In the US, Xolegel (ketoconazole topical) is a member of the drug class topical antifungals and is used to treat Cutaneous Candidiasis, Dandruff, Seborrheic Dermatitis, Tinea Corporis, Tinea Cruris, Tinea Pedis and Tinea Versicolor.
US matches:
Ketoconazole is reported as an ingredient of Xolegel in the following countries:
International Drug Name Search
Diamorphine Hydrochloride 500mg for Injection
Each ampoule contains 500mg of diamorphine hydrochloride
For full list of excipients, see section 6.1.
A white to off-white, sterile, freeze dried powder of Diamorphine Hydrochloride BP for reconstitution for injection.
Diamorphine may be used in the treatment of severe pain associated with surgical procedures, myocardial infarction or pain in the terminally ill and for the relief of dyspnoea in acute pulmonary oedema.
Diamorphine may be given by the intramuscular, intravenous or subcutaneous routes. Glucose intravenous infusion is the preferred diluent, particularly when the drug is administered by a continuous infusion pump over 24 to 48 hours, although it is also compatible with sodium chloride intravenous infusion.
The dose should be suited to the individual patient.
Adults:
Acute pain, 5mg repeated every four hours if necessary (up to 10mg for heavier, well muscled patients) by subcutaneous or intramuscular injection. By slow intravenous injection, one quarter to one half the corresponding intramuscular dose.
Chronic pain, 5-10mg regularly every four hours by subcutaneous or intramuscular injection. The dose may be increased according to individual needs.
Myocardial infarction, 5mg by slow intravenous injection (1mg/minute) followed by a further 2.5mg to 5mg if necessary.
Acute pulmonary oedema, 2.5mg to 5mg by slow intravenous injection (1mg/minute).
Children and Elderly:
As diamorphine has a respiratory depressant effect, care should be taken when giving the drug to the very young and the elderly and a lower starting dose than normal is recommended.
Hepatic impairment:
A reduction in dosage should be considered in hepatic impairment.
Renal impairment:
The dosage should be reduced in moderate to severe renal impairment.
Debilitated patients:
A reduction in dosage should be considered in debilitated patients.
For concomitant illnesses/conditions where dose reduction may be appropriate see 4.4 Special Warnings and Precautions for Use.
Acute respiratory depression.
Known hypersensitivity to diamorphine or morphine.
Phaeochromocytoma (endogenous release of histamine may stimulate catecholamine release).
Biliary colic (see also biliary tract disorders, 4.4 Special Warnings and Precautions).
Coma. Raised intracranial pressure. Head injuries, as there is an increased risk of respiratory depression that may lead to elevation of CSF pressure. The sedation and pupillary changes produced may interfere with accurate monitoring of the patient
Acute alcoholism.
Diamorphine is also contra-indicated where there is a risk of paralytic ileus, or in acute diarrhoeal conditions associated with antibiotic-induced pseudomembranous colitis or diarrhoea caused by poisoning (until the toxic material has been eliminated).
Repeated administration of diamorphine may lead to dependence and tolerance developing. Abrupt withdrawal in patients who have developed dependence may precipitate a withdrawal syndrome. Great caution should be exercised in patients with a known tendency or history of drug abuse.
Morphine-like opioids should either be avoided in patients with biliary tract disorders or they should be given with an antispasmodic (use in biliary colic is a contraindication see 4.3 Contraindications).
Diamorphine should be given in reduced doses or with caution to patients with asthma or decreased respiratory reserve (including kyphoscoliosis, emphysema, severe obesity, cor pulmonale). Avoid use during an acute asthma attack (see 4.3 Contraindications).
Use with caution or in reduced doses in patients with toxic psychosis, CNS depression, myxoedema, prostatic hypertrophy or urethral stricture, severe inflammatory or obstructive bowel disorders, hypotension, shock, convulsive disorders, adrenal insufficiency or debilitated patients.
Care should be exercised in treating the elderly, children or debilitated patients and those with hepatic or renal impairment (see 4.2 Posology for dosage recommendations).
Palliative care - in the control of pain in terminal illness, these conditions should not necessarily be a deterrent to use.
Alcohol: Alcohol may enhance the sedative and hypotensive effects of diamorphine.
Anti-arrhythmics: Diamorphine may delay the absorption of mexiletine.
Antidepressants, anxiolytics, hypnotics: Severe CNS excitation or depression (hypertension or hypotension) has been reported with the concomitant use of monoamine oxidase inhibitors (MAOIs) and pethidine. It is therefore possible that a similar interaction may occur with other opioid analgesics - avoid concomitant use and for two weeks after stopping MAOIs.
The depressant effects of diamorphine may be exaggerated and prolonged by tricyclic antidepressants, anxiolytics and hypnotics.
Antivirals: Plasma concentration of opioid analgesics (except methadone) is possibly increased by ritinovir.
Opioids potentiate the effects of CNS depressants including tricyclic antidepressants, anxiolytics and hypnotics.
Antipsychotics: enhanced sedative and hypotensive effect.
Antidiarrhoeal and antiperistaltic agents (such as loperamide and kaolin): concurrent use may increase the risk of severe constipation.
Antimuscarinics: The risk of severe constipation and/or urinary retention is increased by administration of antimuscarinic drugs (e.g. atropine).
Motility stimulants: There may be antagonism of the gastrointestinal effects of domperidone and metoclopramide.
Cimetidine inhibits metabolism of opioid analgesics.
Safety has not been established in pregnancy.
Administration during labour may cause respiratory depression in the neonate and gastric stasis during labour, increasing the risk of inhalation pneumonia. Babies born to diamorphine-dependant mothers have been reported to suffer withdrawal symptoms.
Diamorphine should not be given to women who are breast-feeding as there is limited information available on diamorphine in breast milk.
Diamorphine causes drowsiness and mental clouding. If affected patients should not drive or use machines.
