Miacalcic 50 IU / ml and 100 IU / ml Ampoules and 400 IU / 2ml Solution for Injection and Infusion

Miacalcic 50 IU/1 ml,

Miacalcic 100 IU/1 ml,

Miacalcic 400 IU/2 ml Solution for Injection and Infusion

Calcitonin (salmon, synthetic)

This medicine will usually be referred to just as Miacalcic in this leaflet.

Read all of this leaflet carefully before you start treatment with this medicine.

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


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


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


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

In this leaflet:

• 1. What Miacalcic is and what it is used for


• 2. Before you take Miacalcic


• 3. How to take Miacalcic


• 4. Possible side effects


• 5. How to store Miacalcic


• 6. Further information

What Miacalcic Is And What It Is Used For

Miacalcic contains the active substance calcitonin (salmon, synthetic).

Calcitonin is a hormone that occurs naturally in the body of both humans and animals. It regulates the level of calcium in the blood. Calcitonin is used to reverse bone loss and may also help in bone formation.

Miacalcic can be given for the following conditions:

• Prevention of bone loss in patients who have suddenly become immobile. For example patients who have osteoporosis (thin and weak bones) and are bed-bound because of a fracture.


• Paget’s disease of bone: A slowly progressing illness which can cause a change in the size and shape of certain bones.


• Treatment of high levels of calcium in the blood (hypercalcemia) due to cancer.

Before You Take Miacalcic

Do not take Miacalcic

• if you are allergic (hypersensitive) to calcitonin (salmon, synthetic) or any of the other ingredients of Miacalcic;


• if you have a very low calcium level in your blood (hypocalcaemia).

Take special care with Miacalcic

Before treatment with Miacalcic tell your doctor if you think you may be allergic to calcitonin (salmon, synthetic). Your doctor will perform a skin test before you start taking Miacalcic.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

It is particularly important to tell your doctor if you are taking medicines:

• used to treat heart problems (e.g. digoxin) or high blood pressure (e.g. amlodipine, diltiazem);


• containing lithium, as the dose of lithium may need to be changed;


• containing bisphosphonate (used to treat osteoporosis).

Children and adolescents (age under 18 years)

Use of Miacalcic is not recommended in patients under 18 years of age.

Older people

Miacalcic can be used by older people without any specific requirements.

Pregnancy and breast-feeding

Miacalcic should not be used by pregnant and breast-feeding women.

If you are, or think you may be pregnant, ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Miacalcic may cause tiredness, dizziness and disturbed vision which could impair your reactions. If this happens to you, do not drive or use any machines.

Important information about some of the ingredients of Miacalcic

The solution contained in Miacalcic ampoules contains less than 23 mg sodium per 1 ml and can therefore be considered as sodium-free.

How To Take Miacalcic

Always take Miacalcic exactly as your doctor has told you. You should check with your doctor, nurse or pharmacist if you are not sure. It is advisable to administer the medication at bedtime in order to reduce the occurrence of nausea (feeling sick) or vomiting (being sick) which may occur especially at the beginning of the therapy.

Do not exceed the recommended dosage. Do not take Miacalcic if you notice that the solution is not clear and colourless. Do not change the dose or stop treatment without first talking to your doctor.

Miacalcic is usually given by injection either into the tissue just under the skin (subcutaneous injection) or into a muscle (intramuscular injection). Occasionally, the injection is given by a slow infusion into a vein (slow intravenous infusion).

If you will be giving yourself subcutaneous injections, make sure you understand exactly how to prepare and give them. Your doctor or nurse will give you precise instructions. Do not inject yourself unless you are confident of your ability to do so.

You should not use the injection or infusion straight from the fridge. Let it reach room temperature naturally first. The ampoules should be used immediately after opening. Excess amount of Miacalcic should be discharged.

The dosage to be used depends on your condition and response to the medicine. Your doctor will tell you exactly how much Miacalcic you should take.

The usual doses are:

• 
  For prevention of bone loss: 100 IU per day or 50 IU twice daily for 2 to 4 weeks, given into the muscle or the tissue just under the skin.


• 
  For Paget’s disease: 100 IU daily injected into a muscle or into the tissue just under the skin.


• 
  For the treatment of high calcium levels: 100 IU every 6 to 8 hours, given into a
  muscle or into the tissue just under the skin. In some cases, it may be given by injection into a vein.

If you inject more Miacalcic than you should

If you accidentally inject too much Miacalcic, contact your doctor immediately. You may require medical attention.

If you forget to inject Miacalcic

If you forget to inject yourself a dose, give it as soon as you remember it unless it is less than 4 hours until your next dose is due. In that case, wait and inject your next dose at the usual time. Do not inject a double dose to make up for a forgotten one.

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

Possible Side Effects

Like all medicines, Miacalcic can cause side effects, although not everybody gets them. The most frequently observed side effects are nausea, vomiting and redness of the face/neck.

Some side effects could be serious:

• Increased heartbeat, nettle rash (hives), difficulty breathing, swelling of the tongue and throat, tightness in your chest, a sudden fall in blood pressure or shock. These may be signs of a severe allergic reaction (anaphylaxis) and are very rare.


• Swelling of your face, limbs or entire body (uncommon).

If you experience any of these, contact a doctor immediately.

Other side effects:

Very common side effects (affecting more than 1 in 10 patients):

• Feeling sick with or without being sick. These are less frequent when the injection is done in the evening and after meals.


• Sudden waves of redness of the face and/or neck, usually observed 10 to 20 minutes after injection.

Common side effects (affecting less than 1 in 10 patients):

• diarrhoea, stomach pain,


• tiredness,


• pain in bone, joints or muscles


• dizziness,


• headache,


• changes in the way things taste

Uncommon side effects (affecting less than 1 in 100 patients):

• high blood pressure (hypertension),


• flu-like symptoms,


• redness and swelling at the injection site, skin rash, itching


• disturbed vision


• frequent need to pass water,


• allergic reactions

Rare side effects (affecting less than 1 in 1,000 patients):

Calcium levels in your blood can fall 4 to 6 hours after dose administration, it is unlikely that you notice any symptoms because of this.

In rare cases, the effectiveness of Miacalcic may be reduced.

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

How To Store Miacalcic

Keep out of the reach and sight of children.

Do not use Miacalcic after the expiry date which is stated on the label after “exp”. The expiry date refers to the last day of that month.

The unopened ampoules and vials should be stored in a refrigerator (2-8°C). Do not freeze.

The ampoules should be used immediately after opening. If you do not use the whole of the ampoule, DO NOT keep the remainder.

Once the vial has been opened it can be kept at room temperature (not above 25°C) for up to one month. If there is anything left afterwards throw it away.

For infusion, use Miacalcic immediately after dilution in 0.9% w/v sodium chloride in soft PVC bags.

Do not take Miacalcic if you notice that the solution is not clear and colourless.

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

Further Information

What Miacalcic contains

Miacalcic is available in three different strengths.

It comes in ampoules containing 1 ml of solution containing either 50 or 100 IU of the active ingredient, calcitonin (salmon, synthetic). These are for single use only. The solution also contains acetic acid, sodium acetate trihydrate, sodium chloride and water for injections.

It also comes as a vial containing 2 ml of solution containing 400 IU of calcitonin (salmon, synthetic). The vials can be used more than once. The solution also contains acetic acid, sodium acetate trihydrate, sodium chloride, water for injections and the preservative, phenol.

One IU (International Unit) corresponds to 0.167 micrograms calcitonin (salmon, synthetic).

What Miacalcic looks like and contents of the pack

Miacalcic is a solution for injection and infusion.

Miacalcic ampoules are made of uncoloured glass that contain 1 ml of clear, colourless solution for injection and infusion.

Packs of 5, 10, 50 and 100 ampoules are registered. Some of these may not be available.

Miacalcic vials are made of clear glass and contain 2 ml of clear, colourless solution for injection and infusion.

Each Miacalcic pack contains one vial.

The product licence holder is

Novartis Pharmaceuticals UK Ltd

Trading as Sandoz Pharmaceuticals

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

England

The manufacturer responsible for release on to the market is

Novartis Pharmaceuticals UK Ltd

Wimblehurst Road

Horsham

West Sussex

RH12 5AB

England

This leaflet was approved in July 2009.

