, myelosuppression appears to be the dose-limiting adverse reaction at the recommended dose of 20 mg/m2 [see Adverse Reactions (6.2)]. Leukopenia is the most common adverse reaction experienced in this population; anemia and thrombocytopenia can also be expected. Sepsis occurred in 5% of patients; for 0.7% of patients the event was considered possibly or probably related to Doxil. Eleven patients (1.6%) discontinued study because of bone marrow suppression or neutropenia.
Table 10 presents data on myelosuppression in patients with multiple myeloma receiving Doxil and bortezomib in combination [see Adverse Reactions (6.2)].
In the randomized ovarian cancer study, 50.6% of patients treated with Doxil at 50 mg/m2 every 4 weeks experienced HFS (developed palmar-plantar skin eruptions characterized by swelling, pain, erythema and, for some patients, desquamation of the skin on the hands and the feet), with 23.8% of the patients reporting HFS Grade 3 or 4 events. Ten subjects (4.2%) discontinued treatment due to HFS or other skin toxicity. HFS toxicity grades are described above [see definitions of HFS grades in Dosage and Administration (2.5)].
Among 705 patients with AIDS-related Kaposi's sarcoma treated with Doxil at 20 mg/m2 every 2 weeks, 24 (3.4%) developed HFS, with 3 (0.9%) discontinuing.
In the randomized multiple myeloma study, 19% of patients treated with Doxil at 30 mg/m2 every three weeks experienced HFS.
HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. In most patients the reaction is mild and resolves in one to two weeks so that prolonged delay of therapy need not occur. However, dose modification may be required to manage HFS [see Dosage and Administration (2.5)]. The reaction can be severe and debilitating in some patients and may require discontinuation of treatment.
Recall reaction has occurred with Doxil administration after radiotherapy.
Pregnancy Category D
Doxil can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. If Doxil is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. If pregnancy occurs in the first few months following treatment with Doxil, the prolonged half-life of the drug must be considered. Women of childbearing potential should be advised to avoid pregnancy during treatment with Doxil. [see Use in Specific Populations (8.1)].
The doxorubicin in Doxil may potentiate the toxicity of other anticancer therapies. Exacerbation of cyclophosphamide-induced hemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with the conventional formulation of doxorubicin HCl. Radiation-induced toxicity to the myocardium, mucosae, skin, and liver have been reported to be increased by the administration of doxorubicin HCl.
Complete blood counts, including platelet counts, should be obtained frequently and at a minimum prior to each dose of Doxil [see Warnings and Precautions (5.3)].
The following adverse reactions are discussed in more detail in other sections of the labeling.
The most common adverse reactions observed with Doxil are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia.
The most common serious adverse reactions observed with Doxil are described in Section 6.2.
The safety data described below reflect exposure to Doxil in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi's sarcoma and 318 patients with multiple myeloma [see Adverse Reactions in Clinical Trials (6.2)].
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice.
The following tables present adverse reactions from clinical trials of Doxil in ovarian cancer and AIDS-Related Kaposi's sarcoma.
Patients With Ovarian Cancer
The safety data described below are from 239 patients with ovarian cancer treated with Doxil (doxorubicin HCl liposome injection) at 50 mg/m2 once every 4 weeks for a minimum of 4 courses in a randomized, multicenter, open-label study. In this study, patients received Doxil for a median number of 98.0 days (range 1–785 days). The population studied was 27–87 years of age, 91% Caucasian, 6% Black and 3% Hispanic and other.
Table 6 presents the hematologic adverse reactions from the randomized study of Doxil compared to topotecan.
| Doxil Patients (n = 239) | Topotecan Patients (n = 235) | |
|---|---|---|
| Neutropenia | ||
| 500 – <1000/mm3 | 19 (7.9%) | 33 (14.0%) |
| <500/mm3 | 10 (4.2%) | 146 (62.1%) |
| Anemia | ||
| 6.5 – <8 g/dL | 13 (5.4%) | 59 (25.1%) |
| < 6.5 g/dL | 1 (0.4%) | 10 (4.3%) |
| Thrombocytopenia | ||
| 10,000 – <50,000/mm3 | 3 (1.3%) | 40 (17.0%) |
| <10,000/mm3 | 0 (0.0%) | 40 (17.0%) |
Table 7 presents a comparative profile of the non-hematologic adverse reactions from the randomized study of Doxil compared to topotecan.