The most serious hazard of therapy is respiratory (see also 4.9 Overdose).
The most common side effects are sedation, nausea and vomiting, constipation and sweating. Tolerance generally develops with long-term use, but not to constipation. Other side effects include the following:
Anaphylaxis: Anaphylactic reactions following intravenous injection have been reported rarely.
Cardiovascular: orthostatic hypotension, facial flushing, palpitations, tachycardia, bradycardia.
Central Nervous System: dizziness, vertigo, mental clouding, confusion (with large doses), hallucinations, headache, mood changes including dysphoria and euphoria.
Gastrointestinal: dry mouth, biliary spasm.
Disorders of the eye: blurred or double vision or other changes in vision, miosis.
Sexual dysfunction: long term use may lead to a reversible decrease in libido or potency.
Skin: rash, pruritus, urticaria.
Urinary: urinary retention, difficulty with micturition, ureteric spasm, antidiuretic effect. Tolerance develops to the effects of opioids on the bladder.
The euphoric activity of diamorphine has led to its abuse and physical and psychological dependence may occur (see also 4.4 Special Warnings and Precautions for use).
a) Symptoms
The triad of respiratory depression, coma and constricted pupils is considered indicative of opioid overdosage with dilatation of the pupils occurring as hypoxia develops.
Pulmonary oedema after overdosage is a common cause of fatalities among diamorphine addicts.
Other opioid overdose symptoms include cold, clammy skin, hypotension, bradycardia, circulatory failure, muscle flaccidity, severe weakness, severe nervousness or restlessness, confusion, severe dizziness, severe drowsiness, hallucinations, convulsions (especially in infants and children), rhabdomyolysis progressing to renal failure.
b) Treatment
Respiration and circulation should be maintained and the specific opioid antagonist, naloxone is indicated if coma or bradypnoea are present, using one of the recommended dosage regimens. Oxygen and assisted ventilation should be administered if necessary.
Diamorphine is a narcotic analgesic which acts primarily on the central nervous system and smooth muscle. It is predominantly a central nervous system depressant but it has stimulant actions resulting in nausea, vomiting and miosis.
Diamorphine is a potent opiate analgesic which has a more rapid onset of activity than morphine as the first metabolite, monoacetylmorphine, more readily crosses the blood brain barrier. In man, diamorphine has a half life of two to three minutes. Its first metabolite, monoacetylmorphine, is more slowly hydrolysed in the blood to be concentrated mainly in skeletal muscle, kidney, lung, liver and spleen. Monoacetylmorphine is metabolised to morphine. Morphine forms conjugates with glucuronic acid. The majority of the drug is excreted via the kidney as glucuronides and to a much lesser extent as morphine. About 7-10% is eliminated via the biliary system into the faeces.
Diamorphine does not bind to protein. However, morphine is about 35% bound to human plasma proteins, mainly to albumin. The analgesic effect lasts approximately three to four hours.
There are no additional pre-cliical data of relevance to the prescriber.
Water for Injections (Not detectable in the finished product).
Physical incompatibility has been reported with mineral acids and alkalis and with chlorocresol. Mixtures of diamorphine with cyclizine, haloperidol or dexamethasone may result in precipitation. Mixtures of diamorphine and metoclopramide may become discoloured and should be discarded. Specialised references should be consulted for specific compatibility information.
Three years from date of manufacture
Do not store above 25°C.
Keep container in the outer carton.
5ml Neutral glass ampoules, PhEur. Type 1. Ampoules are packed into cartons of 5, 10 or 50.
The solution should be used immediately after preparation.
Wockhardt UK Limited
Ash Road North
Wrexham
LL13 9UF
UK
PL 29831/0060
27/04/2007
27/04/2007
Treating symptoms of the common cold, flu, or hayfever, and other upper respiratory allergies such as cough, runny nose, sneezing, itching of the nose and throat, and itchy, watery eyes. S-T Forte 2 Liquid may also be used for other conditions as determined by your doctor.
S-T Forte 2 Liquid is a narcotic antitussive (cough suppressant) and antihistamine combination. The antitussive (hydrocodone) works by suppressing the cough center in the brain. The antihistamine (chlorpheniramine) works by blocking the action of histamine, which reduces the symptoms of an allergic reaction such as itch, watery eyes and runny nose.
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with S-T Forte 2 Liquid. 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 S-T Forte 2 Liquid. 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 S-T Forte 2 Liquid 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 S-T Forte 2 Liquid 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 S-T Forte 2 Liquid.
When used for long periods of time or at high doses, S-T Forte 2 Liquid may not work as well and may require higher doses to obtain the same effect as when originally taken. This is known as TOLERANCE. Talk with your doctor if S-T Forte 2 Liquid stops working well. Do not take more than prescribed.
Some people who use S-T Forte 2 Liquid for a long time without a break may develop a physical need to continue taking it. This is known as physical DEPENDENCE. The early sign of addiction is medicine ineffectiveness. Dependence is not an issue in terminal illness where pain relief is more important. If using S-T Forte 2 Liquid for an extended period of time, do not suddenly stop taking S-T Forte 2 Liquid without your doctor's approval. If you suddenly stop taking S-T Forte 2 Liquid, you may experience WITHDRAWAL symptoms, including anxiety; diarrhea; fever; runny nose or sneezing; goose bumps and abnormal skin sensations; nausea and vomiting; pain; rigid muscles; seeing, hearing, or feeling things that are not there; shivering or tremors; sweating; trouble sleeping. Contact your doctor if you notice any of these symptoms after stopping this medication.
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:
Constipation; dizziness; drowsiness; dry mouth, throat, or nose; excitement; nausea; stomach upset; thickening or mucus in nose or throat.
Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); difficulty urinating; flushing or redness of face; rapid or pounding heartbeat.