If you would like any more information, or would like the leaflet in a different format, please contact Medical Information at Novartis Pharmaceuticals UK Ltd, tel. 01276 698370.

MIACALCIC is a registered Trade Mark

Copyright Novartis Pharmaceuticals UK Ltd

Alkeran injection 50 mg (Laboratories Genopharm)

1. Name Of The Medicinal Product

Alkeran 50 mg Injection

2. Qualitative And Quantitative Composition

Melphalan Hydrochloride BP equivalent to 50 mg mephalan per vial.

3. Pharmaceutical Form

Freeze-dried powder for injection.

4. Clinical Particulars

4.1 Therapeutic Indications

Alkeran Injection, at conventional intravenous dosage, is indicated in the treatment of multiple myeloma and ovarian cancer.

Alkeran Injection, at high intravenous dosage, is indicated, with or without haematopoietic stem cell transplantation, for the treatment of multiple myeloma and childhood neuroblastoma.

Alkeran Injection, administered by regional arterial perfusion, is indicated in the treatment of localised malignant melanoma of the extremities and localised soft tissue sarcoma of the extremities.

In the above indications, Alkeran may be used alone or in combination with other cytotoxic drugs.

4.2 Posology And Method Of Administration

Parenteral administration:

Alkeran Injection is for intravenous use and regional arterial perfusion only. Alkeran Injection should not be given without haematopoietic stem cell rescue at doses of above 140 mg/m².

For intravenous administration, it is recommended that Alkeran Injection solution is injected slowly into a fast-running infusion solution via a swabbed injection port.

If direct injection into a fast-running infusion is not appropriate, Alkeran Injection solution may be administered diluted in an infusion bag.

Alkeran is not compatible with infusion solutions containing dextrose and it is recommended that only sodium chloride intravenous infusion 0.9% w/v is used.

When further diluted in an infusion solution, Alkeran has reduced stability and the rate of degradation increases rapidly with rise in temperature. If Alkeran is infused at a room temperature of approximately 25°C, the total time from preparation of the injection solution to the completion of infusion should not exceed 1.5 hours.

Should any visible turbidity or crystallisation appear in the reconstituted or diluted solutions, the preparation must be discarded.

Care should be taken to avoid possible extravasation of Alkeran and in cases of poor peripheral venous access, consideration should be given to use of a central venous line.

If high dose Alkeran Injection is administered with or without autologous bone marrow transplantation, administration via a central venous line is recommended.

For regional arterial perfusion, the literature should be consulted for detailed methodology.

Multiple myeloma: Alkeran Injection is administered on an intermittent basis alone, or in combination with other cytotoxic drugs. Administration of prednisone has also been included in a number of regimens.

When used as a single agent, a typical intravenous Alkeran dosage schedule is 0.4 mg/kg body weight (16 mg/m² body surface area) repeated at appropriate intervals (e.g. once every 4 weeks), provided there has been recovery of the peripheral blood count during this period.

High-dose regimens generally employ single intravenous doses of between 100 and 200 mg/m² body surface area (approximately 2.5 to 5.0 mg/kg body weight), but haematopoietic stem cell rescue becomes essential following doses in excess of 140 mg/m² body surface area. Hydration and forced diuresis are also recommended.

Ovarian adenocarcinoma: When used intravenously as a single agent, a dose of 1 mg/kg body weight (approximately 40 mg/m² body surface area) given at intervals of 4 weeks has often been used.

When combined with other cytotoxic drugs, intravenous doses of between 0.3 and 0.4 mg/kg body weight (12 to 16 mg/m² body surface area) have been used at intervals of 4 to 6 weeks.

Advanced neuroblastoma: Doses of between 100 and 240 mg/m² body surface area (sometimes divided equally over 3 consecutive days) together with haematopoietic stem cell rescue, have been used either alone or in combination with radiotherapy and/or other cytotoxic drugs.

Malignant melanoma: Hyperthermic regional perfusion with Alkeran has been used as an adjuvant to surgery for early malignant melanoma and as palliative treatment for advanced but localised disease. The scientific literature should be consulted for details of perfusion technique and dosage used. A typical dose range for upper extremity perfusions is 0.6-1.0 mg/kg bodyweight and for lower extremity perfusions is 0.8-1.5 mg/kg body weight.

Soft tissue sarcoma: Hyperthermic regional perfusion with Alkeran has been used in the management of all stages of localised soft tissue sarcoma, usually in combination with surgery. A typical dose range for upper extremity perfusions is 0.6-1.0 mg/kg body weight and for lower extremity perfusions is 1-1.4 mg/kg body weight.

Use in Children

Alkeran, at conventional dosage, is only rarely indicated in children and dosage guidelines cannot be stated.

High dose Alkeran Injection, in association with haematopoietic stem cell rescue, has been used in childhood neuroblastoma and dosage guidelines based on body surface area, as for adults, may be used.

Use in the elderly

Although Alkeran is frequently used at conventional dosage in the elderly, there is no specific information available relating to its administration to this patient sub-group.

Experience in the use of high dose Alkeran in elderly patients is limited. Consideration should therefore be given to ensure adequate performance status and organ function, before using high dose Alkeran Injection in elderly patients.

Dosage in renal impairment

Alkeran clearance, though variable, may be decreased in renal impairment.

Currently available pharmacokinetic data do not justify an absolute recommendation on dosage reduction when administering Alkeran Tablets to patients with renal impairment, but it may be prudent to use a reduced dosage initially until tolerance is established.

When Alkeran Injection is used at conventional intravenous dosage (16-40 mg/m² body surface area), it is recommended that the initial dose should be reduced by 50% and subsequent dosage determined according to the degree of haematological suppression.

For high intravenous doses of Alkeran (100 to 240 mg/m² body surface area), the need for dose reduction depends upon the degree of renal impairment, whether haematopoietic stem cells are re-infused, and therapeutic need. Alkeran Injection should not be given without haematopoietic stem cell rescue at doses of above 140 mg/m².

As a guide, for high dose Alkeran treatment without haematopoietic stem cell rescue in patients with moderate renal impairment (creatinine clearance 30 to 50 ml/min) a dose reduction of 50% is usual. High dose Alkeran (above 140 mg/m²) without haematopoietic stem cell rescue should not be used in patients with more severe renal impairment.

High dose Alkeran with haematopoietic stem cell rescue has been used successfully even in dialysis dependent patients with end-stage renal failure. The relevant literature should be consulted for details.

4.3 Contraindications

Alkeran should not be given to patients who have suffered a previous hypersensitivity reaction to melphalan.

4.4 Special Warnings And Precautions For Use

Alkeran is a cytotoxic drug, which falls into the general class of alkylating agents. It should be prescribed only by physicians experienced in the management of malignant disease with such agents. As with all high dose chemotherapy, precautions should be taken to prevent tumour lysis syndrome.

Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended.

Since Alkeran is myelosuppressive, frequent blood counts are essential during therapy and the dosage should be delayed or adjusted if necessary.

Alkeran Injection solution can cause local tissue damage, should extravasation occur and consequently, it should not be administered by direct injection into a peripheral vein. It is recommended that Alkeran Injection solution is administered by injecting slowly into a fast-running intravenous infusion via a swabbed injection port, or via a central venous line.

In view of the hazards involved and the level of supportive care required, the administration of high dose Alkeran Injection should be confined to specialist centres, with the appropriate facilities and only be conducted by experienced clinicians.

In patients receiving high dose Alkeran Injection, consideration should be given to the prophylactic administration of anti-infective agents and the administration of blood products as required.

Consideration should be given to ensure adequate performance status and organ function before using high dose Alkeran Injection. Alkeran Injection should not be given without haematopoietic stem cell rescue at doses of above 140 mg/m².

As with all cytotoxic chemotherapy, adequate contraceptive precautions should be practised when either partner is receiving Alkeran.

Safe handling of Alkeran

The handling of Alkeran formulations should follow guidelines for the handling of cytotoxic drugs according to the Royal Pharmaceutical Society of Great Britain Working Party on the handling of cytotoxic drugs.

