Kapastat - instructions for use, doses, side effects, contraindications

Capreomycin for injection is a polypeptide antibiotic isolated from Streptomyces capreolus. It is a complex of 4 microbiologically active components, which have been characterized in part; completely the structure of all components is not installed.

Pharmacodynamics

Microbiology. Capreomycin has activity against strains Mycobacterium tuberculosis, found in humans.

Sensitivity testsь. Sensitivity of strains M. tuberculosis to capreomycin in vitro varies depending on the environment and the technique used. Typically, the minimum inhibitory concentration for M. tuberculosis is the lowest in a liquid medium that does not contain the egg protein (7H10 or Dubos), and is from 1 to 5 mg / l when using an indirect method. Comparable inhibitory concentrations are obtained by applying 7H10 agar in a direct sensitivity test.When carrying out an indirect sensitivity test on standard test tubes with chopped 7H10 agar, sensitive strains are inhibited by the concentration of capreomycin from 10 to 25 mg / l. Environments containing egg white, Lowenstein-Jensen or ATS, require for inhibition of sensitive strains concentrations from 25 to 50 mg / l.

Cross-resistanceь. Cross-resistance is often observed between capreomycin and iniomycin. There is a possibility of cross-resistance of varying degrees between capreomycin and kanamycin, neomycin. Cross resistance was not observed between capreomycin and isoniazid, aminosalicylic acid, cycloserine, streptomycin, ethionamide and ethambutol.

Pharmacokinetics:

Capreomycin is not absorbed in sufficient quantity from the gastrointestinal tract and therefore must be administered parenterally. After intramuscular injection of 1 g of capreomycin, the peak of its concentration in the serum is achieved after 1-2 hours, and its maximum level is 28-32 mg / l, respectively (from 20 to 47 mg / l). After 24 hours, low concentrations of the drug remained in the serum. Daily administration of 1 g of capreomycin for 30 days andno longer leads to its any significant accumulation in the majority of patients with normal and reduced renal function. With intramuscular injection of 1 g of capreomycin to healthy volunteers, 52% of it was excreted in the urine for 12 hours.

In the study of the pharmacokinetics of single doses of capreomycin (1 g), administered intramuscularly and by intravenous infusion (within 1 hour), it was established that the area under the curve reflecting the concentration of capreomycin in time was the same for both administration routes. The peak concentration of capreomycin after intravenous infusion was 30 mg / l ± 47%, which is higher than after intramuscular injection.

Capreomycin is excreted mainly unchanged. Its concentration in urine within 6 hours after the administration of 1 g averages 1.68 mg / ml (average urine volume 228 ml).

Indications:

Tuberculosis of the lungs (if first-line drugs (isoniazid, rifampin, aminosalicylic acid and streptomycin) have been ineffective or can not be used due to toxic effects or the presence of resistant tubercle bacilli).

To confirm the presence of a capreomycin-sensitive strain M. tuberculosis a sensitivity test should be carried out.

Contraindications:

Capreomycin for injection is contraindicated in children, patients with hypersensitivity to capreomycin, pregnant and lactating mothers.

Carefully:

Renal failure, hearing impairment, dehydration, myasthenia gravis gravis, parkinsonism, old age.

Pregnancy and lactation:

Capreomycin is contraindicated in pregnancy. If you need to use the drug during lactation, you should stop breastfeeding.

Dosing and Administration:Capreomycin for injection can be used intramuscularly or intravenously with the following dilution: the contents of the vial (1 g) are dissolved in 2 ml of 0.9% sodium chloride for injection or sterile water for injection. It should wait 2-3 minutes, until the contents of the bottle finally dissolve. Intravenously. For intravenous infusion, dissolved capreomycin for injections should be diluted in 100 ml of 0.9% sodium chloride solution for injection and injected for 60 minutes.

Intramuscularly. Diluted capreomycin for injections are administered by deep intramuscular injection,since surface injection can cause increased soreness and the development of sterile abscesses.

To introduce a dose of 1 g, you must use the entire contents of the vial. For a dose of less than 1 g, the following dilution table can be used.

DIVISION TABLE

The amount of solvent added to a 10 ml vial containing a dose of 1 g	Volume of capreomycin solution for injection	Concentration of solution (approx.)
2.15 ml	2.85 ml	370 mg * / ml
2.63 ml	3.33 ml	315 mg * / ml
3.3 ml	4 ml	260 mg * / ml
4.3 ml	5 ml	210 mg * / ml

* Equivalent activity of capreomycin.