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: S-T Forte 2 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. Symptoms may include agitation; coma; confusion; deep sleep or loss of consciousness; difficulty breathing; diminished mental alertness; hallucinations; hot or cold skin; large and unchanging pupils; sedation; seizures; shaking; sleeplessness; slowed breathing; slow heartbeat.
Store S-T Forte 2 Liquid at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep S-T Forte 2 Liquid out of the reach of children and away from pets.
This information is a summary only. It does not contain all information about S-T Forte 2 Liquid. 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.
Ferrum Hausmann may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Ferrous Fumarate is reported as an ingredient of Ferrum Hausmann in the following countries:
Iron Dextran is reported as an ingredient of Ferrum Hausmann in the following countries:
Iron Polymaltose is reported as an ingredient of Ferrum Hausmann in the following countries:
International Drug Name Search
Carbolitium may be available in the countries listed below.
Lithium carbonate (a derivative of Lithium) is reported as an ingredient of Carbolitium in the following countries:
International Drug Name Search
DUODOPA intestinal gel
Levodopa 20mg/ml, carbidopa monohydrate 5mg/ml
Duodopa contains a combination of levodopa and carbidopa for treatment of Parkinson’s disease.
Levodopa is transformed in the body to dopamine, a substance present in the brain and in the spinal cord where it assists in the transfer of impulses between the nerve cells. Too little dopamine can give symptoms like those in Parkinson’s disease, e.g. tremor, rigidity, slow movements, difficulty keeping one’s balance. The treatment with levodopa increases the amount of dopamine and hence reduces these symptoms.
Carbidopa is added to improve the effect and reduce the undesirable effects of levodopa.
Duodopa is a gel that is administered with a pump via a tube directly into the duodenum (the first part of the gut). This means that the two active ingredients are supplied continuously in small doses. Consequently, the content of drug in the blood becomes more constant and the risk of symptoms such as movement disorders is reduced.
If you are pregnant or think you may be pregnant, tell your doctor.
You should not breast-feed while under treatment with Duodopa.
Duodopa can cause somnolence (drowsiness) and/or sudden sleep episodes. You should therefore refrain from driving a car or engaging in activities such as operating machines where impaired alertness may put you, or others, at risk of serious injury or death until you are certain that you are not affected in this way.
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, even those which are not prescribed.
It is particularly important for you to tell your doctor if you are already taking iron tablets or certain medicines used for the treatment of depression, schizophrenia, tuberculosis (TB), high blood pressure, tremor (muscle twitches) or epilepsy. Your doctor may wish to change you to a different medicine or adjust the dose of Duodopa.
Always take Duodopa exactly as your doctor has instructed you. You should check with your doctor or pharmacist if you are not sure.
Usually, a larger morning dose is administered with the pump (bolus dose) to quickly reach the correct blood level. After that a lower maintenance dose is given. If needed, extra doses may be given. The dose is different for each patient and may need regular fine-tuning.
Do not change the dosage or discontinue the treatment without consulting your doctor. Abrupt interruption of treatment may result in complications.
If you have taken too large a dose of Duodopa, always contact a doctor or hospital.
Like all medicines, Duodopa can have side effects.
If you experience any of these side effects, contact your doctor as soon as you can. Many of the side effects can be relieved by adjusting the dose.
The following very common complications have been reported for the tube system: dislocation of the intestinal tube to the stomach (which leads to an irregular response to treatment); local infection around the tube through the abdominal wall; and stomach pain. If any problem occurs with the pump or the tube system, please contact your doctor.
If you notice any side effects not mentioned in this leaflet, please inform your doctor or pharmacist.
Do not use Duodopa after the expiry date printed on the carton. Used cassettes should not be re-used but returned to your nearest pharmacy.
Store at 2ºC - 8ºC (in a refrigerator). Duodopa is sensitive to light, so always keep the cassettes in the outer carton, and close it carefully.
The drug cassettes are for single use only and should not be used for longer than one day (up to 16 hours) even if some intestinal gel remains.
Keep Duodopa out of the reach and sight of children.
The active ingredients in Duodopa are levodopa and carbidopa (as monohydrate). The other ingredients are carmellose sodium and purified water. 1 ml of intestinal gel contains 20 mg levodopa and 5 mg carbidopa (as monohydrate). One cassette (100 ml) of Duodopa intestinal gel contains 2000 mg levodopa and 500 mg carbidopa (as monohydrate).
The other ingredients are carmellose sodium and purified water.
and also by
Duodopa is distributed in the UK by
and in Ireland by
This leaflet was last approved in October 2008
DOMPERIDONE 1MG/ML ORAL SUSPENSION
The name of your medicine is Domperidone 1mg/ml Oral Suspension (called domperidone in this leaflet). The active ingredient in this medicine is called domperidone. This belongs to a group of medicines called ‘dopamine antagonists’.
Domperidone works by helping to move food faster through your food pipe (oesophagus), stomach and gut. This is so that it does not stay in the same place for too long. It also helps stop food flowing the wrong way back up your food pipe.
Adults
Children
Do not take domperidone if any of the above applies to you. If you are not sure, talk to your doctor or pharmacist before taking domperidone.
If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking domperidone. Do this even if they have applied in the past.
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This includes medicines you can buy without a prescription, including herbal medicines. This is because domperidone can affect the way some other medicines work. Also, some medicines can affect the way domperidone works.
In particular, tell your doctor if you are taking any of the following:
Talk to your doctor or pharmacist before taking domperidone if:
You may feel sleepy, confused or have less control over your movements while taking domperidone. If this happens, do not drive or use any tools or machines.
This medicine contains sorbitol. If you have been told that you cannot digest or tolerate some sugars, talk to your doctor before taking domperidone.
Always take Domperidone Oral Suspension exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.
The usual dose is:
Your doctor may tell you to take a lower dose or to take the medicine less often.
Your doctor will decide how long you will need to take this medicine.
If you take domperidone for more than 4 weeks your doctor may wish to see you again. This is to check if you need to keep taking the treatment.
