Injectable Medications and Preservative-free Vials and Preserved, Multiple Dose Vials

McGuff Compounding Pharmacy Services, Inc. is taking this opportunity to inform you of the difference between preservative-free vials and vials containing a preservative:

Vials of injectable preparations are sterile when you receive them. It is only after you penetrate the stopper with the needle that bacteria or other microbes may be inadvertently introduced into the vial. It is essential that you use proper aseptic technique throughout the process of administering an injection regardless whether the vial is preservative-free or contains a preservative.

Vials that will be used more than once should be stored in the refrigerator after they have been opened (with the possible exception of some minerals that may precipitate at cold temperatures). Refrigeration will retard the growth of microbes that may be inadvertently introduced into the vial via the needle.

Preservative-free Vials

These vials contain no preservative. These vials should be penetrated only once and then discarded.

However, some doctors may have instructed their patients to use a preservative-free vial more than one time. These physicians may be concerned that the patient is allergic to preservatives or that the patient may experience an adverse effect from the preservative. Because these vials contain no antimicrobial preservative, there is nothing to inhibit the growth of bacteria that may be inadvertently introduced when the stopper is penetrated by the needle. Strict aseptic technique must be followed in these instances.

Preserved, Multiple Dose Vials

“Multiple Dose Vials” are intended to be used more than once. They contain antimicrobial preservative agents to help retard the growth of bacteria that may be introduced when the stopper is penetrated via the needle. The great majority of patients can use medications containing preservatives without any problem.

Use after Initial Puncture

Preservative-free vials should be penetrated only once and then discarded.

For multiple dose vials (vials that contain an antimicrobial preservative) the USP states that the effectiveness of antimicrobial preservatives cannot be ensured beyond 28 days following initial penetration of the stopper, unless specified otherwise by the manufacturer. In general, you should date the vial upon initial penetration of the stopper, store the vial in the refrigerator, and discard it 28 days later. An unopened vial may be retained for use until the date indicated on the label if properly stored.

Basic steps to follow to properly manipulate injectable medications for administering intramuscular or subcutaneous injections

It is of utmost importance that the medication vial and the materials used for withdrawing and injecting the medication are sterile before use and that all precautions are taken to ensure that the medication and the materials are not contaminated during the procedure.

To begin, you should have a clean, well-lighted space, which is clear of clutter. Assemble all of the materials you will need: vial of medication, sterile alcohol pads, syringes, needles, and sharps container for used needles and syringes. Wash your hands with soap and dry them well.

If the vial of medication should be shaken before use, shake now. This will allow time for the bubbles to disperse. Remove the flip-top cap from the vial and wipe the rubber stopper with a sterile alcohol pad. Rub well using pressure, and use a new pad for each vial. Allow to air dry while completing the next steps. Assemble the proper syringes/needles for the dose you will be using.

Remove the outer wrapper from the syringe and needle (if applicable) and discard. Remove the plastic cover from the needle end of the syringe and set the cover aside. Be careful not to touch the needle to any surface except for the sanitized rubber stopper of the vial.

Pull back on the syringe plunger to the same volume as the dose you are going to prepare. This allows air to go into the syringe. Slowly push the needle into the rubber stopper at an angle. Invert the vial and push the air into the vial. Draw back on the plunger to the correct dose as measured on the side of the syringe. Invert the vial to its original position and remove the needle.

When you have removed the needle from the vial, carefully recap the needle with the plastic cover without injuring yourself. Allowing the dose of medication to come to room temperature may help to reduce discomfort during administration.

Wipe the injection site on your skin well with a new sterile alcohol pad. Allow the skin to air dry. Remove the plastic cover from the end of the needle and inject the medication in the manner you were shown in the physician’s office. When the entire dose has been injected, remove the needle from the skin and place the entire syringe/needle assembly into the sharps container for used needles and syringes. It is not necessary to recap the needle with the plastic cover. Any materials you used which may have come in contact with blood or are sharp should be discarded in the container. You may place a bandage on the injection site if you wish.

If you will be reusing the vial of medication, store it in the refrigerator. Consult a pharmacist if you are unsure which type of medication should be refrigerated or stored at room temperature.

Note: This information is not intended to cover all aspects of intramuscular or subcutaneous injections.

If you have further questions, please call us at 877-444-1133. Pharmacists are available for consultation from 8 AM to 5 PM, Pacific Standard Time.