The solution may become pale straw color and eventually darken, but this is not accompanied by loss of activity or the appearance of toxicity. After dilution, all solutions of capreomycin for injection can be stored in the refrigerator for no more than 24 hours.

Capreomycin is always prescribed in combination with at least one antituberculous drug, to which the strain of tubercle bacilli that is present in the patient is sensitive. The usual dose is 1 g per day (do not exceed 20 mg / kg / day). It is administered intramuscularly or intravenously for 60-120 days, and then 1 g in either of the two ways 2-3 times a week.

Note. Treatment of tuberculosis should be continued for 12-24 months.If it is not possible to inject drugs for injections, then when they are discharged from the hospital, they should be replaced with oral medications.

Patients with reduced renal function should reduce the dose based on creatinine clearance in accordance with the instructions given in Table 1. These dosages are chosen so as to achieve an average equilibrium level of capreomycin of 10 mg / l.

Table 1. Calculation of dosages to achieve an average equilibrium concentration of capreomycin in the serum of 10 mg / l (based on creatinine clearance):

Creatinine clearance (ml / min)	Clearance of capreomycin (l / kg / h x 10²)	The elimination half-life T_1/2(h)	Dose^a (mg / kg) for the following intervals between administrations
Creatinine clearance (ml / min)	Clearance of capreomycin (l / kg / h x 10²)	The elimination half-life T_1/2(h)	24 h	48 h	72 h
0	0,54	55,5	1,29	2,58	3,87
10	1,01	29,4	2,43	4,87	7,3
20	1,49	20,0	3,58	7,16	10,7
30	1,97	15,1	4,72	9,45	14,2
40	2,45	12,2	5,87	11,7
50	2,92	10,2	7,01	14,0
60	3,40	8,8	8,16
80	4,35	6,8	10,4^b
100	5,31	5,6	12,7^b
110	5,78	5,2	13,9 ^b

^a For patients with reduced renal function, the calculation of the initial maintenance dose is given for optional dosage materials; it is expected that an increase in the intervals between dosages will lead to an increase in the maximum and a decrease in the minimum serum capreomycin level as compared to shorter intervals.

^b The usual dosage for patients with normal kidney function, which is 1 g per day and not exceeding 20 mg / kg / day, is administered for 60-120 days, and then 1 g 2 or 3 times a week.

Side effects:

Nephrotoxic effect. In 36% of patients who received capreomycin for injections, there was an increase in the AMC level of more than 20 mg / 100 ml. In many cases there was also a decrease in phenol sulfonphthalein release and the appearance of an abnormal urinary sediment. In 10% of patients in this series, the AMC level exceeded 30 mg / 100 ml.

There are violations of electrolyte balance, reminiscent of the syndrome of Barter and the development of toxic jade.

Ototoxic effect. Approximately 11% of 722 patients treated with capreomycin for injection had subclinical hearing loss, which was 5 to 10 decibels in the range of CPS 4000-8000. Clinically expressed hearing loss was observed in 3% of 722 patients. Some auditory changes were reversible. In other cases, a constant decrease in hearing did not progress after stopping capreomycin for injections.

There was a noise in the ears and dizziness.

Liver. Violation of liver function was found in patients who received capreomycin for injections in combination with other anti-tuberculosis drugs, which are known to cause changes in liver function.The role of capreomycin for injection in the manifestation of these disorders is unclear, but it is recommended to periodically check the function of the liver.

Blood. Most patients who received daily injections of capreomycin for injection had eosinophilia exceeding 5%. This was eliminated by reducing the dose of capreomycin for injection to 2-3 grams per day. Leucocytosis, leukopenia and thrombocytopenia were also observed.

Possible soreness, tightness and increased bleeding at the injection site. Aseptic abscesses were also noted.

From the nervous system. Neurotoxicity, neuromuscular blockade.

Hypersensitivity. With simultaneous treatment with capreomycin for injections and other anti-tuberculosis drugs, urticaria and skin rashes in the form of specks and nodules were noted, accompanied sometimes by a febrile reaction.