| Non-Hematologic Adverse Reaction 10% or Greater | Doxil (%) treated (n = 239) | Topotecan (%) treated (n =235) | ||
|---|---|---|---|---|
| All grades | Grades 3–4 | All grades | Grades 3–4 | |
| Body as a Whole | ||||
| Asthenia | 40.2 | 7.1 | 51.5 | 8.1 |
| Fever | 21.3 | 0.8 | 30.6 | 5.5 |
| Mucous Membrane Disorder | 14.2 | 3.8 | 3.4 | 0 |
| Back Pain | 11.7 | 1.7 | 10.2 | 0.9 |
| Infection | 11.7 | 2.1 | 6.4 | 0.9 |
| Headache | 10.5 | 0.8 | 14.9 | 0 |
| Digestive | ||||
| Nausea | 46.0 | 5.4 | 63.0 | 8.1 |
| Stomatitis | 41.4 | 8.3 | 15.3 | 0.4 |
| Vomiting | 32.6 | 7.9 | 43.8 | 9.8 |
| Diarrhea | 20.9 | 2.5 | 34.9 | 4.2 |
| Anorexia | 20.1 | 2.5 | 21.7 | 1.3 |
| Dyspepsia | 12.1 | 0.8 | 14.0 | 0 |
| Nervous | ||||
| Dizziness | 4.2 | 0 | 10.2 | 0 |
| Respiratory | ||||
| Pharyngitis | 15.9 | 0 | 17.9 | 0.4 |
| Dyspnea | 15.1 | 4.1 | 23.4 | 4.3 |
| Cough increased | 9.6 | 0 | 11.5 | 0 |
| Skin and Appendages | ||||
| Hand-foot syndrome | 50.6 | 23.8 | 0.9 | 0 |
| Rash | 28.5 | 4.2 | 12.3 | 0.4 |
| Alopecia | 19.2 | N/A | 52.3 | N/A |
The following additional adverse reactions (not in table) were observed in patients with ovarian cancer with doses administered every four weeks.
Incidence 1% to 10%
Cardiovascular: vasodilation, tachycardia, deep thrombophlebitis, hypotension, cardiac arrest.
Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus.
Hemic and Lymphatic: ecchymosis.
Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia.
Nervous: somnolence, dizziness, depression.
Respiratory: rhinitis, pneumonia, sinusitis, epistaxis.
Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne.
Special Senses: conjunctivitis, taste perversion, dry eyes.
Urinary: urinary tract infection, hematuria, vaginal moniliasis.
Patients With AIDS-Related Kaposi's Sarcoma
The safety data below is based on the experience reported in 753 patients with AIDS-related Kaposi's sarcoma enrolled in four studies. The median age of the population was 38.7 years (range 24–70 years), which was 99% male, 1% female, 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m2 of Doxil every two to three weeks. The median time on study was 127 days and ranged from 1 to 811 days. The median cumulative dose was 120 mg/m2 and ranged from 3.3 to 798.6 mg/m2. Twenty-six patients (3.0%) received cumulative doses of greater than 450 mg/m2.
Of these 753 patients, 61.2% were considered poor risk for KS tumor burden, 91.5% poor for immune system, and 46.9% for systemic illness; 36.2% were poor risk for all three categories. Patients' median CD4 count was 21.0 cells/mm3, with 50.8% of patients having less than 50 cells/mm3. The mean absolute neutrophil count at study entry was approximately 3,000 cells/mm3.
Patients received a variety of potentially myelotoxic drugs in combination with Doxil. Of the 693 patients with concomitant medication information, 58.7% were on one or more antiretroviral medications; 34.9% patients were on zidovudine (AZT), 20.8% on didanosine (ddI), 16.5% on zalcitabine (ddC), and 9.5% on stavudine (D4T). A total of 85.1% patients were on PCP prophylaxis, most (54.4%) on sulfamethoxazole/trimethoprim. Eighty-five percent of patients were receiving antifungal medications, primarily fluconazole (75.8%). Seventy-two percent of patients were receiving antivirals, 56.3% acyclovir, 29% ganciclovir, and 16% foscarnet. In addition, 47.8% patients received colony-stimulating factors (sargramostim/filgrastim) sometime during their course of treatment.
Adverse reactions led to discontinuation of treatment in 5% of patients with AIDS related Kaposi's sarcoma. Those that did so included bone marrow suppression, cardiac adverse reactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis, progression of a non-KS tumor, allergy to penicillin, and unspecified reasons.
| Patients With Refractory or Intolerant AIDS-Related Kaposi's Sarcoma (n = 74) | Total Patients With AIDS-Related Kaposi's Sarcoma (n = 720) | ||||
|---|---|---|---|---|---|
| Neutropenia | |||||
| < 1000/mm3 | 34 | (45.9%) | 352 | (48.9%) | |
| < 500/mm3 | 8 | (10.8%) | 96 | (13.3%) | |
| Anemia | |||||
| < 10 g/dL | 43 | (58.1%) | 399 | (55.4%) | |
| < 8 g/dL | 12 | (16.2%) | 131 | (18.2%) | |
| Thrombocytopenia | |||||
| < 150,000/mm3 | 45 | (60.8%) | 439 | (60.9%) | |
| < 25,000/mm3 | 1 | (1.4%) | 30 | (4.2%) | |
| Adverse Reactions | Patients With Refractory or Intolerant AIDS-Related Kaposi's Sarcoma (n = 77) | Total Patients With AIDS-Related Kaposi's Sarcoma (n = 705) | ||
|---|---|---|---|---|
| Nausea | 14 | (18.2%) | 119 | (16.9%) |
| Asthenia | 5 | (6.5%) | 70 | (9.9%) |
| Fever | 6 | (7.8%) | 64 | (9.1%) |
| Alopecia | 7 | (9.1%) | 63 | |