APP Pharmaceuticals releasing more preservative-free methotrexate

Continuing to work with FDA to ease the ongoing shortage of injectable methotrexate, APP Pharmaceuticals this week released another 10,000 vials of preservative-free methotrexate (Methotrexate Injection), a drug used in the treatment of pediatric oncology and hematology.  

FDA approved Methotrexate Injection in February. Earlier this month, the Schaumberg, Ill.-based company released 35,000 vials of the sterile injectable chemotherapeutic product.  It expects to release another 10,000 vials by the end of the month, an APP spokesman said.

Scott Meacham, executive vice president and chief commercial officer of APP, said the company benefits from the cooperative efforts with the FDA toward solving drug shortages. 

“APP has repeatedly demonstrated that it can meet the challenges of critical drug shortages and the company was able to easily collaborate with the FDA to obtain expedited approval of preservative-free Methotrexate Injection,” Meacham told
Drug Topics.

Meacham said that after FDA approval, “we quickly adapted our manufacturing schedule in order to produce more doses, so that we are able to get this critically needed drug to clinicians across the United States. ”

For pediatric oncologist Carl Lenarsky, MD, director of the Dallas/Fort Worth-area Pediatric Hematology and Oncology of Texas, release of the preservative-free drug is very good news.

“It just now has gotten to the point where we were beginning to ration our supply. We have been able to give out the drug but we were just a few weeks away from coming down to zero supply,” Lenarsky said.

Lenarsky explained that treatment in pediatric cancers such as “leukemia and certain types of bone cancer” requires therapy with a non-preservative methotrexate injectable, as the antimicrobial preservative benzyl alcohol is known to cause illness in children.

“We inject a high-dose methotrexate directly into the nervous system via the spinal cord to prevent the cancer from going to the brain, so it is essential we use preservative-free methotrexate,” he said.

Each year there are 3,000 children diagnosed with acute lymphoblastic leukemia, which Lenarsky said projects to “9,000 or 10,000 patients who are on the therapy at any given time, and, as the treatment typically lasts 3 years, that’s a lot of patients who would have been denied proper therapy. ” 

The current FDA boxed warning says that “methotrexate formulations and diluents containing preservatives must not be used for intrathecal or high-dose methotrexate therapy.”

Determination That Methotrexate Injection, USP, Preservative Free, Equivalent to 500 Milligrams Base/20 Milliliters (25 Milligrams/Milliliter), Was Not Withdrawn From Sale for Reasons of Safety or Effectiveness

Start Preamble

Food and Drug Administration, HHS.

Notice.

The Food and Drug Administration (FDA) has determined that methotrexate injection, USP, preservative free, equivalent to (Eq.) 500 milligrams (mg) base/20 milliliters (mL) (25 mg/mL), was not withdrawn from sale for reasons of safety or effectiveness. This determination will allow FDA to approve abbreviated new drug applications (ANDAs) for methotrexate injection, preservative free, Eq. 500 mg base/20 mL (25 mg/mL).

Start Further Info

Elena Cohen, Center for Drug Evaluation and Research (HFD-7), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-594-2041.

End Further Info
End Preamble
Start Supplemental Information

In 1984, Congress enacted the Drug Price Competition and Patent Term Restoration Act of 1984 (Public Law 98-417) (the 1984 amendments), which authorized the approval of duplicate versions of drug products approved under an ANDA procedure. ANDA applicants must, with certain exceptions, show that the drug for which they are seeking approval contains the same active ingredient in the same strength and dosage form as the “listed drug,” which is typically a version of the drug that was previously approved. ANDA applicants do not have to repeat the extensive clinical testing otherwise necessary to gain approval of a new drug application (NDA). The only clinical data required in an ANDA are data to show that the drug that is the subject of the ANDA is bioequivalent to the listed drug.

The 1984 amendments include what is now section 505(j)(7) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(j)(7)), which requires FDA to publish a list of all approved drugs. FDA publishes this list as part of the “Approved Drug Products With Therapeutic Equivalence Evaluations” which is generally known as the “Orange Book.” Under FDA regulations, drugs are removed from the list if the agency withdraws or suspends approval of the drug’s NDA or ANDA for reasons of safety or effectiveness or if FDA determines that the listed drug was withdrawn from sale for reasons of safety or effectiveness (21 CFR 314.162).

