Capreomycin - instructions for use, dose, side effects, contraindications

Selectively active against mycobacteria, localized outside and inside the cell. Inhibits the synthesis of protein in a bacterial cell due to a violation of the interaction of ribosomal proteins. Has a bacteriostatic effect.

With monotherapy, resistance develops rapidly. Has full cross resistance to kanamycin, viomycin and in some cases to amikacin and neomycin. Cross-resistance between capreomycin and isoniazid, aminosalicylic acid, cycloserine, streptomycin, ethionamide, ethambutol is not observed.

Capreomycin should be used only as part of complex therapy, as an anti-tuberculosis drug of the II series, including with inefficiency and intolerance of anti-tuberculosis drugs I series (isoniazid, rifampicin, pyrazinamide, streptomycin, ethambutol) and in the presence of sensitivity of the patient's mycobacteria to capreomycin and to simultaneously used other antituberculous drugs.

Capreomycin has a teratogenic effect (anomalies in the development of the skeleton in experiments on rats).

Pharmacokinetics:

Capreomycin is practically not absorbed in the gastrointestinal tract (less than 1%), therefore it is introduced into the body only parenterally.

When administered intramuscularly at a dose of 1 g, the maximum concentration (C_max) in plasma is 20-47 mg / l and is achieved after 1-2 hours. After 10 hours the concentration is 4 mg / l. After intravenous infusion of capreomycin for 1 hour in a dose of 1 g FROM_max is 30-50 mg / l. The area under the pharmacokinetic curve (AUC) for intravenous and intramuscular injection is the same. Capreomycin does not penetrate the blood-brain barrier, but penetrates the placental barrier. In organism capreomycin not metabolized.

Excreted unchanged, mainly kidneys (within 12 hours - 50-60% of the dose) by glomerular filtration and in small amounts - with bile. The concentration in the urine within 6 hours after the administration at a dose of 1 g averages 1.68 mg / ml.

The half-life is 3-6 hours. In patients with normal renal function, it does not cumulate with a daily dose of 1 g for 30 days. If renal function is impaired, the elimination half-life increases and a tendency to accumulation appears.

Indications:

Tuberculosis of the lungs (including with ineffectiveness and intolerance of drugs of the I series).

Capreomycin sulfate is administered together with other antituberculosis drugs, provided that the sensitivity of the isolated strains Mycobacterium tuberculosis to capreomycin, when antituberculous therapy I line is ineffective or can not be administered due to toxic effects or resistance of the pathogen.

ICD-10

I.A15-A19.A16.9 Tuberculosis of respiratory organs, unspecified, without mention of bacteriological or histological confirmation

I.A15-A19.A18 Tuberculosis of other organs

Contraindications:

Hypersensitivity.

Child age (safety and efficacy not determined).

Carefully:- defeat of the VIII pair of cranial nerves (can cause auditory and vestibular disorders);

- Myasthenia gravis;

- Parkinsonism;

- dehydration (may increase the risk of toxic effects due to elevated serum concentrations);

- impaired renal function (due to nephrotoxic action);

- elderly age.

Pregnancy and lactation:

When pregnancy is possible, if the potential benefit to the mother exceeds the possible risk to the fetus (capreomycin passes through the placenta, adequate and strictly controlled studies in pregnant women are not conducted).

In experiments on rats that received daily doses ≥ 50 mg / kg (3.5 doses for humans), a teratogenic effect is indicated.

Action category for fetus by FDA - S.

For the period of treatment it is necessary to stop breastfeeding (it is not known whether it penetrates capreomycin in breast milk).

Dosing and Administration:

Before the start of therapy, it is necessary to confirm the presence of a patient sensitive to capreomycin strain Mycobacterium tuberculosis.

Only parenterally: intramuscularly (deep into the muscle) or intravenously drip (within 60 minutes).

With intramuscular injection capreomycin is injected deep into the muscle, as a superficial injection can cause increased soreness and development of aseptic abscesses.

