Colistimethate sodium powder for injection (colistin)

1 miu, 2 miu, 4.5 miu

1. What Colistimethate is and what it is used for

Colistimethate is given by injection to treat some types of serious infections caused by certain bacteria. Colistimethate is used when other antibiotics are not suitable.

2. What you need to know before you take Colistimethate

Colistimethate is not suitable for everyone. Some people must not have this injection. Do not have the injection:

If you are allergic (hypersensitive) to colistimethate, colistin or to other polymyxins. If you are unsure about anything, ask your doctor before you have the injection.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before using Colistimethate

- If you have or have had kidney problems.

- If you suffer from myasthenia gravis

- If you suffer from porphyria

In premature and new-born babies, special care should be taken when using Colistimethate as the kidneys are not yet fully developed.

Other medicines and Colistimethate

- medicines which can affect how your kidneys function. Taking such medicines at the same time as Colistimethate can increase the risk of damage to the kidneys

- medicines which can affect your nervous system. Taking such medicines at the same time as Colistimethate can increase the risk of side effects in your nervous system

- medicines called muscle relaxants, often used during general anaesthesia. Colistimethate can increase the effects of these medicines. If you have a general anaesthetic, let your anaesthetist know that you are having Colistimethate.

If you suffer from myasthenia gravis and are also taking other antibiotics called macrolides (such as azithromycin, clarithromycin or erythromycin) or antibiotics called fluoroquinolones (such as ofloxacin,norfloxacin and ciprofloxacin), taking Colistimethate further increases the risk of muscle weakness and breathing difficulties.

Having Colistimethate as an infusion at the same time as receiving colistimethate as an inhalation can increase your risk of side effects.

Make sure the doctor knows about any other medicines that you are taking, including medicines that you obtained without a prescription.

Each vial of Colistimethate contains about 5mg of sodium. This means that you could receive up to 60mg sodium each day if you are having the maximum adult dose. Please take this into account if you are on a low sodium (salt) diet and let your doctor or pharmacist know about this.

Pregnancy and breastfeeding

• Colistimethate is not known to harm the unborn child but, like all medicines, it will only be given to a pregnant woman if it is really needed.

• Small amounts of Colistimethate enter the milk. If you cannot stop breastfeeding while you have the injections, you should watch your baby carefully for any signs of illness and tell your doctor if you notice anything wrong.

Driving and operating machinery

Some people have reported side effects such as dizziness, confusion or problems with vision. If you are affected do not drive or operate machinery.

3. How to take Colistimethate

Colistimethate Sodium is given to you by your doctor as an infusion into a vein over 30 – 60 minutes.

The usual daily dose in adults is 9 million units, divided into two or three doses. If you are quite unwell, you will be given a higher dose of 9 million units once at the start of treatment.

In some cases, your doctor may decide to give a higher daily dose of up to 12 million units.

The usual daily dose in children weighing up to 40 kg is 75,000 to 150,000 units per kilogram body weight, divided into three doses. Higher doses have occasionally been given in cystic fibrosis.

Children and adults with kidney problems, including those on dialysis, are usually given lower doses.

Your doctor will monitor your kidney function regularly while you receive Colistimethate.

4. Possible side effects

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

Some side effects can be serious

Tell the doctor or nurse immediately if you notice any of the following symptoms:

• Wheezing or breathing difficulties which can lead to collapse, a rash, itching or hives on the skin, or sudden swelling of the face, throat or lips. These can be signs of a severe allergic reaction.

The following side effects have also been reported:

• Reactions, such as irritation, at the injection site.

• Kidney problems. These are more likely in patients who already have poor kidneys, or who are given Colistimethate at the same time as other medicines that can affect the kidneys, or who are given a dose that is too high. These problems will normally get better if treatment is stopped, or the dose of Colistimethate is reduced.

• Neurological problems such as inability to breathe because of paralysis of the chest muscles, numbness or tingling (especially around the face), dizziness or loss of balance, rapid changes in blood pressure or blood flow (including faintness and flushing), slurred speech, problems with vision, confusion and mental problems (including loss of sense of reality). Side effects that affect the nervous system are more likely to occur when the dose of Colistimethate is too high, in people who have poor kidneys or in those who are also receiving muscle relaxants or other medicines with a similar effect on how the nerves work.

Reporting of side effects

If you get any side effects, talk to your doctor, nurse or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Colistimethate

Keep this medicine out of the sight and reach of children. The vials of powder must not be stored above 25°C. The vials must be protected from light by storing in the outer carton. The vials must not be used after the expiry date printed on the carton and vial label. Do not freeze.