Under 21 CFR 314.161(a)(1), the agency must determine whether a listed drug was withdrawn from sale for reasons of safety or effectiveness before an ANDA that refers to that listed drug may be approved. FDA may not approve an ANDA that does not refer to a listed drug.

Methotrexate injection, USP, preservative free, Eq. 500 mg base/20 mL (25 mg/mL), is the subject of approved NDA 11-719 currently held by Mayne Pharma USA (Mayne). Although NDA 11-719 was originally approved in 1959, this formulation and dosage was approved in April 2005 (S-108). Methotrexate is an antifolate cytotoxic drug used in the treatment of a variety of malignancies, including acute lymphoblastic leukemia, osteosarcoma, advanced metastatic breast cancer, and others. It is also used to treat some inflammatory conditions such as rheumatoid arthritis. To date, Mayne has not marketed methotrexate injection, USP, preservative free, Eq. 500 mg base/20 mL (25 mg/mL). At the request of the sponsor, the product was moved to the discontinued section of the Orange Book in June 2005. In previous instances (see, e.g., the Federal Register document of December 30, 2002 (67 FR 79640), addressing a relisting request for Diazepam Autoinjector), the agency has determined that, for purposes of §§ 314. 161 and 314.162, never marketing an approved drug product is equivalent to withdrawing the drug from sale.

SICOR Pharmaceuticals, Inc., submitted a citizen petition dated Start Printed Page 44560December 15, 2006 (Docket No. 2006P-0520/CP1), under 21 CFR 10.30, requesting that the agency determine whether methotrexate injection, preservative free, Eq. 500 mg base/20 mL (25 mg/mL), was withdrawn from sale for reasons of safety or effectiveness. The petitioner has identified no data or other information suggesting that methotrexate injection, preservative free, Eq. 500 mg base/20 mL (25 mg/mL), was withdrawn from sale for reasons of safety or effectiveness. FDA has independently evaluated relevant literature and data for possible postmarketing adverse events and has found no information that would indicate this product was withdrawn for reasons of safety or effectiveness.

After considering the citizen petition and reviewing agency records, FDA has determined that, for the reasons outlined in this document, methotrexate injection, preservative free, Eq. 500 mg base/20 mL (25 mg/mL), was not withdrawn from sale for reasons of safety or effectiveness. Accordingly, the agency will continue to list methotrexate injection, preservative free, Eq. 500 mg base/20 mL (25 mg/mL), in the “Discontinued Drug Product List” section of the Orange Book. The “Discontinued Drug Product List” delineates, among other items, drug products that have been discontinued from marketing for reasons other than safety or effectiveness. ANDAs that refer to methotrexate injection, preservative free, Eq. 500 mg base/20 mL (25 mg/mL), may be approved by the agency as long as they meet all relevant legal and regulatory requirements for the approval of ANDAs. If FDA determines that labeling for these drug products should be revised to meet current standards, the agency will advise ANDA applicants to submit such labeling.

Start Signature

Dated: July 30, 2007.

Randall W. Lutter,

Deputy Commissioner for Policy.

End Signature
End Supplemental Information

[FR Doc. E7-15490 Filed 8-7-07; 8:45 am]

BILLING CODE 4160-01-S

Methotrexate Injections for Rheumatoid Arthritis

 

Why inject methotrexate for RA?

There are 3 main reasons that methotrexate injections may be used instead of oral tablets.

1. Methotrexate side effects may be much less with injectable methotrexate.
2. More methotrexate is absorbed with injections, so often it works better to fight RA.
3. A higher dose can be administered with injectable methotrexate than is tolerable with oral methotrexate.

 

Is all methotrexate for RA the same?

There are major brands like Trexall or Rheumatrex, but methotrexate comes in generics as well. With a drug as old as methotrexate, the generics are considered virtually equivalent. However, using methotrexate from the same manufacturer each time is best.

Injectable methotrexate comes in cute little glass vials so you see its revolting yellow color. The bottles are different sizes. Some are intended for using a single time and then discarding. Larger bottles can be used several times. It’s much easier for RA hands to use the larger bottles.

What about preservative-free methotrexate

If a methotrexate vial is being reused, it ought to contain preservatives. The preservatives are added to prevent deterioration of the medicine or inhibit growth of bacteria or fungus. Preservatives are particularly necessary to maintain sterility of medicine intended for multiple use.