Like all medicines, domperidone can have side effects, although not everybody gets them.
Rare (affects less than 1 in 1,000 people)
Very rare (affects less than 1 in 10,000 people)
Talk to your doctor or pharmacist if any of the side effects get serious or last longer than a few days, or if you notice any side effects not listed in this leaflet.
Domperidone 1mg/ml Oral Suspension contains domperidone (the active ingredient). It also contains sorbitol, microcrystalline cellulose and carmellose sodium, methylhydroxybenzoate, propylhydroxybenzoate, sodium saccharin, polysorbate 20, sodium hydroxide and water.
Each pack contains a 200 millilitre bottle of a white coloured liquid suspension.
Marketing Authorisation Holder is:
Manufacturer is:
This leaflet was last revised in: September 2008
‘Winthrop’ is a registered trademark. ©2008 Winthrop Pharmaceuticals.
2020635.06
Doxorubicin Hydrochloride 2 mg/ml solution for infusion
1ml contains 2 mg Doxorubicin hydrochloride.
Each 5ml vial contains a total content of Doxorubicin hydrochloride of 10 mg.
Each 10ml vial contains a total content of Doxorubicin hydrochloride of 20 mg.
Each 25ml vial contains a total content of Doxorubicin hydrochloride of 50 mg.
Each 75ml vial contains a total content of Doxorubicin hydrochloride of 150 mg.
Each 100ml vial contains a total content of Doxorubicin hydrochloride of 200 mg.
The product contains sodium chloride (3.5 mg sodium per 1 ml). For full list of excipients, see section 6.1.
Solution for infusion
The product is a clear, red solution which is practically free of particles.
Antimitotic and cytotoxic. Doxorubicin has been used with success to produce regression in a wide range of neoplastic conditions including acute leukaemia, lymphomas, soft-tissue and osteogenic sarcomas, paediatric malignancies and adult solid tumours, in particular of breast and lung. Doxorubicin can be used in the treatment of non-metastatic transitional cell carcinoma, carcinoma in situ and papillary tumours of the bladder, by intravesical administration.
Doxorubicin is frequently used in combination chemotherapy regimens with other cytostatic drugs.
4.2.1 For intravenous use
The solution is given via the tubing of a freely running intravenous infusion of sodium chloride 0.9 % or dextrose 5 % into a large vein using a Butterfly needle, taking 2 to 3 minutes over the injection. This technique minimises the risk of thrombosis or perivenous extravasation, which can lead to severe local cellulitis and necrosis.
Dosage is usually calculated on the basis of body surface area. On this basis, a dose of 60 - 75 mg/m2 body surface area is recommended every three weeks when doxorubicin is used alone. If using the body weight to calculate the dose, dosages of 1.2 – 2.4 mg/kg are recommended. If it is used in combination with other antitumour agents with overlapping toxicity, such as high-dose i.v. cyclophosphamide or related anthracycline compounds such as daunorubicin, idarubicin and/or epirubicin, the dosage of doxorubicin should be reduced to 30 - 40 mg/m2 every three weeks.
Dividing the dose over three successive days (20 - 25mg/m2 or 0.4 - 0.8mg/kg on each day) gives greater effectiveness at the cost of higher toxicity. Administration of doxorubicin in a weekly regimen has been shown to be as effective as the 32 weekly, although objective responses have been seen at 6 – 12 mg/m2. Weekly administration has been shown to be associated with reduced cardiotoxicity compared with a 3-weekly schedule.
Patients who have received prior radiotherapy to the mediastinal/pericardial area should not receive doxorubicin greater than a total cumulative dose of 400 mg/m2.
Dosage may also need to be reduced in young children and the elderly. It is recommended that the total cumulative dose of doxorubicin for adults aged 70 or older be restricted to 450 mg/m2 body surface area.
4.2.2 For intravesical use
Doxorubicin may be used by intravesical instillation for the treatment of superficial bladder carcinoma after transurethral resection. However, this method is contraindicated in invasive bladder tumours.
The patient should not drink fluids for 12 hours prior to the treatment.
25 ml of the solution, containing 50 mg of doxorubicin hydrochloride, is mixed under sterile conditions with 20 ml normal saline and instilled via catheter into the bladder.
After removal of the catheter, the patient stays lying on his back for 15 minutes.
At 15-minute intervals, the patient makes a quarter turn over a period of 1 hour. At the end of this period, the patient may void.
This procedure can be repeated at monthly intervals.
4.2.3 Impaired hepatic function
If hepatic function is impaired, the dosage should be reduced according to the following table:
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Hypersensitivity to the active substance doxorubicin hydrochloride or to any of the excipients.
Doxorubicin Hydrochloride is contra-indicated in patients with pre-existing myelosuppression (e.g. induced by previous antitumour treatment).
Dosage should not be repeated in the presence or development of bone marrow depression or buccal ulceration. The latter may be preceded by premonitory buccal burning sensations and repetition in the presence of this symptom is not advised.
Doxorubicin Hydrochloride is contraindicated in patients with impaired cardiac function and in patients who have been treated previously with complete cumulative doses of anthracyclines (see section 4.4, Special warnings and precautions for use). In patients who have received anthracyclines previously, addition of further anthracycline therapy can be contemplated only after careful assessment of the cardiac status of the patient. The potential benefit of additional anthracycline therapy must carefully be weighed against the possible risks of cardiotoxicity.
Doxorubicin Hydrochloride is further contraindicated in patients with increased haemorrhagic tendency, stomatitis, generalised infections, markedly impaired liver function and cystitis (in the case of intravesical application).
A cumulative dose of 450 - 500 mg/m2 should only be exceeded with extreme caution. Above this level, the risk of irreversible congestive cardiac failure increases greatly, but this condition could even occur with doses of 240 mg/m2. These effects may occur during infusion, but also several weeks after termination of therapy.