For intramuscular administration, 1 g is pre-dissolved in 2 ml of a 0.9% solution of sodium chloride or sterile water for injection (wait 2-3 minutes until the powder is completely dissolved).

For intravenous administration, the contents of the vial (1 g) are dissolved in 100 ml of 0.9% sodium chloride solution (NaCl) and injected for 60 minutes (intravenously drip).

The usual dose is 1 g once a day, daily for 60-120 days, then 2-3 times a week for 12-24 months, in combination with other anti-TB drugs. The maximum daily dose is no more than 20 mg / kg.

Patients with impaired function of the night should reduce the dose in accordance with the creatinine clearance according to the following table:

Clearance creatinine (ml / min)	Clearance capreomycin (l / kg / h x 102)	Period half-life (h)	Dose (mg / kg) for the following dosage intervals
Clearance creatinine (ml / min)	Clearance capreomycin (l / kg / h x 102)	Period half-life (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	7,30
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
100	5,31	5,6	12,7
110	5,78	5,2	13,9

To introduce a dose of 1 g, you must use the entire contents of the vial containing 1 g of the drug. To introduce a dose of less than 1 g of this vial, the following dilution table is recommended:

DIVISION TABLE

The amount of solvent, added to vial 10 ml, containing a dose of 1 g	Volume of solution capreomycin for injection	Concentration solution (approximate)
2.5 ml	2.83 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.

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

Capreomycin is always prescribed in combination with at least one other antituberculous drug, to which the isolated strain of mycobacterium is sensitive.

Side effects:

From the genitourinary system: nephrotoxicity - toxic nephritis, kidney damage with necrosis of the tubules, dysuria (increase / decrease in the frequency of urination or amount of urine), renal failure, increased blood urea nitrogen in a 20-30 mg / 100 ml (46% of patients) and serum creatinine , cylindruria, microhematuria, leukocyturia.

From the nervous system and sensory organs: unusual fatigue or weakness, drowsiness,neuromuscular blockade, shortness of breath (due to the lower tone muscle activation) until respiratory arrest; ototoxicity - hearing loss (subkliniche skoe - 11%, clinically significant - 3%), including permanent, noise, ringing, humming or oschu schenie "laying" in the ears; vestibulotoksichnost - violation of coordination of movements, unsteadiness of gait, dizziness.

On the part of the digestive system: nausea, vomiting, anorexia, thirst, hepatotoxicity with impaired functional parameters of the liver (especially against the background of liver diseases in the anamnesis and with simultaneous use with other anti-tuberculosis drugs that cause changes in liver function).

Allergic reactions: urticaria, maculopapular skin rash, itching, redness of the skin, fever.

From the side of the cardiovascular system and blood (hematopoiesis, hemostasis): arrhythmia (due to electrolyte disturbance), leukocytosis, leukopenia, eosinophilia (5% of patients), thrombocytopenia.

Other: violation of electrolyte balance, including hypokalemia, hypocalcemia, hypomagnesemia; myalgia; morbidity, infiltration, the development of sterile abscesses or increased bleeding at the site of administration.

Overdose:

Symptoms: impaired renal function, up to acute tubular necrosis (the risk rises in patients over 65 years old, against the background of an initial impairment of kidney function, dehydration, simultaneous use of other drugs with nephrotoxicity).

Dizziness, noise in the ears,damage to the auditory and vestibular departments of the VIII pair of cranial nerves (the risk increases in elderly patients, against the background of an initial impairment of kidney function, dehydration, simultaneous use of other drugs that have ototoxicity), neuromuscular blockade until respiratory arrest (especially with rapid intravenous introduction), electrolyte imbalance (hypokalemia, hypocalcemia, hypomagnesemia).