Pharmaceutical preservatives contain antioxidants or antimicrobials. The antioxidants may be familiar things like vitamin A or citric acid. There are also some synthetic preservatives. Methotrexate does come in a preservative-free form for those who have shown hypersensitivity to pharmaceutical preservatives.

Buying injectable methotrexate

My own injectable methotrexate prescription has been filled several different ways. I finally learned to inquire of the pharmacist each time. I just ask: “How many times am I intended to use this vial? Does this methotrexate contain preservatives?” Otherwise, it is possible to request exactly what I need in advance.

There have been times when all that was available were larger bottles in a preservative-free formula. Imagine how difficult it was for a thrifty girl like me to throw away almost full bottles because the pharmacist told me it was not safe for a second use.

Perhaps that sounds overly cautious. However, infection is the arch rival of an RA’er living on immune suppressing medicine. Preventative first aid, as I call it, is an art that we attempt to perfect.         

Click here to read part 2 of Methotrexate Injections for Rheumatoid Arthritis: Needles. 

Recommended reading:

End to cancer drug shortage is unclear – Amy in the News

By: Associated Press report

TRENTON, N.J. — A severe shortage of a childhood cancer drug should ease before hospitals run out of it in a couple weeks, a top federal regulator said Tuesday. But the companies that make the drug are giving few details about how they will find a long-term solution to end the problem.

Valerie Jensen, associate director of the Food and Drug Administration’s drug shortage program, said her team is working with the three makers of preservative-free methotrexate, which is used to treat the most common childhood cancer, acute lymphoblastic leukemia, or ALL.

The drug, which cures up to 90 percent of children with ALL, has been in very short supply in recent weeks because a leading maker of the drug shut down some of its factories late last year.

Hospitals have warned the FDA that treatments for children with ALL could be stalled if new shipments of the drug aren’t received within a couple weeks. That could lessen the chances of children being cured of the disease.

“We understand from all three companies that they will be starting to ship by the end of the month,” Jensen told the Associated Press. She noted that federal regulations bar the FDA from discussing plans of specific companies, as that’s considered proprietary information.

The three manufacturers of the drug — Mylan Inc., Hospira Inc. and Sandoz Inc. — weren’t specific about how they plan to resolve the shortage of the cancer medicine:

Mylan says it’s working on increasing manufacturing capacity, which includes getting approval for that from the FDA. The company has an emergency supply of small vials of methotrexate, and plans to ship larger vials at the end of the month.

Hospira temporarily boosted production to address the shortage issue, but then ran out of the active ingredient. It is still producing some of the drug, but is trying to get more of the active ingredient.

Sandoz is aiming to ship some of the drug in late February. The company did not provide any details.

APP Pharmaceuticals LLC, which makes a form of methotrexate with preservative, said it is working with the FDA to determine whether it could get approval for a preservative-free formula. The preservative-free version is needed by both children and adults when methotrexate is given in very high doses intravenously or by injection in spinal fluid. Preservatives in the drug can cause potentially fatal respiratory and organ damage or, when put into spinal fluid, paralysis.

Dr. Peter Adamson, chairman of the Children’s Oncology Group, a network of 200-plus North American hospitals treating children with cancer, said FDA officials “have been reassuring in discussions that this is not going to be a prolonged shortage.”

Still, he said: “Until the drug is actually delivered, we can’t be sure.”

Until late last year, five drugmakers in the U.S. manufactured the generic injected cancer medicine methotrexate, which is crucial for treating children and adults with ALL as well as children with other, less-common cancers.

Four of those companies made a preservative-free version. So, when one of the biggest makers of the preservative-free methotrexate, Ben Venue Laboratories Inc. , recently shut down its four factories in Bedford, Ohio, possibly for a year, due to serious quality problems, the on-again, off-again methotrexate shortage that began in late 2008 quickly turned into a crisis. That’s because the other companies cannot quickly pick up the slack.

Methotrexate is just one of 283 drugs currently in short supply. Those include 27 new shortages reported this year and 215 that began in 2010 or 2011 and remain unresolved, according to Erin R. Fox, manager of the University of Utah Drug Information Service, which tracks national drug shortages.

Meanwhile, several members of Congress have been introducing bills aimed at addressing various causes for the shortage and price gouging that’s been reported by marketers outside hospitals’ normal distribution channel.

