A L P H A R M A

Colistimet AF 2 000 000 ED

Colistimet AF 2000000 ED

Colistimet-AF

THE MINISTRY OF HEALTH OF THE RUSSIAN FEDERATION
INSTRUCTIONS FOR MEDICAL USE
OF THE DRUG
Colistimet AF

Registration Number:
Trade Name: Colistimet AF
International Non-Proprietary or Generic Name: Colistimethate sodium
Dosage form: powder for solution for injection, infusion and inhalation
Composition
One bottle of the drug contains:
Active ingredient: colistimethate sodium 80 mg (1,000,000 IU) or 160 mg (2,000,000 IU).
One ampoule of solvent contains:
Sodium chloride solution 0.9% – 5 mL
Description
White or almost white hygroscopic рowder.
Pharmacotherapeutic group: cyclic polypeptide antibiotic.
ATC Code: J01XB01

Pharmacological properties
Pharmacodynamics

Mechanism of action
Colistimethate sodium is a cyclic polypeptide antibiotic produced by Bacillus polymexa var. colistinus, which belongs to the group of polymyxins.
It has a bactericidal effect against gram-negative bacteria with a hydrophobic outer membrane, which is based on a change in the structure and disruption of function of the cytoplasmic and outer membranes due to a violation of the processes of polarization of membrane structures.

 

Resistance
The mechanism of development of resistance is due to the modification of lipopolysaccharide (LPS) or other components in the membrane of bacterial cells. Resistance to colistimethate sodium has been reported in approximately 3% of Pseudomonas aeruginosa.

However, resistance rates may vary by geographic location and over time. In the treatment of severe infections or antimicrobial treatment failure, consideration should be given to the local geographic distribution of resistance, as well as microbiological detection of the pathogen and its sensitivity testing to colistimethate sodium is required.

Cross-resistance
There is a cross-resistance between colistimethate sodium and polymyxin B. Since the mechanism of action of polymyxins differs from that of other antibiotics, resistance to colistimethate sodium and polymyxin B does not imply resistance to other groups of drugs (antibiotics).

Pharmacokinetics/pharmacodynamics ratio
The bactericidal effect of polymyxins on susceptible bacteria is concentration-dependent. The AUC/MIC ratio (area under the pharmacokinetic concentration-time curve / minimum inhibitory concentration) correlates with clinical efficacy.

Epidemiological thresholds
The MIC cut-off value for identifying bacteria sensitive to colistimethate sodium is ≤ 4 mg/L.

Susceptible microorganisms:
Acinetobacter baumannii, Haemophillus influenzae, Klebsiella spp., Pseudomonas aeruginosa.

Microorganisms with acquired resistance:
Stenotrophomonas maltophillia, Achromobacter xylosoxidans (former Alcaligenes xylosoxidans).

Resistant microorganisms:
Burkholderia cepacia and related species, Proteus species, Providencia species, Serratia species.

Pharmacokinetics
Absorption
Limited data is available on the pharmacokinetics of colistimethate sodium (CMS) and colistin. There is evidence that the pharmacokinetics in patients with life-threatening infections differs from that in patients with less serious diseases or healthy volunteers. After infusion, the inactive prodrug, colistimethate sodium, is converted to active colistin. The maximum plasma concentrations of colistin are observed 7 hours after the administration of colistimethate sodium to patients with life-threatening infections.

The absorption of colistimethate sodium after inhalation has strong individual differences. The reported maximum concentrations of colistimethate sodium in blood plasma after inhalation at a dose of 2 million IU lie in the range from concentrations below the detection limit to 0.53 mg/L. When comparing these rates with the drug concentration in blood plasma after parenteral administration, it can be concluded that its absorption is insignificant, which is also confirmed by the fact that after inhalation of 2 million IU of colistimethate sodium, the average total renal excretion rate is approximately 4%. However, with inhalation use, the possibility of systemic absorption should always be kept in mind. After 1 to 4 hours following inhalation of 1-2 million IU of colistimethate sodium, its concentration in sputum is 16-180 mg/L. About 15% of the administered dose is retained in the lungs.

Distribution
The volume of distribution of colistin in healthy volunteers is low and corresponds approximately to the volume of extracellular fluid. The volume of distribution increases proportionately in patients with life-threatening infections. Penetration of colistimethate sodium into tissues and body fluids is limited, including into the cerebrospinal fluid through the inflamed meninges. Concentrations in urine are 20-40 times higher than those in serum. Plasma protein binding is low (less than 10%). The elimination half-life from blood serum is 2-3 hours. Colistimethate sodium crosses the placenta.