Monitoring

Since Alkeran is a potent myelosuppressive agent, it is essential that careful attention should be paid to the monitoring of blood counts, to avoid the possibility of excessive myelosuppression and the risk of irreversible bone marrow aplasia. Blood counts may continue to fall after treatment is stopped, so at the first sign of an abnormally large fall in leukocyte or platelet counts, treatment should be temporarily interrupted. Alkeran should be used with caution in patients who have undergone recent radiotherapy or chemotherapy in view of increased bone marrow toxicity.

Renal Impairment

Alkeran clearance may be reduced in patients with renal impairment who may also have uraemic marrow suppression. Dose reduction may therefore be necessary (see Posology and Method of Administration). See Undesirable Effects for elevation of blood urea.

Mutagenicity

Melphalan is mutagenic in animals and chromosome aberrations have been observed in patients being treated with the drug.

Carcinogenicity

Melphalan, in common with other alkylating agents, has been reported to be leukaemogenic. There have been reports of acute leukaemia occurring after melphalan treatment for diseases such as amyloid, malignant melanoma, multiple myeloma, macroglobulinaemia, cold agglutinin syndrome and ovarian cancer.

A comparison of patients with ovarian cancer who received alkylating agents with those who did not, showed that the use of alkylating agents, including melphalan, significantly increased the incidence of acute leukaemia.

The leukaemogenic risk must be balanced against the potential therapeutic benefit when considering the use of melphalan.

Effects on Fertility

Alkeran causes suppression of ovarian function in premenopausal women resulting in amenorrhoea in a significant number of patients.

There is evidence from some animal studies that Alkeran can have an adverse effect on spermatogenesis. Therefore, it is possible that Alkeran may cause temporary or permanent sterility in male patients.

The label for the product will contain the following statements:

Keep out of the reach of children.

Store below 30° C

Do not refrigerate.

Protect from light

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see Warnings and Precautions).

Nalidixic acid together with high-dose intravenous melphalan has caused deaths in children due to haemorrhagic entercolitis.

Impaired renal function has been described in bone marrow transplant patients who received high dose intravenous melphalan and who subsequently received ciclosporin to prevent graft-versus-host disease.

4.6 Pregnancy And Lactation

The teratogenic potential of Alkeran has not been studied. In view of its mutagenic properties and structural similarity to known teratogenic compounds, it is possible that melphalan could cause congenital defects in the offspring of patients treated with the drug.

The use of melphalan should be avoided whenever possible during pregnancy, particularly during the first trimester. In any individual case, the potential hazard to the foetus must be balanced against the expected benefit to the mother.

Mothers receiving Alkeran should not breastfeed.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

For this product there is no modern clinical documentation which can be used as support for determining the frequency of undesirable effects. Undesirable effects may vary in their incidence depending on the indication and dose received and also when given in combination with other therapeutic agents.

The following convention has been utilised for the classification of frequency:- Very common

Blood and Lymphatic System Disorders
Very common:	bone marrow depression leading to leucopenia, thrombocytopenia and anaemia
Rare:	haemolytic anaemia
Immune System Disorders
Rare:	allergic reactions (see Skin and Subcutaneous Tissue Disorders)

Allergic reactions to melphalan such as urticaria, oedema, skin rashes and anaphylactic shock have been reported uncommonly following initial or subsequent dosing, particularly after intravenous administration. Cardiac arrest has also been reported rarely in association with such events.

Respiratory, Thoracic and Mediastinal Disorders
Rare:	interstitial pneumonitis and pulmonary fibrosis (including fatal reports)
Gastrointestinal Disorders
Very common:	nausea, vomiting and diarrhoea; stomatitis at high dose
Rare:	stomatitis at conventional dose

The incidence of diarrhoea, vomiting and stomatitis becomes the dose-limiting toxicity in patients given high intravenous doses of melphalan in association with autologous bone marrow transplantation. Cyclophosphamide pretreatment appears to reduce the severity of gastro-intestinal damage induced by high-dose melphalan and the literature should be consulted for details.

Hepatobiliary Disorders
Rare:	hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice; veno-occlusive disease following high dose treatment
Skin and Subcutaneous Tissue Disorders
Very common:	alopecia at high dose
Common:	alopecia at conventional dose
Rare:	maculopapular rashes and pruritus (see Immune System Disorders)
Musculoskeletal and Connective Tissue Disorders
Injection, following isolated limb perfusion:
Very common:	muscle atrophy, muscle fibrosis, myalgia, blood creatine phosphokinase increased.
Common:	compartment syndrome
Not known:	muscle necrosis, rhabdomyolysis
Renal and Urinary Disorders
Common:	temporary significant elevation of the blood urea has been seen in the early stages of melphalan therapy in myeloma patients with renal damage
General Disorders and Administration Site Conditions
Very common:	subjective and transient sensation of warmth and/or tingling

4.9 Overdose

Gastro-intestinal effects, including nausea, vomiting and diarrhoea are the most likely signs of acute oral overdosage. The immediate effects of acute intravenous overdosage are nausea and vomiting. Damage to the gastro-intestinal mucosa may also ensue and diarrhoea, sometimes haemorrhagic, has been reported after overdosage. The principal toxic effect is bone marrow suppression, leading to leucopenia, thrombocytopenia and anaemia.

General supportive measures, together with appropriate blood and platelet transfusions, should be instituted if necessary and consideration given to hospitalisation, antibiotic cover, the use of haematological growth factors.

There is no specific antidote. The blood picture should be closely monitored for at least four weeks following overdosage until there is evidence of recovery.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Melphalan is a bifunctional alkylating agent. Formation of carbonium intermediates from each of the two bis-2-chloroethyl groups enables alkylation through covalent binding with the 7-nitrogen of guanine on DNA, cross-linking the two DNA strands and thereby preventing cell replication.

5.2 Pharmacokinetic Properties

Absorption

The absorption of oral melphalan is highly variable with respect to both the time to first appearance of the drug in plasma and peak plasma concentration.

In studies of the absolute bioavailability of melphalan the mean absolute bioavailability ranged from 56 to 85%.

Intravenous administration can be used to avoid variability in absorption associated with myeloablative treatment.

Distribution

Melphalan is moderately bound to plasma proteins with reported percent binding ranging from 69% to 78%. There is evidence that the protein binding is linear in the range of plasma concentrations usually achieved in standard dose therapy, but that the binding may become concentration-dependent at the concentrations observed in high-dose therapy. Serum albumin is the major binding protein, accounting for about 55 to 60% the binding, and 20% is bound to α₁-acid glycoprotein. In addition, melphalan binding studies have revealed the existence of an irreversible component attributable to the alkylation reaction with plasma proteins.

Following administration of a two-minute infusion of doses ranging from 5 to 23 mg/m² body surface area (approximately 0.1 to 0.6 mg/kg bodyweight) to 10 patients with ovarian cancer or multiple myeloma, the mean volumes of distribution at steady state and central compartment were 29.1 ± 13.6 litres and 12.2 ± 6.5 litres, respectively.

In 28 patients with various malignancies who were given doses of between 70 and 200 mg/m² body surface area as a 2- to 20-min infusion, the mean volumes of distribution at steady state and central compartment were, respectively, 40.2 ± 18.3 litres and 18.2 ± 11.7 litres.

Melphalan displays limited penetration of the blood-brain barrier. Several investigators have sampled cerebrospinal fluid and found no measurable drug. Low concentrations (~10% of that in plasma) were observed in a single high-dose study in children.

Metabolism

In vivo and in vitro data suggest that spontaneous degradation rather than enzymatic metabolism is the major determinant of the drug's half-life in man.

Elimination

In 13 patients given oral melphalan at 0.6 mg/kg bodyweight, the plasma mean terminal elimination half-life was 90 ± 57 min with 11% of the drug being recovered in the urine over 24 h.

In 8 patients given a single bolus dose of 0.5 to 0.6 mg/kg bodyweight, the composite initial and terminal half-lives were reported to be 7.7 ± 3.3 min and 108 ± 20.8 min, respectively. Following injection of melphalan, monohydroxymelphalan and dihydroxymelphalan were detected in the patients' plasma, reaching peak levels at approximately 60 min and 105 min, respectively. A similar half-life of 126 ± 6 min was seen when melphalan was added to the patients' serum in vitro (37C), suggesting that spontaneous degradation rather than enzymic metabolism may be the major determinant of the drug's half-life in man.