Sen. Amy Klobuchar, D-Minn., for a year has been trying to win passage for her bill requiring all drug manufacturers to notify the FDA in advance when they anticipate shortages. Currently, that’s only required if there is only one manufacturer of a particular drug, and there are no penalties for not doing so.

On Tuesday, she proposed adding her bill as an amendment to a pending transportation funding bill.

“In the Senate, it’s so hard to get an individual bill to pass,” Klobuchar said, adding that she’ll keep trying this strategy until it works.

 

Supply of Methotrexate, a Cancer Drug, May Run Out Soon

A crucial medicine to treat childhood leukemia is in such short supply that hospitals across the country may exhaust their stores within the next two weeks, leaving hundreds and perhaps thousands of children at risk of dying from a largely curable disease, federal officials and cancer doctors say.

“This is dire,” said Valerie Jensen, associate director of the Food and Drug Administration’s drug shortages program. “Supplies are just not meeting demand.”

The drug is methotrexate, and the cancer it treats is known as acute lymphoblastic leukemia, or A. L.L., which most often strikes children ages 2 to 5. It is an unusually virulent cancer of white blood cells that are overproduced in bone marrow and invade other parts of the body.

The cancer commonly spreads to the lining of the spine and brain, and oncologists prevent this by injecting large quantities of preservative-free methotrexate directly into the spinal fluid. The preservative can cause paralysis when injected into the spinal column, so cannot be used for this disease. Methotrexate is also used to treat rheumatoid arthritis.

Ben Venue Laboratories was one of the nation’s largest suppliers of injectable preservative-free methotrexate, but the company voluntarily suspended operations at its plant in Bedford, Ohio, in November because of “significant manufacturing and quality concerns,” the company announced.

Since then, supplies of methotrexate have gradually dwindled to the point where oncologists now say they are fearful that shortfalls may occur at many hospitals within two weeks.

“This is a crisis that I hope the F.D.A.’s hard work can help to avert,” said Dr. Michael P. Link, president of the American Society of Clinical Oncology. “We have worked very hard to take what was an incurable disease and make it curable for 90 percent of the cases. But if we can’t get this drug anymore, that sets us back decades.”

Jackson Schwartz, 6, of Langhorne, Pa., received a diagnosis of A.L.L. in August after he complained of terrible stomach pains and spent much of his family’s vacation sleeping on the beach, said his father, Jon Schwartz. A doctor initially gave Jackson a diagnosis of constipation, but when the constipation medicine did not ease his symptoms, Jackson’s parents took him to Children’s Hospital of Philadelphia.

Within a day, doctors started Jackson on methotrexate, and the drug has been an essential part of his treatment ever since. Jackson is scheduled to have methotrexate injected into his spine weekly for the next eight weeks to ensure that his cancer does not return. If the hospital is unable to get more supplies, however, Jackson’s treatment and life may be in serious jeopardy, Mr. Schwartz said.

“It would be devastating if we can’t get this drug,” he said.

There are four other manufacturers of methotrexate in the United States, and they are trying to increase production, Ms. Jensen said. The F.D.A. is also seeking a foreign supplier to provide emergency imports until the approved domestic ones can meet demand, she said.

“We’re working on many fronts, and will keep this a priority,” Ms. Jensen said.

So far this year, at least 180 drugs that are crucial for treating childhood leukemia, breast and colon cancer, infections and other diseases have been declared in short supply — a record number. Prices for some have risen as much as eightyfold. President Obama issued an executive order in October to help ease the problems.

“People are panicking” about the methotrexate shortage, said Erin Fox, manager of the drug information service at the University of Utah. “There isn’t a lot of hope that supplies will improve drastically over the next few weeks, which is why people are so worried.”

Methotrexate Injection (generic methotrexate 50 mg/2 mL, Otrexup, Rasuvo)

Methotrexate Injection (generic methotrexate 50 mg/2 mL, Otrexup™, Rasuvo®)

SELF ADMINISTERED – Injection

FDA Approved Indications:

• Magagement of patients with severe, active rheumatoid arthritis (RA) and polyarticular juvenile idiopathic arthritis (pJIA), who are intolerant of or had an inadequate response to first-line therapy
• Symptomatic control of severe, recalcitrant, disabling psoriasis in adults who are not adequately responsive to other forms of therapy

Approved Indications and Usage Guidelines:

• Generic Methotrexate Injection
  • 1. Diagnosis of severe, active rheumatoid arthritis, polyarticular juvenile idiopathic arthritis or severe, recalcitrant, disabling psoriasis.