Elimination
After intravenous administration, about 60% of the administered dose is excreted unchanged by the kidneys, where maximum concentrations are observed 2-4 hours after administration. This presumably also applies to the portion absorbed by the inhalation route. Colistimethate sodium not absorbed after inhalation presumably is mainly excreted with sputum. Colistin is extensively reabsorbed by the renal tubules and can be excreted both extrarenally and through renal metabolism with the possibility of cumulation in the kidneys. After administration to healthy volunteers and patients with cystic fibrosis, the half-life of colistin is approximately 3 hours and 4 hours, respectively, with a total clearance of about 3 L/hour. In patients with life-threatening infections, the half-life may be increased to 9-18 hours.

Kinetics in certain patient subgroups
The clearance of colistimethate sodium depends on the creatinine clearance, therefore, as kidney function decreases, more and more CMS is converted to colistin. In patients with renal failure (creatinine clearance (CC) less than 30 mL/min), the conversion rate can reach 60-70%. Colistin clearance is reduced in renal failure, probably due to increased CMS conversion.
Due to the low systemic bioavailability during inhalation of colistimethate sodium, the risk of drug accumulation in the body of patients with renal failure is assessed as low.

Indications
Systemic use:
Treatment of serious infections caused by certain susceptible aerobic Gram-negative microorganisms in adults and children with limited choice of antibiotic therapy.

Inhalation use:
Chronic respiratory tract infections caused by Gram-negative bacteria susceptible to colistimethate sodium, especially Pseudomonas aeruginosa; cystic fibrosis.
Official guidelines for the proper use of antibacterial agents should be followed.

Contraindications

  • Hypersensitivity to colistimethate sodium, colistin or polymyxin B;
  • myasthenia gravis;
  • children under 6 years old (for inhalation administration);
  • impaired renal function in children under 18 years old (for systemic use).

With caution
General: impaired renal function, impaired liver function, porphyria, concomitant use with potentially nephrotoxic or neurotoxic drugs (see “Interaction with other drugs”), concomitant use of different dosage forms of colistimethate sodium.
Additionally for systemic use: hypovolemia, children under 18 years old.
Additionally for inhalation use: hemoptysis, bronchial hyperreactivity (see “Special Instructions”).

Use during pregnancy and breastfeeding
Pregnancy
The clinical safety of the use of colistimethate sodium during pregnancy has not been studied.
Colistimethate sodium crosses the placental barrier and may lead to fetal toxicity. The drug should not be used during pregnancy unless the benefit to the mother outweighs the potential risk to the fetus.
Breastfeeding
Colistimethate sodium is excreted in breast milk. If the use of colistimethate sodium during lactation is necessary, breastfeeding should be discontinued.

Dosage and administration
Systemic use
The use of colistimethate sodium for the treatment of patients with Gram-negative aerobic infections with limited choice of antibiotic therapy should be done only after consultation with a physician having relevant experience in the treatment of infectious diseases.

The dose and duration of therapy should be adjusted according to the type and severity of the infection and the patient condition. Appropriate clinical guidelines should also be followed. The following dosing recommendations are based on the results of a pharmacokinetic study in a limited population of patients with life-threatening infections.

The maintenance daily dose of the drug for adults and adolescents is 9 million IU divided into 2-3 administrations. Patients with life-threatening infections are administered an initial loading dose of 9 million IU. The most appropriate time interval for the administration of the first maintenance daily dose has not been established. Pharmacokinetic modeling shows that, in some cases, patients with normal renal function may require loading and maintenance daily doses of up to 12 million IU. However, clinical experience with these doses is extremely limited and their safety has not been established.

The loading dose is applicable to patients with normal and impaired renal function, including patients on renal replacement therapy.

Special populations
Impaired renal function
Patients with impaired renal function require dose adjustment, but very few pharmacokinetic data is available for this category of patients.
The following information on dose adjustment should be considered as recommendations. Dosage reduction is recommended for patients with CC less than 50 mL/min:
It is recommended to use twice a day.