Following administration of a two-minute infusion of doses ranging from 5 to 23 mg/m² body surface area (approximately 0.1 to 0.6 mg/kg bodyweight) to 10 patients with ovarian cancer or multiple myeloma, the pooled initial and terminal half-lives were, respectively, 8.1 ± 6.6 min and 76.9 ± 40.7 min. A mean clearance of 342.7 ± 96.8 ml/min was recorded.

In 15 children and 11 adults given high-dose i.v. melphalan (140 mg/m² body surface area) with forced diuresis, the mean initial and terminal half-lives were found to be 6.5 ± 3.6 min and 41.4 ± 16.5 min, respectively. Mean initial and terminal half-lives of 8.8 ± 6.6 min and 73.1 ± 45.9 min, respectively, were recorded in 28 patients with various malignancies who were given doses of between 70 and 200 mg/m² body surface area as a 2- to 20-min infusion. The mean clearance was 564.6 ± 159.1 ml/min.

Following hyperthermic (39C) perfusion of the lower limb with 1.75 mg/kg bodyweight, mean initial and terminal half-lives of 3.6 ± 1.5 min and 46.5 ± 17.2 min, respectively, were recorded in 11 patients with advanced malignant melanoma. A mean clearance of 55.0 ± 9.4 ml/min was recorded.

Special Patient Populations

• Renal impairment

Melphalan clearance may be decreased in renal impairment (see Dosage and Administration - Renal impairment and Warnings and Precautions - Renal impairment).

• Elderly

No correlation has been shown between age and melphalan clearance or with melphalan terminal elimination half-life (see Dosage and Administration).

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SmPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Hydrochloric Acid Ph.Eur.

Povidone K12 Ph.Eur.

Water for Injections BP

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Store below 30° C

Protect from light

Do not refrigerate.

6.5 Nature And Contents Of Container

Clear, neutral glass vial and bromobutyl rubber stopper with an aluminium collar.

Pack size: 50 mg

6.6 Special Precautions For Disposal And Other Handling

Preparation of Alkeran Injection Solution:

Alkeran Injection should be prepared at room temperature (approximately 25°C), by reconstituting the freeze-dried powder with the solvent-diluent provided.

It is important that both the freeze-dried powder and the solvent provided are at room temperature before starting reconstitution. Warming the diluent in the hand may aid reconstitution. 10 ml of this vehicle should be added quickly, as a single quantity into the vial containing the freeze dried powder, and immediately shaken vigorously (for approximately 1 minute) until a clear solution, without visible particles, is obtained. Each vial must be reconstituted individually in this manner. The resulting solution contains the equivalent of 5 mg per ml anhydrous melphalan and has a pH of approximately 6.5.

Alkeran Injection solution has limited stability and should be prepared immediately before use. Any solution unused after one hour should be discarded according to standard guidelines for handling and disposal of cytotoxic drugs.

The reconstituted solution should not be refrigerated as this will cause precipitation.

7. Marketing Authorisation Holder

Laboratoires GENOPHARM

ZI de l'Esplanade

2, rue Niels Bohr

F – 77400 Saint-Thibault-des-Vignes

8. Marketing Authorisation Number(S)

PL 26946/0001

9. Date Of First Authorisation/Renewal Of The Authorisation

18 January 2004

10. Date Of Revision Of The Text

September 2010

11 LEGAL STATUS

POM

Warfarin Sodium

Class: Coumarin Derivatives
CAS Number: 129-06-6
Brands: Coumadin

Special Alerts:

[Posted 08/16/2007] FDA approved updated labeling to include pharmacogenomics information to the CLINICAL PHARMACOLOGY, PRECAUTIONS, and DOSAGE AND ADMINISTRATION sections of the prescribing information for the widely used blood-thinning drug, warfarin (Coumadin). This new information explains that people’s genetic makeup may influence how they respond to the drug. Specifically, people with variations in two genes may need lower warfarin doses than people without these genetic variations. The two genes are called CYP2C9 and VKORC1. The CYP2C9 gene is involved in the breakdown (metabolism) of warfarin and the VKORC1 gene helps regulate the ability of warfarin to prevent blood from clotting.

The dosage and administration of warfarin must be individualized for each patient according to the particular patient’s prothrombin time (PT) / International Normalized Ratio (INR) response to the drug. The specific dose recommendations are described in the warfarin product labeling, along with the new information regarding the impact of genetic information upon the initial dose and the response to warfarin. Ongoing warfarin therapy should be guided by continued INR monitoring. For more information visit the FDA website at: .

[Posted 10/06/2006] FDA and Bristol-Myers Squibb notified pharmacists and physicians of revisions to the labeling for warfarin (Coumadin), to include a new patient Medication Guide as well as a reorganization and highlighting of the current safety information to better inform providers and patients.

The FDA regulation 21CFR 208 requires a Medication Guide to be provided with each prescription that is dispensed for products that FDA determines pose a serious and significant public health concern. Information about all currently approved Medication Guides is available at: . For more information visit the FDA website at: , and .

Introduction

Anticoagulant; a coumarin derivative.²¹¹

Uses for Warfarin Sodium

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Treatment/Secondary Prevention of Venous Thrombosis and Pulmonary Embolism

Used as follow-up to initial heparin anticoagulation for treatment of proximal DVT or nonmassive acute pulmonary embolism; initiate concomitantly with full-dose IV or adjusted-dose sub-Q unfractionated heparin or a weight-based dosage of sub-Q low molecular weight (LMW) heparin.^{365 407 427 446} May consider thrombolytic therapy in those with massive pulmonary embolism with hemodynamic instability or severe ileofemoral thrombosis.^{332 427}

LMW heparin or sub-Q unfractionated heparin used as alternative therapy for secondary prevention of DVT and pulmonary embolism when warfarin is contraindicated or inconvenient.^{429 446}

Secondary prevention of DVT and pulmonary embolism in patients with concurrent cancer; LMW heparin preferred in such patients.⁴²⁷

Secondary prevention of venous thromboembolism or pulmonary embolism associated with reversible or time-limited risk factors (e.g., transient immobilization, trauma, surgery, pharmacologic doses of estrogen, central venous catheter).^{365 437 446}

Secondary prevention of venous thromboembolism associated with thrombophilic conditions (e.g., combined factor V Leiden and prothrombin 20210 gene mutations).^{427 429}

Secondary prevention of venous thromboembolism in children with ongoing risk factors such as active nephrotic syndrome, ongoing asparaginase therapy, or lupus anticoagulant.⁴⁴⁶

Prophylaxis in General Surgery

American College of Chest Physicians (ACCP) prefers other drug therapies (LMW heparin or low-dose unfractionated heparin) or non-drug therapies (intermittent pneumatic compression, elastic stockings) in most moderate- to high-risk general surgery patients†.^{333 366 430}

Prophylaxis in Hip-Replacement Surgery

Short-term prophylaxis in patients undergoing hip-replacement surgery as one of several therapeutic options (fondaparinux, LMW heparin).^{366 430 200 208 333 366 430}

Consider extended prophylaxis (≤28–35 days) in patients undergoing hip-replacement surgery who have ongoing risk factors for venous thromboembolism (e.g., obesity, delayed mobilization, cancer, history of venous thromboembolism).⁴³⁰

Prophylaxis in Hip-fracture Surgery

Short-term prophylaxis in patients undergoing hip-fracture surgery†, as one of several therapeutic options (fondaparinux, LMW heparin).^{200 208 333 366 430}

Consider extended prophylaxis (≤28–35 days) in patients undergoing hip-fracture surgery who have ongoing risk factors for venous thromboembolism (e.g., obesity, delayed mobilization, cancer, history of venous thromboembolism).⁴³⁰

Prophylaxis in Knee-replacement Surgery

Short-term prophylaxis in patients undergoing knee-replacement surgery† as one of several therapeutic options (LMW heparin, fondaparinux, intermittent pneumatic compression).^{200 208 333 366 430}