Cardiac failure may not respond to treatment. Early clinical diagnosis of drug-induced heart failure appears to be essential for successful treatment with digitalis, diuretics, low salt diet and bed rest. Severe cardiac toxicity may occur precipitously without antecedent ECG changes. Base line ECG and periodic follow up ECG during and immediately after active drug therapy is an advisable precaution. Transient ECG changes, such as T-wave flattening, S-T depression and arrhythmias are not considered indications for suspension of doxorubicin therapy. A persistent reduction in the voltage of the QRS wave is presently considered more specifically predictive for cardiac toxicity. If this occurs, the benefit of continued therapy must be carefully evaluated against the risk of producing irreversible cardiac damage.
Precaution is also required during simultaneous or previous radiotherapy of the mediastinal/pericardial area or after treatment with other cardiotoxic substances.
Doxorubicin must not be given intrathecally or intramuscularly or by long-term infusion. Direct intravenous infusion is not advised due to the tissue damage that may occur if the infusion infiltrates the tissues. If a central vein catheter is used then infusion of doxorubicin in sodium chloride 0.9% injection is advised.
Local erythematous streaking along the vein as well as facial flushing may be indicative of too rapid administration.
On intravenous administration of doxorubicin, a stinging or burning sensation signifies extravasation. Even if blood return from aspiration of the infusion needle is good, the injection or infusion should be immediately terminated and restarted in another vein. In the event of inadvertent extravasation, ice packs should be applied to the injection site. Local injection of dexamethasone or hydrocortisone may be used to minimise local tissue necrosis. Hydrocortisone cream 1% may also be applied locally.
Careful haematological monitoring is required due to the myelosuppressive effects. Pre-treatment with digoxin (250 μg daily starting 7 days before doxorubicin) showed a protective effect against cardiotoxicity. In cases of hyperuricaemia, an application of xanthinoxidase-blocking drugs may be indicated.
Like all chemotherapy, therapy with doxorubicin hydrochloride should be carried out only under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.
This medicinal product contains 3.5 mg sodium per 1 ml of doxorubicin hydrochloride solution for infusion. This should be taken into consideration by patients on a controlled sodium diet.
Concurrent administration of other antineoplastic agents, e.g.: anthracyclines (daunorubicin, epirubicin, idarubicin), cisplatin, cyclophosphamide, cyclosporin, cytarabine, dacarbazine, dactinomycin, fluorouracil, mitomycin C and taxanes can potentiate the risk of doxorubicin-induced congestive heart failure. The disposition of doxorubicin was found to be significantly altered when it was administered immediately after a short intravenous infusion of paclitaxel. The co-administration of paclitaxel causes a decreased clearance of doxorubicin and more neutropenic and stomatitis episodes have been observed.
Increased cardiotoxicity has also been reported after simultaneous intake of cardioactive drugs, e.g., calcium channel blockers and verapamil (with an increase of doxorubicin peak levels, terminal-half life and volume of distribution). The bioavailibility of digoxin decreases during doxorubicin therapy. Careful monitoring of the heart function is required in all such concomitant therapeutic regimens.
Inhibitors of cytochrome P-450 (e.g. cimetidine) may decrease the metabolism of doxorubicin, with a possible increase in toxic effects, especially in cardiotoxicity. Drugs inducing cytochrome P-450 (e.g. rifampicin, barbiturates including phenobarbital) may increase the metabolism of doxorubicin, possibly decreasing the efficacy of doxorubicin.
If doxorubicin therapy is followed by administration of cyclophosphamide, an increased rate of haemorrhagic cystitis has been reported.
The absorption of antiepileptic drugs (e.g. carbamazepine, phenytoin, valproate) is decreased after concomitant use of doxorubicin.
As doxorubicin is rapidly metabolised and predominantly eliminated by the biliary system, the concomitant administration of known hepatotoxic chemotherapeutic agents (e.g. mercaptopurine, methotrexate, streptozocin) could potentially increase the toxicity of doxorubicin as a result of reduced hepatic clearance of the drug. Dosing of doxorubicin must be modified if concomitant therapy with hepatotoxic drugs is mandatory.
Co-administration of heparin and doxorubicin can lead to an increase in the rate of doxorubicin clearance. Furthermore, precipitates may form and lead to a loss of efficacy of both drugs (see section 6.2, Incompatibilities).
Disturbed haemotopoesis has been observed after co-administration of substances influencing the bone-marrow function (e.g. amidopyrine derivatives, antiretroviral drugs, chloramphenicol, phenytoin, sulphonamides). Increased neutropenia and thrombocytopenia have been reported after simultaneous use of progesterone. Marked nephrotoxicity of Amphotericin B can occur during doxorubicin therapy.
Live vaccines must not be used during doxorubicin therapy due to the risk of generalised disease, which may be lethal. The risk is increased in patients who are immunodepressed due to the underlying disease.
Pregnancy
Doxorubicin has been found in foetal tissue (liver, kidney, lungs) at concentrations several times those in maternal plasma indicating that it does pass the placenta. Doxorubicin proved to be highly teratogenic in rats and mutagenic in the Ames test. Pregnancy is therefore a contraindication for Doxorubicin Hydrochloride.
For safety reasons, men wanting a baby should preserve unexposed sperm prior to treatment with doxorubicin and abstain from engendering a child during and 6 months after therapy. Women with childbearing potential should avoid pregnancy during doxorubicin therapy and 6 months thereafter.
Lactation
The drug has been shown to concentrate in human milk. Because of the potential for serious adverse reactions in nursing infants a decision should be made whether to discontinue breast-feeding or the drug, taking into account the importance of the drug for the woman.
Drowsiness may occur.