Creatinine clearance, mL/min Daily dose, mln U/day
<50-30 5,5-7,5
<30-10 4,5-5,5
<10 3,5

Hemodialysis and long-term hemodiafiltration

Colistin is removed during conventional hemodialysis and continuous veno-venous hemodiafiltration (CVVHF, CVVHDF). Very few data is available on the pharmacokinetics of colistimethate sodium in patients on renal replacement therapy. No specific dosage recommendations can be made. The following dosing regimens can be considered.

Hemodialysis
Dose on days without hemodialysis: 2.25 mln U/day (2.2 – 2.3 mln U/day).
Dose on days of hemodialysis: 3 mln U/day on the day of hemodialysis, after a hemodialysis session. It is recommended to administer twice a day.
Veno-venous hemodiafiltration (CVVH, CVVHDF)
Doses as for patients with normal renal function. It is recommended to use three times a day.
Impaired hepatic function
Data on patients with impaired liver function is not available. Caution is required when using the drug in this patient population.
Elderly patients (over 65 years old)
Dose adjustment in elderly patients with normal renal function is not required.

Children
Very little data is available on dosing regimen in children. When choosing a dose, the maturity of the kidneys should be taken into account. The dose is calculated on the basis of dry body weight (excluding adipose tissue).
Children weighing ≤ 40 kg: 75,000 – 150,000 U/kg/day divided into three administrations.
In children weighing more than 40 kg use the doses recommended for adults and adolescents.
Doses above 150,000 U/kg/day have been reported in children with cystic fibrosis.
There is no data on the use or on the loading dose in children with life-threatening infections. There are no recommendations for dosing regimen in children with impaired renal function.

Route of administration and preparation:
The drug can be administered intravenously as a slow infusion during 30-60 minutes. In patients with a fully implanted venous access device, the drug can be administered as a bolus injection over at least 5 minutes at a dose of up to 2 million IU in 10 mL of solvent.

To prepare a solution for bolus administration, dissolve the contents of the vial in 0.9% sodium chloride solution or water for injection. The volume of the solution is not more than 10 mL. The powder dissolves by gentle shaking. Strong agitation should be avoided due to excessive foaming.

To prepare a solution for infusion, dissolve the contents of the vial first in 0.9% sodium chloride solution or water for injection. The volume of the solution is not more than 10 mL. The powder dissolves by gentle shaking. Strong agitation should be avoided due to excessive foaming. Then add the reconstituted solution, as a rule, to 50 mL of 0.9% sodium chloride solution.

Colistimethate sodium undergoes hydrolysis in aqueous solution to colistin. The solution for injection, especially when several vials are used, should be prepared under strict aseptic conditions. The hydrolysis of colistimethate sodium increases significantly after reconstitution and dilution to a concentration below the critical micellization concentration, which is about 80,000 IU/mL. Solutions below the specified concentration should be used immediately.

Table of drug doses conversion in various units
The dose of comistimethate sodium (CMS) should be calculated and administered in IU only. The drug label specifies IU per vial. The dose in different countries can be expressed in milligrams of colistin base potency (mg CBA).
See the CMS dose conversion table below. The specified values are considered nominal and approximate.

Strength
International units (IU) ≈ mg СВА ≈ CMS weight (mg)*
12 500  0.4 1
150 000 5 12
1 000 000 34 80
4 500 000 150 360
9 000 000 300 720

* Nominal drug substance concentration = 12.500 U/mg

Inhalation use:
It is recommended that the inhalation use of the drug be carried out under the supervision of doctors having relevant experience in its use.

Dose regimen
The dosage is determined individually and may be adjusted depending on the condition severity and the clinical response.
It is administered by inhalation, for example through a nebulizer. The solution for inhalation should be prepared immediately before the inhalation procedure.
The daily dose of the drug for adults and children over 6 years old ranges from 2 million IU to 6 million IU, depending on the severity of the disease. Usually 1 million IU 2 times a day every 12 hours is used. With the development of pathogen resistance, the dose can be increased up to 2 million IU 3 times a day. The duration of sanitation therapy for primary colonization/infection caused by Pseudomonas aeruginosa ranges from 3 weeks to 3 months. There are no time constraints on the duration of therapy for chronic infection caused by Pseudomonas aeruginosa. Special populations

Impaired renal function
No dose adjustment is required. It is recommended to use caution when treating patients with renal failure (see “Pharmacokinetics” and “Special Instructions”).
Impaired hepatic function No dose adjustment is required.
Elderly patients (over 65 years old)
No dose adjustment is required.