Prophylaxis in Trauma

Prevention of thromboembolism in the rehabilitation phase of acute spinal cord injury†, as an alternative to continued therapy with an LMW heparin.^{366 430}

Prevention of thromboembolism in other types of trauma† after initial treatment with an LMW heparin in patients with an ongoing risk of venous thromboembolism requiring extended hospital stays.⁴³⁰

Continued prophylaxis with warfarin or an LMW heparin after hospital discharge suggested by ACCP in selected patients with impaired mobility.⁴³⁰

Embolism Associated with Atrial Fibrillation/Flutter

Prophylaxis of thromboembolic episodes in patients with persistent or paroxysmal atrial fibrillation who are at high risk for stroke (e.g., history of stroke, TIA, or systemic embolism; poor left ventricular systolic function and/or CHF; hypertension; diabetes mellitus; >75 years of age) or as alternative to aspirin in patients with persistent or paroxysmal atrial fibrillation and no other high-risk factors.^{211 431 434 e}

Prevention of thromboembolism in patients with atrial flutter† with or without mitral valve stenosis.^{a 431} Use alone or in combination with aspirin in patients with atrial flutter and prosthetic heart valves.⁴³¹

Patients with “lone” atrial fibrillation should be offered aspirin rather than warfarin because of their relatively low risk of stroke.^{223 279 283 335 339 344 346 367 368 369 431} ACCP, ACC, and AHA state that patients who decline therapy with warfarin or who are extremely poor candidates for oral anticoagulation also should be offered aspirin, except when contraindicated.^{335 339 349 367 368 431}

Short-term prevention of thromboembolism in patients with atrial fibrillation (>48 hours) who are at high risk for stroke after open-heart surgery.⁴³¹

Thromboprophylaxis during Cardioversion of Atrial Fibrillation/Flutter

Prevention of embolization in patients undergoing pharmacologic or electrical cardioversion of atrial fibrillation/flutter†.^{a 431}

Embolism Associated with Valvular Heart Disease

Prevention of thromboembolism associated with various types of valvular heart disease†, in combination with or as alternative to low-dose aspirin; choice of antithrombotic therapy depends on risks of thromboembolism versus hemorrhagic complications from such therapy.^{340 344 371 c}

Many experts recommend long-term oral anticoagulation with warfarin therapy in patients with rheumatic mitral valve disease† and atrial fibrillation or a history of systemic embolism (e.g., stroke).^{340 341 371 c} Add low-dose aspirin therapy in patients with atrial fibrillation or history of systemic embolism who have a breakthrough embolic event despite prophylactic anticoagulation; may use another oral platelet-aggregation inhibitor (e.g., dipyridamole, clopidogrel) if aspirin not tolerated.^{371 433 c}

Consider long-term anticoagulation in patients with rheumatic mitral valve disease† and normal sinus rhythm who have a left atrial diameter >5.5 cm (high risk of atrial fibrillation).^{340 371 c}

Prophylaxis with warfarin (target INR 2.5, range 2–3) recommended by ACC/AHA in selected high-risk patients with mitral valve prolapse† and atrial fibrillation (i.e., those ≥65 years of age or those with mitral valve regurgitation, hypertension, or a history of heart failure).³⁴¹ Patients <65 years of age with mitral valve prolapse and atrial fibrillation who do not have these risk factors for thromboembolism and those with mitral valve prolapse and unexplained TIAs should be considered for low-dose aspirin therapy.^{340 341 371 c} Also consider long-term warfarin prophylaxis in patients with mitral valve prolapse who have atrial fibrillation, a history of systemic embolism (e.g., stroke), or recurrent TIAs despite aspirin therapy.^{340 341 371 c}

Adjusted-dose warfarin also recommended by some clinicians for prevention of thromboembolic events in patients with mitral valve regurgitation and concomitant atrial fibrillation or a history of systemic embolism.^{341 371}

Long-term antithrombotic therapy generally not recommended in patients with mitral annular calcification who lack a history of thromboembolism or atrial fibrillation.^{340 371 c} However, ACCP suggests that long-term warfarin therapy be given to patients with mitral annular calcification complicated by systemic embolism not documented to be calcific embolism or in those who have atrial fibrillation.^{340 371 c}

Generally should not initiate anticoagulant therapy in patients with uncomplicated infective endocarditis involving a native valve because of the risk of hemorrhage and lack of documented efficacy.^{340 371}

Oral anticoagulant therapy recommended in patients undergoing mitral valvuloplasty beginning 3 weeks prior to the procedure and continuing for 4 weeks following the procedure.^c

Generally should not initiate long-term anticoagulant therapy in patients with aortic arch valve disease unless warranted by a coexisting condition.^{371 c} However, ACCP states that patients with mobile aortic atheromas and aortic plaques >4 mm (as measured by transesophageal echocardiography) should receive long-term anticoagulation with warfarin.^{371 c}

Thromboembolism Associated with Prosthetic Heart Valves

Follow-up anticoagulation after unfractionated heparin or an LMW heparin for prevention of thromboembolic complications associated with heart valve replacement.^{211 341 347 370 433 c}

Risk of systemic embolism is higher with prosthetic mechanical than with bioprosthetic heart valves, higher with first-generation mechanical (e.g., caged ball, caged disk) valves than with newer mechanical (e.g., bileaflet, Medtronic Hall tilting disk) heart valves, higher with more than one prosthetic valve, and higher with prosthetic mitral than with aortic valves; risk also increases in the presence of atrial fibrillation.^{341 342 343 347 370 431 433} Lifelong prophylaxis required in all patients with mechanical heart valves because of associated high risk of thromboembolism.^{341 347 370}

Combination therapy with aspirin recommended in patients with mechanical heart valves and additional risk factors (e.g., atrial fibrillation, left atrial enlargement, endocardial damage, low ejection fraction).⁴³³

Combination therapy with aspirin recommended in patients with first-generation mechanical heart valves.⁴³³

Short-term (3 months) prophylaxis in patients with a bioprosthetic valve in the mitral position; follow-up with long-term aspirin therapy in patients with no continuing risk factors who are in normal sinus rhythm.⁴³³

Short-term (3 months) prophylaxis with warfarin or aspirin in patients with a bioprosthetic valve in the aortic position; follow-up with aspirin in patients with no continuing risk factors who are in normal sinus rhythm.⁴³³

Short-term prophylaxis in patients with a bioprosthetic valve and evidence of a left atrial thrombus.⁴³³

Long-term prophylaxis in patients with a bioprosthetic valve and other risk factors (e.g., atrial fibrillation, prior thromboembolism, left ventricular dysfunction, hypercoagulable states).^{341 347 370 433}

Generally should not initiate anticoagulant therapy in patients with uncomplicated infective endocarditis involving a bioprosthetic heart valve because of the risk of hemorrhage and lack of documented efficacy.^{340 371 433} However, ACCP states that patients with mechanical prosthetic valves receiving long-term anticoagulation who develop infective endocarditis generally should remain on anticoagulant therapy unless there are specific contraindications, keeping in mind the substantial risk of intracranial hemorrhage.^{340 371 c}

Treatment of “breakthrough” thromboembolic events in patients with prosthetic heart valves receiving thromboprophylaxis.^{211 341 433 c} Combination therapy with aspirin recommended in patients with breakthrough embolic event despite warfarin therapy.^{433 341 370 433 c}

Thromboembolism Following ST-Segment Elevation MI

Used as adjunctive therapy with platelet-aggregation inhibitors (e.g., aspirin, clopidogrel) after coronary artery reperfusion for the prevention of early reocclusion and death.^{211 226 242 243 244 245 246 247 248 249 250 251 252 348 350 372 432 440}

Used short-term with an LMW heparin in the treatment of DVT or pulmonary embolism following MI in hospitalized patients.⁴³²

Used in selected patients to reduce the incidence of thromboembolic events such as stroke or systemic embolization following MI.^{211 226 256 268 269 270 271 272 348 432 440} ACC and AHA recommend follow-up anticoagulation (3 months) at hospital discharge and adjunctive aspirin after initiation of unfractionated heparin or an LMW heparin in patients at high risk for systemic emboli.⁴³² ACCP suggests oral anticoagulation and aspirin following MI for 3 months in those at high risk for embolism.^{348 350 372 437}