Overdose:

Signs and symptoms. The nephrotoxic effect observed with the parenteral administration of capreomycin for injection is associated with the concentration of the drug in the blood serum. For elderly patients, patients with impaired renal function or dehydration and patients receiving other nephrotoxic drugs, the risk of acute tubular necrosis is much higher.

Damage to the auditory and vestibular divisions of the VIII pair of cranial nerves occurs in patients with impaired renal function or dehydration, as well as in those who receive drugs that have an additional ototoxic effect. Often such patients experience dizziness and noise in the ears.

After rapid intravenous administration, neuromuscular blockade or respiratory paralysis may develop.

With the onset of toxic effects of capreomycin, hypokalemia, hypocalcemia, hypomagnesemia and electrolyte imbalance resembling Barter's syndrome were observed in patients.

Treatment. In the treatment of overdose, it is necessary to carry out activities aimed at maintaining respiration and circulation, as well as careful monitoring of the concentration of blood gases, serum electrolytes, etc. Absorption of the drug from the gastrointestinal tract can be slowed down, giving the patient Activated carbon, which in many cases is more effective than vomiting and gastric lavage. Repeated intake of activated carbon can speed up the excretion of certain drugs that have already been absorbed.

To excrete capreomycin in patients with severe kidney disease, hemodialysis can be effectively used.

Interaction:

Since other anti-tuberculosis drugs (streptomycin, viomycin) also have a similar and sometimes irreversible toxic effect, especially on the VIII pair of cranial nerves and kidney function, concomitant administration of these drugs with capreomycin for injections is not recommended. Use capreomycin with polymyxin A sulfate, colistin sulfate, amikacin, gentamicin, tobramycin, vancomycin, kanamycin and neomycin, which may have ototoxic and nephrotoxic effects, should be taken with great care.

Special instructions:Are common. Prior to treatment with capreomycin for injection and regularly during the treatment should be audiometry and vestibular function evaluation. Renal damage was noted with tubular necrosis, an increase in the level of urea nitrogen in the blood (AMK) or serum creatinine and the appearance of an abnormal urinary sediment. A slight increase in AMK and serum creatinine was observed in a significant proportion of patients undergoing long-term treatment.In a large percentage of these cases, the appearance in the urine of cylinders, erythrocytes and leukocytes. An increase in the AMC level of more than 30 mg / 100 ml, as well as any other signs of a decrease in renal function, with or without an increase in the level of AMC, requires careful examination of the patient, a reduction in the dose or complete withdrawal of the drug. The clinically significant occurrence of an abnormal urinary sediment and a significant increase in the level of AMK (or serum creatinine) by capreomycin for injection has not been established. When intravenous administration of large doses of capreomycin for injection, partial neuromuscular blockade was observed. This action was intensified by ether anesthesia (as was shown for neomycin) and was attenuated by neostigmine.

Care should be taken when prescribing antibiotics, including capreomycin for injection, to patients with any form of allergy, especially drug.

Lab tests. During the entire period of treatment, a regular check of kidney function should be performed, and in patients with a detected or suspected decrease in renal function, the dose should be reduced.Renal function testing should be performed both before the treatment with capreomycin for injections and weekly during treatment.

Since hypokalemia may develop during treatment, frequent serum potassium levels should be performed.

It is necessary to compare the risk of additional impairment of the function of the VIII pair of cranial nerves and kidney damage with a positive effect of treatment.

Form release / dosage:

Lyophilizate for the preparation of a solution for intravenous and intramuscular injection 1 g.

Packaging:The preparation is in a neutral-glass vial (Type I or III), sealed with a rubber stopper under an aluminum roll, and closed with a protective plastic cover. Each vial with instructions for use is placed in a cardboard pack.

Storage conditions:

At a temperature of 15-30 ° C.

The prepared solution: in the refrigerator no more than 24 hours.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:П N013861 / 01

Date of registration:01.04.2008

Expiration Date:Unlimited

Date of cancellation:2016-09-20

The owner of the registration certificate:Lilly Pharma Fertigung und Distribution GmbH & Co. KGLilly Pharma Fertigung und Distribution GmbH & Co. KG Germany

Manufacturer: & nbsp

LILLY PHARMA Fertigung und Distribution, GmbH & Co. KG. KG Germany

Representation: & nbspELI LILLY EAST SA ELI LILLY EAST SA Switzerland

Information update date: & nbsp30.11.2017

Illustrated instructions

Instructions

Kapastat® (Capastat®)