Administration method
The procedure for handling the drug
For the use of antibiotics in the form of an aerosol, jet (compressor) or membrane nebulizers are recommended. When using and maintaining the nebulizer, follow the manufacturer’s instructions. Standard nebulizers create a continuous aerosol flow, so particles of colistimate sodium nebulized can evaporate into the environment. To avoid this, it is recommended to use standard nebulizers in well-ventilated areas. The use of appropriate filters/valves will help minimize the evaporation of colistimethate sodium into the atmosphere.

1. Open the powder vial by removing the aluminum cap and the rubber stopper.
2. Dissolve the contents of the vial in 0.9% sodium chloride solution or water for injection. The solution volume should be in accordance with the nebulizer manufacturer’s instructions and, as a rule, no more than 3 mL (for a 1,000,000 IU (80 mg) vial) and no more than 4 mL (for a 2,000,000 IU (160 mg) vial). The powder dissolves by gentle shaking. Strong agitation should be avoided due to excessive foaming.
3. Pour the solution into the nebulizer and use by inhalation according to the nebulizer manufacturer’s instructions. The inhalation procedure is considered over after the complete use of the solution.
4. The patient performs the Colistimet AF inhalation in a sitting or standing upright position, in a normal relaxed state, taking as deep breaths as possible through the nebulizer mouthpiece. A nose clip can facilitate inhalation through the mouth.
5. After each use, the mouthpiece should be rinsed and disinfected following the manufacturer’s instructions. In patients receiving such types of inhalation therapy as bronchodilators, inhalation of Colistimet AF should be done immediately after their use, as well as after physiotherapy procedures on the chest.

Do not mix the prepared solution of Colistimet AF with other drugs.
Prepare a fresh solution immediately before inhalation. The drug should be stored in its original packaging (a vial in a cardboard box) to protect the contents from exposure to light. The contents of the vial are intended for single use only, the unused residue of the drug must be disposed of.

Adverse effects
Systemic administration
The most common adverse reactions reported with the systemic administration of colistimethate sodium are nervous system disorders – in about 27% of patients with cystic fibrosis; nephrotoxicity – in about 20% of patients without cystic fibrosis.
Respiratory, thoracic and mediastinal disorders: apnea
Immune system disorders: hypersensitivity reactions such as rash, drug fever.
Nervous system disorders: facial paresthesia, vertigo, vasomotor instability.
Psychiatric disorders: speech disorder, confusion, psychosis.
Eye disorders: visual disturbances.
Renal and urinary disorders: acute renal failure.
General disorders and administration site conditions: irritation at the injection site.

Inhalation use

The most common adverse reactions reported with sodium colistimethate inhalation are cough and bronchospasm in about 10% of patients.
Adverse reactions are systematized in accordance with the Classification of the World Health Organization (WHO):
Very common ≥ 1/10
Common ≥1/100 – < 1/10
Uncommon ≥ 1/1,000 – <1/100
Rare ≥1/10,000 – <1/1,000
Very rare: ≤ 1/10,000
Frequency unknown (cannot be determined from the data available).

Very common:
Respiratory, thoracic and mediastinal disorders: bronchospasm, dyspnea, increased cough, increased sputum production, respiratory mucositis, pharyngitis.

Insufficient information:
Infections and infestations: oral candidiasis, proliferation of resistant microorganisms is possible with prolonged use.
Immune system disorders: hypersensitivity reactions such as rash, itching, angioedema.
Nervous system disorders: dizziness, paresthesia. Gastrointestinal disorders: nausea, burning sensation in the tongue, unpleasant taste sensations.
Renal and urinary disorders: acute renal failure.

Overdose
Systemic use
Neuromuscular blockade (muscle weakness, apnea, respiratory arrest is likely); acute renal failure (decreased urination volume, increased plasma urea and creatinine concentrations).
Treatment: supportive care. Measures to increase the elimination rate of colistin may be used, such as diuresis with mannitol, prolonged hemodialysis, or peritoneal dialysis, but their effectiveness is unknown. There is no specific antidote.

Inhalation use
With the inhalation use, the entry of colistimethate sodium into the systemic circulation and, therefore, the risk of developing intoxication is extremely low. To date, there have been no reports of the development of such reactions.