• Otrexup or Rasuvo (methotrexate) Injection:
  • 1. Diagnosis of severe, active rheumatoid arthritis, polyarticular juvenile idiopathic arthritis or severe, recalcitrant, disabling psoriasis, AND
  • 2.  Failure or clinically significant adverse effects to generic methotrexate injection, OR medical justification why generic cannot be considered (e.g. inability to use syringe and vial due to severe disfiguring/disabling condition) supported by chart note documentation

Coverage is Not Authorized For:

• Non-FDA approved indications, which are not listed in the Approved Indications and Usage Guidelines section, unless there is sufficient documentation of efficacy and safety in the published literature

General Information:

• Otrexup™ and Rasuvo® are not indicated for the treatment of neoplastic diseases

Recommended Dosing Regimen and Authorization Limit:

• Recommended starting doses:
  • Otrexup™, Rasuvo®:
    • RA: 7. 5 mg once weekly
    • pJIA: 10 mg/m² once weekly
    • Psoriasis: 10-25 mg once weekly

Availability:

• Otrexup™: Autoinjector that administers a single 0.4 mL dose: 10 mg/0.4mL methotrexate, 15 mg/0.4mL methotrexate, 20 mg/0.4mL methotrexate, 25 mg/0.4mL methotrexate
• Rasuvo®: Preservative-free sterile solution for a single subcutaneous injection: 7.5 mg/0.15 mL, 10 mg/0.20 mL, 12.5 mg/0.25 mL, 15 mg/0.30 mL, 17.5 mg/0.35 mL, 20 mg/0.40 mL, 22.5 mg/0.45 mL, 25 mg/0.5 mL, 27.5 mg/0.55 mL, 30 mg/0.60 mL

Approval:

 