ACC and AHA recommend long-term anticoagulation alone or with aspirin at hospital discharge in patients without stent implantation who have coexisting conditions (i.e., atrial fibrillation, left ventricular thrombus, cerebral emboli, extensive wall motion abnormality) that warrant such therapy.⁴³²

Used as an alternative to clopidogrel in patients who are unable to take daily aspirin therapy and who do not have a stent implanted.⁴³²

Primary Prevention of Thromboembolic Events in CAD

Used to reduce the incidence of cardiovascular events and mortality† in patients at high risk for CAD.^{372 437}

Thromboembolism Associated with Other Cardiovascular Diseases

Used in conjunction with aspirin to prevent thrombi and infarction in children with Kawasaki disease†.⁴⁴⁶

Used as primary prophylaxis for thrombotic complications in children with dilated cardiomyopathy† awaiting a cardiac transplant.⁴⁴⁶

May be used as primary prevention of thromboembolic events in children undergoing Fontan surgery for congenital univentricular heart lesions†; use with aspirin (5 mg/kg daily) as follow-up to heparin therapy.⁴⁴⁶

Cerebral Thromboembolism

Secondary prevention in patients with TIAs† or mild ischemic stroke and concurrent atrial fibrillation, provided no contraindications to therapy exist.^{335 338 349 352 373 432 434}

Used in conjunction with aspirin for prevention of recurrent stroke in patients at high risk for recurring cerebral embolism from other cardiac sources (e.g., mechanical prosthetic heart valves, recent MI, left ventricular thrombus, dilated cardiomyopathies, marantic endocarditis, extensive wall-motion abnormalities).^{335 338 349 352 432} Follow-up anticoagulation after heparin or an LMW heparin in patients with recent MI and acute ischemic stroke and cardiac sources of embolism.⁴³²

Has been used as follow-up anticoagulation after heparin therapy for the prevention of embolism in paralyzed or immobile patients with progressive stroke† (when the suspected mechanism is thromboembolic) or stroke-in-evolution†.^{212 373} However, use of heparin or an LMW heparin not recommended by ACCP in patients with a stroke-in-evolution because of lack of conclusive data on efficacy and safety.⁴³⁴

Short-term (3–6 months) follow-up anticoagulation with warfarin or an LMW heparin after heparin or an LMW heparin in children with arterial ischemic stroke from cardiac sources† or vascular dissection.⁴⁴⁶ May initiate aspirin following completion of anticoagulation.⁴⁴⁶

Long-term antithrombotic therapy generally not recommended in asymptomatic patients with a patent foramen ovale or atrial septal aneurysm unless such patients have unexplained system embolism or TIAs and demonstrable venous thrombosis or pulmonary embolism.^{340 371} Treatment of suspected DVT in patients with cryptogenic stroke and patent foramen ovale†.⁴³⁴ ACCP suggests use of antiplatelet agents over warfarin in patients with cryptogenic stroke and patent foramen ovale without DVT.⁴³⁴

ACCP suggests either oral anticoagulation or antiplatelet agents for secondary prophylaxis in patients with cryptogenic stroke and mobile arch thrombi†.⁴³⁴

Oral anticoagulation (3–6 months) recommended by ACCP as follow-up to unfractionated heparin or an LMW heparin in patients with acute cerebral venous sinus thrombosis†.

Thrombosis Associated with CABG

Prevention of saphenous vein or internal mammary artery graft occlusion following CABG†.^{376 448} ACCP recommends use in combination with aspirin when other coexisting conditions (e.g., heart valve replacement) warrant such therapy.^{376 448}

Prevention of Stent Thrombosis and Restenosis Following PCI

Has been used short-term for prevention of stent thrombosis after stent placement† or long-term (1–6 months) for prevention of restenosis following PCI†.⁴⁴⁷ Since warfarin has no apparent advantages over antiplatelet therapy, not routinely recommended by ACCP after PCI if no other indications for anticoagulation exist.⁴⁴⁷

Arterial Occlusive Disease

Has been used in selected patients with peripheral arterial occlusive disease†, but ACCP currently recommends against use of anticoagulants for intermittent claudication.^{377 449}

Treatment/Secondary Prevention in Arterial Vascular Surgery

ACCP recommends long-term follow-up oral anticoagulation after initial heparin treatment in patients undergoing embolectomy†.^{377 449}

ACCP recommends long-term oral anticoagulation in postsurgical patients following pulmonary thromboendarterectomy† and in patients ineligible for such a procedure.⁴²⁷

Prevention (combined with aspirin therapy) of embolism in selected (high risk for graft thrombosis and limb loss) patients after infrainguinal femoropopliteal or distal vein bypass†.^{377 449}

Heparin-Induced Thrombocytopenia^{387 392 393}

Has been administered as follow-up treatment of heparin-induced thrombocytopenia† when substantial recovery has occurred (i.e., platelet counts ≥ 100,000–150,000/mm³ and are stable) after therapy with a direct thrombin inhibitor (e.g., lepirudin, bivalirudin, argatroban).^{392 441 442 443 444} Overlap therapy for approximately 5 days until an adequate response to warfarin is obtained.^{387 392 393}

Warfarin Sodium Dosage and Administration

General

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  Carefully individualize dosage based on clinical and laboratory findings (i.e., determination of INR and/or PT ratios).²¹¹ Adjust dosage in small increments and carefully monitor patient response.^a Determine optimum duration of therapy by the condition being treated and its severity.^a

  
  


• 
  

  Determine PT prior to and 24 hours after initiation of therapy.^{211 a 426} Determine PT daily until the PT/INR is in the therapeutic range.²¹¹ Intervals between subsequent PT determinations based on clinician’s judgment and patient’s response.²¹¹ Determine PT/INR generally every 1–4 weeks after a stable dosage has been determined.^{211 426}

  
  


• 
  

  Determine PT when different warfarin preparations (e.g., proprietary versus generic) are interchanged.^{211 a} Determine PT when concomitant drug therapy is added, discontinued, or taken irregularly.^{211 a}

  
  


• 
  

  Dosage does not vary with the route of administration.²¹¹

  
  


• 
  

  Administration of large loading doses (i.e., >20 mg) not recommended.^{211 426} Possible increased risk of hemorrhage or necrosis.²¹¹ (See Hemorrhage under Cautions.)

  
  


• 
  

  For follow-up therapy after heparin, the manufacturer recommends that therapy with heparin and warfarin be used concurrently for at least 4–5 days or until the desired PT/INR has been achieved.²¹¹ Some clinicians recommend that unfractionated heparin or an LMW heparin be used concurrently with warfarin for about 5–7 days or until the desired INR has been achieved for 2 consecutive days.⁴²⁷

  
  


• 
  

  Increased risk of thrombosis or rebound thromboembolism has been suggested following abrupt discontinuance of warfarin therapy; some manufacturers recommend gradually decreasing dosage (e.g., over 3–4 weeks) when withdrawing therapy.^a

  
  

Transferring from Anticoagulation with Direct Thrombin Inhibitors

• 
  

  For follow-up therapy after most direct thrombin inhibitors, overlap therapy with direct thrombin inhibitors for ≥5 days until desired INR has been achieved for 2 consecutive days.^{441 443}

  
  


• 
  

  Combined therapy with argatroban and warfarin prolongs the PT and INR beyond that produced by warfarin alone.^{392 441} Determine PT and INR daily during concurrent argatroban and warfarin therapy.³⁹² Continue to monitor the effects of argatroban using aPTT during conversion to warfarin.³⁹²

  
  


• 
  

  For an argatroban infusion rate ≤2 mcg/kg per minute, discontinue argatroban therapy when INR on combined therapy >4.³⁹² Avoid overshooting target INR, as supratherapeutic INRs during concomitant therapy with direct thrombin inhibitors and warfarin have been associated with necrosis or gangrene of the skin or limbs.^{441 442 444}

  
  