Interactions with other drugs
Due to the effects of colistimethate sodium on acetylcholine release, non-depolarizing muscle relaxants should be used with caution as their action may be prolonged.
With the simultaneous use of potentially neurotoxic drugs (for example, aminoglycosides, cephalosporins, non-depolarizing muscle relaxants), including those administered intravenously or intramuscularly, treatment with Colistimet AF should be carried out with caution due to the possibility of increased neurotoxicity.

With the simultaneous use of potentially nephrotoxic drugs (aminoglycosides, cephalosporins, cyclosporine, loop diuretics, including furosemide, ethacrynic acid, etc.), treatment with Colistimet AF should be carried out with caution due to the possibility of increased nephrotoxicity.

With the simultaneous use of Colistimet AF with inhalation anesthetics (for example, halothane), muscle relaxants of central and peripheral action and aminoglycosides, the risk of neuromuscular transmission blockade increases.

With the simultaneous use of Colistimet AF with other forms of colistimetate sodium, the risk of adverse reactions may increase. No in vivo interaction studies have been performed. The mechanism for the conversion of colistimethate sodium to colistin has not been established. The elimination mechanism of colistin, including renal clearance, is also unknown. In vitro studies on human hepatocytes have shown that neither colistimethate sodium nor colistin induce the activity of the P450 isoenzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP3A4/5.

Potential drug interactions should be kept in mind when Colistimet AF is used concomitantly with drugs that inhibit or induce metabolizing enzymes or drugs that are substrates for renal transport mechanisms.

Caution should be exercised when co-administering colistimethate sodium intravenously with neurotoxic and/or nephrotoxic drugs. These drugs include aminoglycoside antibiotics: gentamicin, amikacin, netilmicin and tobramycin. Incompatibility: do not mix the prepared solution of Colistimet AF with other drugs.

Special instructions
As with other antibiotics, during the use of Colistimet AF, strains of resistant microorganisms may appear. After discontinuation and/or replacement of therapy, restoration of drug effectiveness is possible.

When possible, concomitant use of intravenous colistimethate sodium with another antibacterial agent should be considered, taking into account the remaining susceptibility of pathogenic microorganisms. Since the development of resistance to intravenous colistin has been reported, in particular when used as monotherapy, the possibility of concomitant use with another antibacterial agent should also be considered to prevent such resistance.

Limited clinical data is available on the efficacy and safety of intravenous colistimethate sodium. All recommended doses for patient subgroups are based on limited data (clinical and pharmacokinetic/pharmacodynamic data). In particular, there is very few data on the safety of high doses (> 6 million U/day) and loading doses, as well as safety in special patient populations (patients with impaired renal function and children). The use of colistimethate sodium is justified only in cases where other, more commonly prescribed antibiotics are ineffective or unacceptable.

Monitoring of renal function should be performed at the beginning of treatment and regularly during treatment in all patients. With systemic use, a dose adjustment of the drug is necessary depending on the CC (see “Dosage and administration”). In patients with hypovolemia or in those taking potentially nephrotoxic drugs the systemic use of colistimethate sodium  increases the risk of developing nephrotoxicity. Some studies reported that the development of nephrotoxicity is associated with the cumulative dose and duration of treatment. The benefits of a long course of treatment should be weighed against the potential increased risk of nephrotoxicity.

Special care should be taken when using colistimethate sodium in children under 1 year old, since in this group of patients renal function is not yet fully developed, and the effect of undeveloped renal and metabolic function on the conversion of colistimethate sodium to colistin is unknown.

In patients with impaired renal function, the possibility of developing nervous system side effects should be carefully monitored and kidney function should be checked regularly.
Caution should be exercised in the treatment of patients taking concomitant nephrotoxic drugs; it is necessary to monitor renal function regularly.
The concomitant neurotoxic drugs should be used with caution under the supervision of a physician.

High plasma concentrations of colistimethate sodium, which may be associated with an overdose or inability to reduce the dose in patients with renal failure, have been reported to cause neurotoxic effects such as facial paresthesia, muscle weakness, vasomotor instability, speech impairment, vertigo, visual disturbances, confusion, psychosis and apnea. Regular monitoring is necessary to control the possible development of paresthesia (perioral paresthesia and limb paresthesia), which is a symptom of an overdose.

Respiratory arrest has been reported following intramuscular administration of colistimethate sodium. Impaired renal function increases the risk of developing apnea and neuromuscular blockade after the use of colistimethate sodium.