4.8.1 General
Bone Marrow Depression (myelosuppression): There is a high incidence of bone marrow depression, primarily of leucocytes, requiring careful haematological monitoring. With the recommended dosage schedule, leukopenia is usually transient, reaching its nadir at 10 – 14 days after treatment, with recovery usually occurring by the 21st day. White blood cell counts as low as 1000/mm3 are to be expected during treatment with ap-propriate doses of doxorubicin. Red blood cell and platelet levels should also be monitored, since they may also be depressed.
Myelosuppression is more common in patients who have had extensive radiotherapy, bone infiltration by tumour, impaired liver function (when appropriate dosage reduction has not been adopted) and simultaneous treatment with other myelosuppressive agents. Haematological toxicity may require dose reduction or suspension or delay of doxorubicin therapy. Persistent severe myelosuppression may result in superinfection or haemorrhage.
Immunosuppression: Doxorubicin is a powerful but temporary immunosuppressant agent. Appropriate measures should be taken to prevent secondary infection.
Enhanced toxicity: It has been reported that doxorubicin may enhance the severity of the toxicity of other anticancer therapies, such as cyclophosphamide induced haemorrhagic cystitis, mucositis induced by radiotherapy, hepatotoxicity of 6
Infertility: Doxorubicin may cause infertility during the time of drug administration. Although ovulation and menstruation appear to return after termination of therapy, there is only scarce information about the restoration of male fertility.
Hepatic impairment: Toxicity to recommended doses of doxorubicin is enhanced by hepatic impairment. It is recommended that an evaluation of hepatic function be carried out prior to individual dosing, using conventional clinical laboratory tests such as AST, ALT, alkaline phosphatase, bilirubin and BSP. If required, dosage schedules should be reduced accordingly (see section 4.2, Posology and method of administration).
The occurrence of secondary acute myeloid leukaemia with or without a pre-leukaemic phase has been reported rarely in patients concurrently treated with doxorubicin in association with DNA damaging antineoplastic agents. Such cases could have a short (1 - 3 year) latency period.
4.8.2 Adverse reactions
4.8.2.1 More frequent reactions
Cardiovascular: Cardiotoxicity, i.e., cardiomyopathy, congestive heart failure, supraventricular tachycardia. Routine ECG monitoring is recommended and caution should be exercised in patients with impaired cardiac function. Severe cardiac failure may occur suddenly, without premonitory ECG changes.
Vascular system: Phlebosclerosis.
Dermatological: Extravasation, skin necrosis, cellulitis, vesication, phlebitis, erythematous streaking along the vein proximal to the site of injection. Alopecia occurs frequently, including the interruption of beard growth, but all hair growth normally returns after treatment is stopped.
The risk of thrombophlebitis at the injection site may be minimised by following the procedure for administration recommended above (see section 4.2, Posology and method of administration).
Gastrointestinal: Nausea and vomiting, mucositis (stomatitis and oesophagitis), diarrhoea, anorexia, ulceration and necrosis of the colon. Mucositis is a frequent and painful complication of doxorubicin treatment. It most commonly develops 5 to 10 days after treatment, and typically begins as a burning sensation in the mouth and pharynx. It may involve the vagina, rectum and oesophagus, and progress to ulceration with risk of secondary infection and usually subsides in 10 days. Retrospective comparison of the incidence of mucositis suggests that it is less frequent as the intervals between doses increase. Mucositis may be severe in patients who have had previous irradiation to the mucosae.
General: Dehydration, facial flushing (if an injection has been given too rapidly). Doxorubicin may impart a red colour to the urine particularly to the first specimen passed after the injection, and patients should be advised that there is no cause for alarm.
4.8.2.2 Less frequent reactions
Dermatological: Urticarial rash, onycholysis, hyperpigmentation of nail beds and dermal increases (primarily in children in a few cases), recall of skin reaction due to prior radiotherapy.
Allergy: Fever, chills, urticaria, anaphylaxis.
Nervous System: Drowsiness.
Ocular: Conjunctivitis, lacrimation.
Renal: Renal damage.
The symptoms of overdosage are likely to be an extension of doxorubicin's pharmacological action. Single doses of 250 mg and 500 mg of doxorubicin have proven to be fatal. Such doses may cause acute myocardial degeneration within 24 hours, and severe myelosuppression, the greatest effects of which are seen between 10 and 15 days after administration. Delayed cardiac failure may occur up to six months after the overdose. Treatment should aim to support the patient during this period. Particular attention should be given to prevention and treatment of possible severe haemorrhage or infections secondary to severe, persistent bone marrow depression. Blood transfusion and reverse barrier nursing may be considered. Hemoperfusion immediately after the overdose proved to be a rescue measure, too.
Delayed cardiac failure may occur up to six month after the overdose. Patients should be observed carefully and, should signs of cardiac failure arise, be treated along conventional lines.
Pharmacotherapeutic group: Cytotoxic agents (anthracyclines and related substances)
ATC code: L01DB01
Doxorubicin is an anthracycline antibiotic. It exerts its antineoplastic effect via cytotoxic mechanisms of action, especially intercalation into DNA, inhibition of the enzyme topoisomerase II, and formation of reactive oxygen species (ROS). All of these have a deleterious effect on DNA synthesis: Intercalation of the doxorubicin molecule leads to an inhibition of RNA and DNA polymerases by way of disturbances in base recognition and sequence specificity. The inhibition of topoisomerase II produces single and double strand breaks of the DNA helix. Scission of DNA also originates from the chemical reaction with highly reactive oxygen species like the hydroxyl radical OH.. Mutagenesis and chromosomal aberrations are the consequences.
The specificity of doxorubicin toxicity appears to be related primarily to proliferative activity of normal tissue. Thus, bone marrow, gastro-intestinal tract and gonads are the main normal tissues damaged.
An important cause of treatment failure with doxorubicin and other anthracyclines is the development of resistance. In an attempt to overcome cellular resistance to doxorubicin, the use of calcium antagonists such as verapamil has been considered since the primary target is the cell membrane. Verapamil inhibits the slow channel of calcium transport and can enhance cellular uptake of doxorubicin. A combination of doxorubicin and verapamil is associated with severe toxic effects in animal experiments.