• 
  

  Determine INR 4–6 hours after discontinuance of argatroban infusion during warfarin monotherapy.³⁹² If INR is below the desired therapeutic range, resume argatroban infusion.³⁹² Repeat attempts to discontinue argatroban daily and until INR (4–6 hours after discontinuance of argatroban) on warfarin alone is in therapeutic range.³⁹²

  
  


• 
  

  For argatroban infusion rates >2 mcg/kg per minute, reduce infusion rate temporarily to 2 mcg/kg per minute, and reinstitute the procedure just described for conversion to oral therapy.³⁹² Repeat INR determination 4–6 hours after reduction of the argatroban infusion and reinstitute procedure just described for conversion to oral therapy.³⁹²

  
  

Administration

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Administer orally.^a Administer by IV injection when a coumarin derivative is indicated and oral therapy is not feasible.²¹¹

IM administration not recommended.²¹¹

Oral Administration

Administer orally in a single, daily dose.^a

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Reconstitution

Reconstitute powder for injection with 2.7 mL of sterile water for injection to a final concentration of 2 mg/mL.²¹¹

Rate of Administration

Inject slowly (over 1–2 minutes) into a peripheral vein.²¹¹

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as warfarin sodium; dosage expressed in terms of the salt.^{211 330}

Pediatric Patients

Venous Thrombosis and Pulmonary Embolism

Treatment or Secondary Prevention

Oral

Neonates with homozygous protein C deficiency and associated purpura fulminans: Maintenance of an INR of 2.5–4.5 long-term suggested.⁴⁴⁶

Children >2 months of age with first episode idiopathic thromboembolic event: Follow-up anticoagulation after heparin or an LMW heparin with dosage adjusted to maintain a target INR of 2.5 (range 2–3) for at least 6 months.⁴⁴⁶

Children >2 months of age with first episode thromboembolic event secondary to precipitating factors: Maintenance of a target INR of 2.5 (range 2–3) is suggested for 3 months or until resolution of such factors.⁴⁴⁶ Such factors include cancer, trauma/surgery, congenital heart disease, or systemic lupus erythematosus.⁴⁴⁶

Children >2 months of age with recurrent thromboembolic events secondary to precipitating factors after previous 3 months of oral anticoagulation: Continued maintenance of a target INR of 2.5 (range 2–3) is suggested for another 3 months or until resolution of such factors.⁴⁴⁶

Children with recurrent idiopathic thromboembolic events: Indefinite oral anticoagulation at low (INR of 1.3–1.8) to moderate intensity (INR of 2–3) suggested.^{426 446}

Children >2 months of age with central venous catheter-associated venous thromboembolic events: Adjust dosage to maintain target INR of 2.5 (range 2–3) for 3 months.⁴⁴⁶

Children >2 months of age with first DVT associated with a central venous catheter after previous 3 months of oral anticoagulation for catheter-related thrombosis: Continue anticoagulation at a lower intensity (INR 1.5–1.8) until the central venous catheter is removed.⁴⁴⁶

Children >2 months of age with recurrent thrombosis associated with a central venous catheter after previous 3 months of oral anticoagulation: Continue anticoagulation at a lower intensity (INR 1.5–1.8) until the central venous catheter is removed.⁴⁴⁶

Children >2 months of age with breakthrough thrombosis associated with central venous catheters despite low-intensity oral anticoagulation: Increase of the anticoagulation to an INR of 2–3 until the catheter is removed or for a minimum of 3 months.⁴⁴⁶

Children >2 months of age receiving long-term total parenteral nutrition via a central venous catheter: Continuous dosage at INR 2–2.5 suggested or alternatively, for the first 3 months after each central venous catheter is inserted.⁴⁴⁶

Cardiovascular Conditions†

Oral

Giant coronary aneurysms following Kawasaki disease†: Adjustment of dosage to maintain an INR of 2–3 with aspirin (3–5 mg/kg daily) is suggested to reduce subsequent thrombosis and infarction.⁴⁴⁶

Neonates and children with dilated cardiomyopathy†: Primary prophylaxis at INR of 2–3 suggested while the child is awaiting a cardiac transplant.⁴⁴⁶

Fontan surgery for congenital univentricular heart lesions†: Maintenance of an INR of 2–3 following full-dose heparin suggested for primary prevention of thromboembolic events; the optimal duration of therapy unknown.⁴⁴⁶

Cerebral Thromboembolism

Acute Cerebral Venous Sinus Thrombosis†

Oral

Secondary prevention†: Follow-up oral anticoagulation at a target INR of 2.5 (range 2–3) for 3–6 months after therapy with unfractionated heparin or an LMW heparin.⁴⁴⁶

Adults

Venous Thrombosis and Pulmonary Embolism

Treatment or Secondary Prevention

Oral

As follow-up to therapy with heparin or an LMW heparin, initial dose is 5–10 mg daily.^{211 332 334 365 407 426} Adjust subsequent daily dosage to achieve and maintain a target INR of 2.5 (range 2–3) for ≥3 months.^{211 332 334 365 407}

Individualize length of treatment of DVT or pulmonary embolism based on age, comorbid conditions, and the likelihood of recurrence.^{365 427}

DVT or pulmonary embolism with reversible or time-limited risk factors for venous thromboembolism: Adjust dosage to maintain a target INR of 2.5 (range 2–3) for at least 3 months.^{365 427}

First episode of idiopathic DVT: Adjust dosage to maintain a target INR of 2.5 (range 2–3) for at least 6–12 months.^{332 365 427 446}

First episode of DVT or pulmonary embolism and continuing risk factors: Adjust dosage to maintain a target INR of 2.5 (range 2–3) for at least 6–12 months.^{365 427} Such factors include cancer, antithrombin III or protein C or S deficiencies, antiphospholipid antibody syndrome, factor V Leiden or prothrombin 20210A gene mutations, homocysteinemia, and high levels of factor VII.^{365 427}

First episode of DVT or pulmonary embolism with antiphospholipid antibodies or ≥2 thrombophilic conditions: Adjust dosage to maintain a target INR of 2.5 (range 2–3) for 12 months.⁴²⁷ Indefinite anticoagulation suggested in these patients.⁴²⁷

Consider long-term therapy in patients with risk factors for recurrent thromboembolism, including venous insufficiency, idiopathic venous thromboembolism, and history of thrombotic events (≥2 episodes).^{211 427 446}

Prophylaxis in Hip-replacement Surgery

Oral

Initially, 5–10 mg daily with dosage adjusted to achieve a target INR of 2.5 (range 2–3) for ≥10 days.^{333 366 430}

Initiate prophylaxis for venous thromboembolism perioperatively (the evening before or after surgery).^{203 208 333 366 430}

Extended prophylaxis for ≤28–35 days with warfarin, fondaparinux, or LMW heparin recommended.⁴³⁰

Prophylaxis in Hip-fracture Surgery

Oral

Initially, 5–10 mg daily with dosage adjusted to achieve a target INR of 2.5 (range 2–3) for ≥10 days.^{333 366 430}

Initiate prophylaxis for venous thromboembolism preoperatively with heparin or a LMW heparin if surgery is delayed or after surgery once hemostasis has been demonstrated.⁴³⁰ Continue prophylactic anticoagulant therapy with warfarin, a LMW heparin, or fondaparinux following surgery for 28–35 days.⁴³⁰

Prophylaxis in Knee-replacement Surgery

Oral

Initially, 5–10 mg daily with dosage adjusted to achieve a target INR of 2.5 (range 2–3) for 10 days.^{333 366 430}

Initiate prophylaxis for venous thromboembolism perioperatively (the evening before or after surgery).^{203 208 333 366 430}

Prophylaxis in Trauma

Oral

Acute spinal cord injury: Following initial therapy with an LMW heparin, adjust warfarin sodium dosage to a target INR of 2.5 (range 2–3) in the rehabilitation phase.^{366 430} Continue prophylactic anticoagulant therapy following trauma for a minimum of 3 months or until completion of the inpatient phase of rehabilitation.⁴³⁰

Trauma patients with impaired mobility: Adjust dosage to a target INR of 2.5 (range 2–3) after hospital discharge.⁴³⁰