In the event of an allergic reaction, treatment with the drug should be discontinued and an appropriate therapy should be given.

After intravenous administration, colistimethate sodium does not cross the blood-brain barrier to a clinically significant extent.

With porphyria, it must be taken into account that Colistimet AF can enhance clinical manifestations of this disease, therefore, in such patients, colistimetate sodium should be used with extreme caution.

Antibiotic-associated colitis, including pseudomembranous colitis, has been observed with virtually all antimicrobial agents and may occur following the use of colistimethate sodium. The severity of symptoms can range from mild to life threatening. It is very important to consider this diagnosis in patients who develop diarrhea during or after the use of colistimethate sodium. Treatment interruption and specific medicines should be considered for the treatment of colitis caused by Clostridium difficile. It is forbidden to take medicines that suppress peristalsis. Colistimet AF as inhalation monotherapy should not be used to treat exacerbations of a chronic infection caused by Pseudomonas aeruginosa.

Inhalation use of Colistimet AF can cause acute bronchospasm in patients with hypersensitivity. In this regard, the first dose of Colistimet AF for inhalation should be administered under the supervision of experienced medical personnel experienced in the treatment of cystic fibrosis, with the inhalation preceded by the use of a bronchodilator, if this is a part of the treatment regimen for this patient. Before and after the Colistimet AF inhalation, the forced expiratory volume in the first second (FEV1) should be measured. If a patient not receiving bronchodilators shows signs of drug-induced bronchial obstruction, the next time of using Colistimet AF the test (FEV1) should be repeated with adding a bronchodilator.

In case of using in hemoptysis, it is necessary to take into account the risk-benefit ratio, since inhalations of Colistimet AF can increase cough.

When giving inhalation treatment with dornase alfa and Colistimet AF, it is necessary to take a break between inhalations.

Effects on the Ability to Drive and Use Machines
Colistimet AF can change the reaction time, for example, due to the possibility of developing dizziness, confusion, visual impairment, therefore, during treatment one should refrain from driving and engaging in potentially hazardous activities that require increased mental alertness and speed of psychomotor reactions; it is forbidden to drink alcohol.

Presentation
Powder for solution for injection, infusion and inhalation 80 mg (1,000,000 IU), 160 mg (2,000,000 IU).
80 mg (1,000,000 IU) or 160 mg (2,000,000 IU) of the active substance in 10 mL 1st hydrolytic class glass vials tightly sealed with medical rubber stoppers and crimped with aluminum caps or combined flip-off caps.

5.0 mL of solvent (0.9% sodium chloride solution) in 5.0 mL grade NS-3 neutral glass or 1st hydrolytic class ampoules. Ampoules with a cut ring or a notch and OPC can be used.

1 vial with the drug and instructions for medical use are placed in an outer carton.

1 vial with the drug and 1 ampoule with the solvent are placed in a blister pack made of PVC film and lacquered aluminum foil or without foil. One blister pack together with instructions for medical use and an ampoule cutter (ampoule scarifier)** are placed in a cardboard box.
** Note: when using OPC or a cut ring ampoules, no ampoule cutter and/or ampoule scarifier is provided.

For inpatient facilities:
10 to 100 vials with the drug with an equal number of instructions for medical use are placed in a cardboard box with or without partitions.

Storage conditions
Store in a dark place below 25 °C.
Keep out of the reach of children.

Shelf life
of the drug is 3 years
of the solvent is 5 years
Do not use after the expiration date.

Prescription status
Rx only.

Manufacturer
Companiya DEKO, LLC, Russia.
Tver region, Vyshnevolotsky district, Zelenogorsky community, 6a Sovetskaya St. Marketing Authorization Holder
AlPharma, LLC, Russia
127238, Moscow, 3 Nizhnelikhoborsky proezd, bldg 1A, floor 4, prem. X, room 12. Tel.: +7(495) 744-30-00

Company Receiving Consumer Complaints
PHARMCOMPLIANCE PHARMACOVIGILANCE AGENCY, Limited Lability Company
117186, Moscow, 15-8 Nagornaya St., prem. I, office 61.
Tel : +7 495 142 24 87
Cell phone: +7 901 369 45 95
e-mail: pv@farmakonadzor.com

Director General of AlPharma, LLC    S.M. Sidorov

Seal: AlPharma, Limited liability company * OGRN 1127746567904 * Moscow