The solution of Colistimethate should be used immediately, or within 8 hours when stored at temperatures not exceeding 25°C or 24 hours in the refrigerator (2 to 8° C). The vials are for single use. Any unused solution should be discarded.

Colistimethate should not be used if there is any discoloration or cloudiness of the solution

6. Further Information

Colistimethate is a creamy white powder for solution for injection in single dose 7ml glass vials. Each carton contains 1 or 10 vials. Each vial contains the active ingredient, Colistimethate (also called colistin) as an amount of powder equivalent to one million international units or two million international units. There are no other ingredients. The sodium content is 0.228 mMol per vial.

Manufactured by:

Taj Pharmaceuticals Limited

220, Mahagujarat Ind. Estate,

Moraiya, Tal. Sanand, Dist.

Ahmedabad, Gujarat, INDIA

Warning! Dosing confusion with colistimethate for injection.

The following alert about the risk of a serious medication error is based on information from the National Medication Error Reporting Program operated by the Institute for Safe Medication Practices [ISMP MERP].

Colistimethate for injection, USP, is a prodrug of colistin, a polymyxin E antibiotic, available for several decades for the treatment of gram-negative infections. While vials are labeled colistimethate for injection, FDA officially lists it on the FDA website as the sodium salt, colistimethate sodium.

Although its popularity has diminished over the years due to its potential for nephrotoxicity and neurotoxicity, its use has been increasing lately as a last resort treatment for multidrugresistant organisms such as Pseudomonas aeruginosa and Acinetobacter species.

Risk for error

In the United States, the strength of all FDA-approved injectable colistimethate for injection products is labeled in terms of the colistin base, colistin, not the prodrug. Thus, the label expresses product strength as 150 mg of colistin base per vial (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm). Dosing is also expressed in terms of the colistin base. By weight, the dose is between 2.5 to 5 mg/kg/day for patients with normal renal function. The usual maximum dose of colistin as the base is not more than 5 mg/kg/day. However, pharmacokinetic studies are still needed to properly determine maximum dose under certain circumstances such as extremely large patients and patients with cystic fibrosis. Data suggest that using a measure of lean body mass, such as ideal body weight, for dosing may be less nephrotoxic (1).

Unfortunately, some ambiguity exists in terms of product nomenclature and dose. Although the US product is labeled in terms of colistin base, listings in various references also refer to the dose in terms of international units or mg of the prodrug, colistimethate sodium (2). Dosing in terms of the prodrug when a dose of colistin base is intended will yield a dose that is approximately 2.5 times higher than if calculated as the base.

We are aware of a recent case where the prescribing physician ordered a dose as mg of the prodrug instead of the base. This went unrecognized by pharmacists and nurses and resulted in a dose approximately 2.5 times greater than it should have been. The patient received higher than intended doses, developed acute renal failure and other complications and later expired.

Error prevention

The following recommendations should be considered for safety reasons:

What is the NAN alert?

The National Alert Network is a coalition of members of the National Coordinating Council on Medication Error Reporting and Prevention (NCCMERP). The network distributes NAN alerts to warn healthcare providers of the risk for medication errors that have caused or may cause serious harm or death. NCC MERP encourages sharing and reporting of medication errors both nationally and locally, so that lessons learned can be used to increase the safety of the medication use system.

1.In the US, colistimethate for injection must ONLY be prescribed as colistin in terms of base activity with dose range of 2.5 to 5 mg/kg/day in patients with normal renal function. As per package insert, use ideal body weight for obese patients. This total daily dose should be given in 2 to 4 divided doses.

2. Dosage reduction in the setting of renal insufficiency is recommended (see product labeling for suggested modification of dosage schedules).

3. If the drug is ordered as “colistimethate” or “colistimethate sodium,” the prescriber should be contacted to verify the dose in terms of colistin base.

4. Consider restricting ordering to infectious disease specialists or intensivists.

5. To prevent errors, pre-approved printed guidelines or computer order sets should be made available with dosing only as colistin base. Include adjustments for renal dysfunction.

6. Dose limits should be established with immediate investigation required for doses outside hospital guidelines. Guidelines should define any circumstances where dosing outside the 2.5 to 5 mg/kg/day range may be appropriate. Testing of CPOE and pharmacy computer systems should be accomplished to assure proper function of alerts.

7. Monitoring of renal function while receiving colistin is important to detect signs of renal toxicity associated with colistin and the appropriateness of dosage should be re-evaluated periodically while on treatment.