Embolism Associated with Atrial Fibrillation/Flutter

Oral

Adjust dosage for long-term oral anticoagulation to a target INR of 2.5 (range 2–3) in patients who are at high risk for stroke.^{335 339 344 345 349 368 431 434}

For atrial fibrillation persisting for >48 hours after open-heart surgery: Maintain a target INR of 2.5 (range 2–3) in patients at high risk for stroke for several weeks following reversion to normal sinus rhythm.⁴³¹

Atrial flutter and mitral stenosis: Adjust dosage to maintain a target INR of 2.5 (range 2–3).⁴³¹

Thromboprophylaxis during Cardioversion of Atrial Fibrillation/Flutter

Oral

Initiate at least 3–4 weeks prior to cardioversion (target INR of 2.5, range 2–3) and continue after the procedure until normal sinus rhythm has been maintained for 3–4 weeks.^{334 335 336 339 367 368 431} For emergency cardioversion, administer for ≥4 weeks as follow-up anticoagulation after initiating periprocedural IV heparin.^{335 336 339 341 367 368 431}

Embolism Associated with Valvular Heart Disease

Oral

Mitral valve disease associated with rheumatic fever or mitral valve regurgitation: Adjust dosage to prolong the INR to a target of 2.5 (range 2–3) in patients who have either concurrent paroxysmal or chronic persistent atrial fibrillation or a history of systemic embolism (e.g., stroke).^{340 371 433} Add aspirin (75–100 mg daily) to therapy in patients who have a breakthrough embolic event.^{371 433}

Rheumatic mitral valve disease with left atrial hypertrophy (left atrial diameter exceeding 5.5 cm) and normal sinus rhythm: Long-term anticoagulation at a target INR of 2.5 (range 2–3).^{340 371 433}

Mitral valve prolapse and a history of systemic embolism (e.g., stroke), or recurrent TIAs despite aspirin therapy: Maintain a target INR of 2.5 (range 2–3).^{340 341 371 433}

Mitral annular calcification complicated by systemic embolism (noncalcific systemic embolism): Long-term prophylaxis at a target INR of 2.5 (range 2–3) suggested.^{340 371 433}

Patients undergoing percutaneous mitral valvuloplasty: Maintain a target INR of 2.5 (range 2–3) for 3 weeks prior to the procedure and for 4 weeks after the procedure.⁴³³

Thromboembolism Associated with Prosthetic Heart Valves

Prophylaxis

Oral

Bioprosthetic valve in the aortic position: Adjust dosage to maintain a target INR of 2.5 (range 2–3) during the first 3 months.⁴³³

Bioprosthetic valve in the mitral position: Adjust dosage to maintain a target INR of 2.5 (range 2–3) for the first 3 months.⁴³³

Mitral bioprosthetic heart valve and additional risk factors (atrial fibrillation, left ventricular dysfunction, prior thromboembolism, hypercoagulable states³⁴¹ ): Maintenance of a target INR of 3 (range 2.5–3.5) for ≥3 months recommended by ACC and AHA.³⁴¹

Bioprosthetic valves with evidence of a left atrial thrombus at valve replacement surgery: Adjust dosage to maintain a target INR of 2.5 (range 2–3) for the first 3 months.⁴³³

Patients with bioprosthetic valves who have a history of systemic embolism: Maintenance of a target INR of 2.5 (range 2–3) for 3–12 months recommended by ACCP.⁴³³

Patients with newer (e.g., bileaflet, Medtronic disk) mechanical heart valves in the aortic position with no additional risk factors: Adjust dosage to a target INR of 2.5 (range 2–3) long-term.^{341 347 370 433}

Tilting disk valves and bileaflet mechanical heart valves i

Ceftriaxone

Pronunciation: SEF-trye-AX-one in DEX-trose
Generic Name: Ceftriaxone
Brand Name: Rocephin

Ceftriaxone is used for:

Treating bacterial infections.

Ceftriaxone is a cephalosporin antibiotic. It works by interfering with the formation of the bacteria's cell wall so that the wall ruptures, resulting in the death of the bacteria.

Do NOT use Ceftriaxone if:

• you are allergic to any ingredient in Ceftriaxone or to any other cephalosporin antibiotic (eg, cephalexin, cefprozil)


• the patient is a newborn (younger than 29 days old) with high blood bilirubin (hyperbilirubinemia) or jaundice


• the patient is a newborn and is receiving or is expected to receive an intravenous (IV) medicine that contains calcium

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

Before using Ceftriaxone:

Tell your health care provider if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances (including corn products)


• if you have had a severe allergic reaction (eg, severe rash, hives, difficulty breathing, dizziness) to a penicillin antibiotic (eg, amoxicillin) or other beta-lactam antibiotic (eg, imipenem)


• if you have diarrhea, stomach or bowel problems (eg, colitis, inflammation, infection), a blood clotting problem, gallbladder disease, low vitamin K levels, poor nutrition, diabetes, or if you cannot tolerate carbohydrates


• if you have a history of liver or kidney problems


• if you are using a medicine or supplement that contains calcium

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

• Calcium-containing IV medicines (eg, parenteral nutrition, Ringer's solution) because severe and sometimes fatal lung and kidney problems may occur, especially in newborns


• Aminoglycosides (eg, gentamicin), anticoagulants (eg, warfarin), cyclosporine, or heparin because the risk of their side effects may be increased by Ceftriaxone


• Certain live vaccines (BCG, oral typhoid) because Ceftriaxone may decrease their effectiveness

This may not be a complete list of all interactions that may occur. Ask your health care provider if Ceftriaxone may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Ceftriaxone:

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

• Ceftriaxone is usually given as an injection at your doctor's office, hospital, or clinic. If you will be using Ceftriaxone at home, a health care provider will teach you how to use it. Be sure you understand how to use Ceftriaxone. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions.


• Ceftriaxone is light yellow to amber in color. Do not use Ceftriaxone if it contains particles, is cloudy or discolored, or if the vial or container is cracked or damaged in any way.


• To clear up your infection completely, use Ceftriaxone for the full course of treatment. Keep using it even if you feel better in a few days.


• Keep this product, as well as syringes and needles, out of the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.


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

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

Important safety information:

• Mild diarrhea is common with antibiotic use. However, a more serious form of diarrhea (pseudomembranous colitis) may rarely occur. This may develop while you use the antibiotic or within several months after you stop using it. Contact your doctor right away if stomach pain or cramps, severe diarrhea, or bloody stools occur. Do not treat diarrhea without first checking with your doctor.


• Ceftriaxone only works against bacteria; it does not treat viral infections (eg, the common cold).


• A severe and sometimes fatal type of anemia (hemolytic anemia) has been reported in patients using cephalosporin antibiotics, including Ceftriaxone. Discuss any questions or concerns with your doctor. Contact your doctor right away if you experience unusual tiredness or weakness, unusually pale skin, dizziness, fever or chills, severe back or stomach pain, or yellowing of the eyes or skin.


• Be sure to use Ceftriaxone for the full course of treatment. If you do not, the medicine may not clear up your infection completely. The bacteria could also become less sensitive to this or other medicines. This could make the infection harder to treat in the future.


• Long-term or repeated use of Ceftriaxone may cause a second infection. Tell your doctor if signs of a second infection occur. Your medicine may need to be changed to treat this.


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


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Ceftriaxone while you are pregnant. Ceftriaxone is found in breast milk. If you are or will be breast-feeding while you use Ceftriaxone, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Ceftriaxone:

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:

Mild diarrhea; mild pain, swelling, or redness at the injection site; nausea; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bloody or watery stools; dizziness; fever or chills; seizures; severe diarrhea; severe or persistent stomach or back pain with nausea and vomiting; stomach pain or cramps; unusual tiredness or weakness; unusually pale skin; vaginal irritation or discharge; 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: Ceftriaxone side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include muscle spasms; seizures.

Proper storage of Ceftriaxone:

Ceftriaxone is usually handled and stored by a health care provider. If you are using Ceftriaxone at home, store Ceftriaxone as directed by your pharmacist or health care provider. Keep Ceftriaxone, as well as needles and syringes, out of the reach of children and away from pets.

General information:

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


• Ceftriaxone is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Ceftriaxone. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Ceftriaxone resources

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

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