Following intravenous injection, doxorubicin is rapidly cleared from the blood, and distributed into tissues including lungs, liver, heart, spleen, lymph nodes, bone marrow and kidneys. Relatively low but persistent levels are found in tumour tissue.
Doxorubicin undergoes rapid metabolism in the liver. Doxorubicinol is the most common metabolite, although a substantial fraction of patients forms doxorubicin
The volume of distribution Vd is 25 l; the degree of protein binding is 60–70%. There is substantial interpatient variation in biotransformation. Clearance is apparently not dose-related, but it is higher in men than in women.
Impairment of liver function results in slower excretion, and consequently, increased retention and accumulation in plasma and tissues. Dose reduction is generally advised although there is no clear relationship between liver function tests, doxorubicin clearance and clinical toxicity. Since doxorubicin and metabolites are excreted in the urine only to a minor degree, there are no clear indications that the pharmacokinetics or toxicity of doxorubicin are altered in patients with impaired renal function.
Doxorubicin behaves as a typical inhibitor of cellular reproduction. Cytotoxicity to the most actively proliferating tissues is more prevalent and occurs earlier with respect to parenchymal damage.
5.3.1 Single dose toxicity
Intravenous LD50 values in different animal species have been reported as follows:
Mouse 9 – 21 mg/kg, rat 8 – 14 mg/kg, rabbit 6 mg/kg and dog 2.5 mg/kg. A clear dose-dependent acute toxicity was observed.
5.3.2 Repeated dose toxicity
In clinical practice, the chronic toxicity of doxorubicin is rather similar to that of other comparable cytotoxic substances used in chemotherapy of malignant neoplasms. However, due to its cardiotoxic adverse effects doxorubicin notably warrants special precautions (cf. section 4.8.2.1).
Intravenous doses of 0.125 to 0.5 mg/kg/d were given to rabbits and dogs for 3 months. The lowest dose caused neither mortality nor other signs of toxicity (except for a mild inhibition of spermatogenesis). With the higher doses mortality, hemorrhagic enterocolitis, arrest or reduction of body growth, alopecia and melanosis, total depression of hemopoiesis with particular damage to the platelets, blood coagulation changes, hypoproteinemia, hyperazotemia, morphologic renal damage and depression of spermatogenesis was observed.
5.3.3 Tumorigenicity and mutagenicity
Single i.v. doses of doxorubicin induce mammary tumours in rats. It is also highly potent in producing malignant transformations and mutations in mammalian cell systems in vitro. In the Salmonella/microsome mutagenicity test system (Salmonella typhimurium + rat liver microsome S
Doxorubicin proved to be mutagenic in the standard plate incorporation method of the Ames reversion test. Doxorubicin was also strongly mutagenic against the frameshift-sensitive strain TA98, especially when Cu++ ions were present. In the dominant lethal heritable translocation and morphological specific locus test doxorubicin did not induce dominant lethal mutations in murine male germ cells but did induce dominant lethal mutations in female oocytes. In the cytokinesis-block micronucleus assay, it demonstrated a significant increase in the rate of micronucleated cells and of chromosomal aberrations.
5.3.4 Toxicity to reproduction
With respect to fertility, embryonal and foetal toxicity clinical data in man are incomplete. A termination of pregnancy may not always be mandatory and can only be judged in individual cases. In any case, cardiologic and blood tests in the foetus or newborn child is strongly recommended. The risk of malformations and malfunctions in children is considered to be high. Doxorubicin has been found in foetal tissue (liver, kidney, lungs) at concentrations several times those in maternal plasma indicating that it passes the placenta. Doxorubicin proved to be highly teratogenic in rats and mutagenic in the Ames test. Pregnancy is therefore a contraindication for Doxorubicin Hydrochloride.
In animal experiments, toxic effects of doxorubicin on reproduction were observed. In the rat, doxorubicin is teratogenic after i.p. doses as low as 1.25 mg/kg/day. Characteristic malformations included oesophageal and intestinal atresia, tracheoesophageal fistula, hypoplasia of the urinary bladder and various cardiovascular anomalies. The frequency of anomalies rose sharply as the dose increased. At 2.25 mg/kg/day, all embryos were abnormal, and doxorubicin at 2.5 mg/kg/day led to resorption of all embryos. Teratogenicity in late organogenesis (reduction anomalies of the distal limbs) was also demonstrated in rat embryo cultures in the concentration range of 0.1 – 20 μMol/l.
In another experiment with female Sprague-Dawley rats, treated i.p. 1 - 10 mg/kg doxorubicin, the examination of the embryos revealed specific teratogenic effects on the caudal region. Histological examination showed signs of cell death at the level of the gut epithelium and bronchial bar mesenchyme. In the latter experiment, the highest dose of doxorubicin was maternolethal. The foetuses showed a dose-related increase of specific malformations of the digestive system (oesophageal and intestinal atresia, stomach hypoplasia,), urinary system (bladder agenesis or hypoplasia, hydronephrosis), and cardiovascular malformations.
The doxorubicin-treated foetal rat is an excellent model for studying the so-called VATER association (Vertebral defects, Anorectal anomaly, TracheoEsophageal fistula with oesophageal atresia, and Radial dysplasia). Exposure of the rat foetus produces a spectrum of anomalies, including oesophageal atresia and other features of VATER association. Vertebral and rib anomalies e.g. were found in 54 % and limb anomalies in 35% of foetuses exposed to teratogenic doses of doxorubicin in utero.
In rats decreased weights of genital organs, an extremely decreased sperm count, a low sperm motility, a low implantation rate, a decreased number of spermatogonia and a decreased number of live foetuses were observed after 4 weeks of treatment with doses of 1 or 2 mg/kg. After 9 weeks of treatment, genital organs showed atrophy.