Treatment: is performed taking into account the possibility of an overdose of several drugs and their interaction - the appointment of activated carbon, gastric lavage, symptomatic therapy: maintaining breathing and circulation, hydration, providing urine outflow at 3-5 ml / kg / h (with normal kidney function), with a pronounced renal function impairment - hemodialysis; for arresting the neuromuscular blockade, including respiratory depression and apnea - the administration of anticholinesterase drugs, calcium preparations, hemodialysis (especially in patients with severe renal dysfunction); It is necessary to monitor the water-electrolyte balance and the clearance of creatinine.

Precautionary measures

The appointment is possible after determining the sensitivity of the strain. Before and during treatment it is necessary to periodically conduct audiometry (1-2 times a week) to diagnose hearing loss at high frequencies, to determine the indices of the function of the vestibular apparatus, kidneys (weekly) and liver, serum potassium level (monthly). During and after surgery, use with caution against the background of drugs that cause neuromuscular blockade (especially with a high probability of incomplete cessation of neuromuscular blockade in the postoperative period). During treatment, it is necessary to constantly monitor the regimen and dosage regimens, the correctness and regularity of the appointments. In case of missed injection, the missed dose is administered as soon as possible, if the time of administration of the next dose has not come. Doses do not double. If there is no improvement in the condition within 2-3 weeks or the appearance of new symptoms of the disease, specialist consultation is necessary.

Interaction:

Vancomycin and cisplatin increase the likelihood of oto- and nephrotoxic action. Incompatible with preparations that have ototoxic (aminoglycosides, polymyxins, furosemide, ethacrynic acid) and nephrotoxic (aminoglycosides, polymyxins, methoxyflurane) and causing neuromuscular blockade (aminoglycosides, polymyxins, diethyl ether and halogenated hydrocarbons for inhalation anesthesia, citrated blood preservatives). The muscle relaxant effect is weakened by neostigmine.

In combination with other anti-tuberculosis drugs (streptomycin, viomycin), as well as when combined with polymyxin, colistin, amikacin, gentamicin, tobramycin, vancomycin, kanamycin, neomycin, furosemide, ethacrynic acid or methoxyfluorane, the ototoxic and nephrotoxic effect is mutually reinforced.

Special instructions:

Prior to treatment with capreomycin and regularly during treatment (1-2 times per week), audiometry and vestibular function evaluation should be performed.

The study of kidney function should be performed before treatment and once a week during treatment. It is recommended to monitor the concentration of the drug in the blood. During treatment, hematologic parameters and liver function are also monitored.

Damage to the kidneys, which can be observed against the background of the use of capreomycin, is accompanied by tubular necrosis,an increase in the level of urea nitrogen in the blood or serum creatinine, the appearance of a pathological sediment in the urine. For elderly patients, patients with impaired renal function or dehydration and patients receiving other nephrotoxic drugs, the risk of developing acute tubal necrosis is significantly higher.

A slight increase in urea nitrogen and serum creatinine was observed in the majority of patients who received long-term therapy. Many of them noted the appearance in the urine of cylinders, erythrocytes and leukocytes. If the urea nitrogen level increases more than 30 mg / 100 ml, as well as any other signs of a decrease in renal function with an increase in the level of urea nitrogen or without it, and if a kidney function is suspected, a thorough examination of the patient, a dose reduction based on creatinine clearance or complete cancellation of the drug.

Damage to the auditory and vestibular divisions of the VIII pair of cranial nerves occurs in patients with renal dysfunction or dehydration, as well as in the treatment with ototoxic agents. Such patients often experience dizziness and noise in the ears.

After rapid intravenous injection of capreomycin, neuromuscular blockade or respiratory paralysis is possible.

Since hypokalemia may develop during treatment, the serum potassium content should be determined on a monthly basis.

During treatment, it is necessary to constantly monitor the regimen and dosage regimens, the correctness and regularity of the appointments. In the case of missed injections, administer as soon as possible, only if the time of the next dose is not reached; Doses do not double.

Simultaneous reception with streptomycin and biomycin is not recommended.

Influence on ability to drive vehicles, mechanisms

During the use of the drug, care should be taken when driving vehicles, mechanisms and other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Instructions

Capreomycin (Capreomycinum)