Doxorubicin was not teratogenic in the rabbit when given at i.v. doses up to 0.6 mg/kg/day, but a high incidence of abortion occurred.
In the chicken, doxorubicin is toxic and teratogenic during the period of early organogenesis of the chick embryos after eggs received a single injection on days 1 and 2 of incubation. Doxorubicin caused embryonic death, stunted growth, and various gross morphological malformations. LD50 values were 2.5 μg/egg on day 1 and 0.9 μg/egg on day 2.
5.3.5 Neurotoxicity
In ganglion cells of the peripheral nervous system and in spinal, paravertebral and trigeminal ganglia, loss of neurones was observed in rats after i.v. injections of 10 mg/kg. The animals developed severe posterior limb ataxia and mild ataxia of the forelimbs.
Water for injections
Sodium chloride
Hydrochloric acid (for pH adjustment)
Doxorubicin should not be mixed with heparin as a precipitate may form and it should not be mixed with 5-fluorouracil as degradation may occur. Prolonged contact with any solution of an alkaline pH should be avoided as it will result in hydrolysis of the drug.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Unopened vials: 2 years
Opened vials: The product should be used immediately after opening the vial.
Prepared infusion solutions :
Chemical and physical in-use stability has been demonstrated in sodium chloride 0.9 % and glucose 5 % for up to 48 hours at 2 – 8°C and for up to 24 hours at 25°C when prepared in glass containers protected from light.
From a 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°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.
Store in a refrigerator (2°C - 8°C).
Keep the vial in the outer carton in order to protect from light.
For storage conditions of the reconstituted product see section 6.3.
Colourless glass vials (type I glass) with nominal volumes of 5 ml, 10 ml, 25 ml, 75 ml or 100 ml. Chlorobutyl rubber stoppers with ETFE layer.
Original pack containing 1 vial of 5 ml / 10 ml / 25 ml / 75 ml / 100 ml.
Original pack containing 5 vials of 25 ml each.
Not all pack sizes may be marketed.
For single use only.
Any unused product or waste material should be disposed of in accordance with local requirements.
Observe guidelines for handling cytotoxic drugs.
The following protective recommendations are given due to the toxic nature of this substance:
− Personnel should be trained in good technique for handling.
− Pregnant staff should be excluded from working with this drug.
− Personnel handling doxorubicin should wear protective clothing: goggles, gowns, disposable gloves and masks.
− A designated area should be defined for reconstitution (preferably under a laminar flow system). The work surface should be protected by disposable, plastic-backed and absorbent paper.
− All items used for administration or cleaning, including gloves, should be placed in high risk waste disposal bags for high temperature (700°C) incineration.
− In case of skin contact, thoroughly wash the affected area with soap and water or sodium bicarbonate solution. However, do not graze the skin by using a scrubbing brush.
− In case of contact with eye(s), hold back the eyelid(s) and flush the affected eyes with copious amounts of water for at least 15 minutes. Then seek medical evaluation by a physician.
− Spillage or leakage should be treated with dilute sodium hypochlorite (1 % available chlorine) solution, preferably soaking overnight and then rinse with water.
− All cleaning materials should be disposed of as indicated previously.
− Always wash hands after removing gloves.
hameln pharma plus gmbh
Langes Feld 13
31789 Hameln / GERMANY
PL 25215/0023
01/08/2008
Generic Name: calcium carbonate (KAL see um KAR boe nate)
Brand Names: Alka-Mints, Cal-Gest, Calcarb, Calci Mix, Calci-Chew, Calci-Mix, Calcium Concentrate, Calcium Liquid Softgel, Calcium Oyster Shell, Caltrate, Chooz, Extra Strength Mylanta Calci Tabs, Icar Prenatal Chewable Calcium, Maalox Antacid Barrier, Maalox Childrens', Maalox Quick Dissolve, Maalox Quick Dissolve Maximum Strength, Maalox Regular Strength, Mylanta Child, Nephro Calci, Os-Cal 500, Oysco 500, Oyst Cal 500, Oyster Cal, Oyster Calcium, Oyster Shell, Pepto Children's, Rolaids Sodium Free, Rolaids Soft Chew, Titralac, Tums, Tums 500, Tums E-X, Tums Kids, Tums QuikPak, Tums Ultra
Calcium is a mineral that is found naturally in foods. Calcium is necessary for many normal functions of the body, especially bone formation and maintenance. Calcium can also bind to other minerals (such as phosphate) and aid in their removal from the body.
Calcium carbonate is used to prevent and to treat calcium deficiencies.
Calcium carbonate may also be used for purposes not listed in this medication guide.
To make sure you can safely take calcium carbonate, tell your doctor if you have any of these other conditions:
a history of kidney stones; or
a parathyroid gland disorder.
Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended.
The chewable tablet should be chewed before you swallow it.
Use the calcium carbonate powder as directed. Allow the powder to dissolve completely, then consume the mixture.
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.
Overdose symptoms may include nausea, vomiting, decreased appetite, constipation, confusion, delirium, stupor, and coma.
Follow your healthcare provider's instructions about any restrictions on food, beverages, or activity.
Less serious side effects may include:
nausea or vomiting;
decreased appetite;
constipation;
dry mouth or increased thirst; or
urinating more than usual.
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.
Calcium carbonate can make it harder for your body to absorb other medications you take by mouth. Tell your doctor if you are taking:
digoxin (Lanoxin, Lanoxicaps);
antacids or other calcium supplements;
calcitriol (Rocaltrol) or vitamin D supplements; or
doxycycline (Adoxa, Doryx, Oracea, Vibramycin), minocycline (Dynacin, Minocin, Solodyn, Vectrin), or tetracycline (Brodspec, Panmycin, Sumycin, Tetracap).
This list is not complete and other drugs may interact with calcium carbonate. 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.
See also: Alka-Mints side effects (in more detail)