Last review date: August 28, 2020

Leukemia Clinical Study: BuCy vs. BuFlu – Clinical Trials Registry

Detailed Description

1. TREATMENT PLAN – Patients will be placed in a laminar flow room. – Patients will receive a Hickman three-lumen central venous catheter (CVC). Vancomycin 1 g IV immediately prior to CVC administration and 1 g every 12 hours for 3 After CVC placement, a chest x-ray should be taken to confirm the location of the CVC and the absence of pneumothorax.- Lumbar puncture and intrathecal methotrexate without preservatives will be done 10 / (the total amount should not exceed 12 given). Folinic acid 15 will be administered orally or intravenously. 24 hours after intrathecal administration of methotrexate and every 6 hours, 4 doses in total. – Women who are menstruating will receive norethindrone (norlutate) 10 μl orally per day. 2. The preparation regimen is as follows: – Conditioning therapy will begin on day 7 in patients randomized to receive intravenous busulfan (Busulfex®; Orphan Medical, Minnetonka, MN) plus cyclophosphamide.Busulfex 3.2 ㎎ / will be administered once a day for 4 days (days -7 to -4) followed by cyclophosphamide 60 / in D5W 200 intravenously for 1-2 hours on days -3 and -2. Busulfex is diluted in physiological solution 500 ㎖ and insisted for 3 days. hours using a pump via a central venous catheter Doses of Busulfex and cyclophosphamide will be calculated using the following guidelines: 1) if the patient’s actual body weight (ABW) is less than or equal to the ideal body weight (IBW), the ABW will be 2) if the ABW is greater than IBW, but less than 20%, then IBW will be used.3) if ABW is greater than IBW greater than or equal to 20%, then the dose will be based on; IBW + 25% (ABW-IBW) IBW is calculated as follows: 50 ㎏ + 2.3 ㎏ (inch height – 60) for men and 45.5 ㎏ +2.3 60 (inch height -60) (1 inch = 2.54 ㎝). – Conditioning therapy will begin on day 7 in patients who are randomized to receive Busulfex plus fludarabine (Fludara®, Schering AG, Berlin, Germany). ㎎ / will be injected once a day for 4 days (days -7 to -4) and fludarabine 30. ㎎ / ㎡ will be injected intravenously over 30 minutes in a D5W 100 ㎖ for 5 consecutive days (-6 to – 2).The Busulfex dose will be calculated using the above (see 5.5.1). Fludarabine dose is calculated using ABW. 3. Prevention of GVHD – All patients will receive cyclosporine 1.5 / v NS 100 intravenously for 2-4 hours every 12 years. hours (the dose of cyclosporine is rounded to the nearest 5 ㎎), the first day of the beginning at 9 am. The dose of cyclosporine will be adjusted to provide an appropriate level and in accordance with the change in renal function (see Appendix II). – When patients can tolerate oral medications, cyclosporin can be administered orally./ (Or twice intravenous dose) every 12 hours. – The dose of cyclosporine will be reduced by 10% every month, starting from the 60th day of BMT. in the absence of clinical data on GVHD. – In addition to cyclosporine, methotrexate 15 15 / will be administered intravenously per day. 1 and 10 / on days 3, 6 and 11 The dose of methotrexate will be reduced or omitted according to the recommendations in Appendix III. – Methotrexate should not be given to patients with acute leukemia or MDS who receive a hematopoietic cell transplant from an HLA-compatible related donor 4. infusion of bone marrow cells – For transplant, selected according to the ABO system or inappropriate insignificant, premedication with Avilom 45.5 mg. Intravenous push and Tylenol 600 ㎎ orally will be given. The stem cells will be injected within 1-2 days. hours – For major transplant with ABO mismatch, premedication Avil 45.5 ㎎ ivpush, Tylenol 600 oral, 10% mannitol 100 g IV over 4 hours will be started 30 minutes before stem cell infusion, and hydrocortisone 250 μL IV will be administered immediately before and 30 min stem cell infusion.5. Supportive therapy. – Dilantin 15 / (ABW) in NS 200 ㎖ intravenously for more than 1 hour for a load per day -8, then 200 orally during the day -5. The dose of dilantin should be adjusted to ensure a therapeutic effect. level. – Allopurinol 300 ㎎ / day orally every day from -8 to -2. – Nystatin powder for groin, armpit and perianal region, 2 times a day from day 8 to absolute neutrophil count (ANC) & gt; 3000 / l. – Sodium bicarbonate / saline mouthwash 4 times a day until mucositis disappears. – Fluconazole 100 / day orally per day until ANC is & gt; 3000 / /. – Ciprofloxacin 500 ㎎ per day (for selective intestinal decontamination) to DRP & gt; 3000 / ㎕. With the first outbreak of fever, ciprofloxacin will be discontinued and spectrum antibiotics will be started. – Hydration will be performed with 0.9% NS at a rate of 100 ㎖ / hour while patients are receiving busulfan. – Immunoglobulin intravenously 500 / (ABW) intravenously over 6 hours every two weeks, starting day -7 to day 120, then every month until day 180.- Herpes simplex virus prophylaxis will include acyclovir 250 ㎎ / in D5W 100 ㎖ intravenously every 8 hours starting at -7 days. When the patient can tolerate oral medications, acyclovir will be given 200 orally for up to 180 days. – Prophylaxis against Pneumocystis carinii will include 2 tablets of Bactrim SS at the rate. with folic acid 7.5 p / d, 2 days a week, starting from engraftment every other day 360. – Amoxacillin 250 ㎎ p.o., starting from the 70th to the 360th day. – Administration of G-CSF.- Starting from the 5th day, G-CSF 300 ㎍ out of 100 D5W will be injected intravenously over 3 hours a day. bye ANC & gt; 3,000 /. – If ANC falls below 1000 / ㎕, G-CSF administration will resume and continue until ANC. & gt; 3000 / ㎕. 6. Patients with acute leukemia or CML with blast crisis intrathecal methotrexate. reception will be resumed after the patient’s platelet count exceeds 50,000 /. Methotrexate 10 / (but no more than 12 in total) will be administered intrathecally. once every 2 weeks three times (a total of four doses, including one previously administered.Folinic acid 15 ㎎ will be administered orally or intravenously 24 hours after methotrexate intrathecally and every 6 hours for a total of 4 doses.

Methotrexate instruction, price in pharmacies for Methotrexate

Composition and form of release

Composition

• active substance: methotrexate;
• 1 ml of concentrate contains 100 mg of methotrexate;
• excipients: sodium hydroxide, water for injection.

Form of issue

• 5 ml (500 mg) or 10 ml (1000 mg), or 50 ml (5000 mg) in a transparent glass bottle, sealed with rubber stoppers and aluminum crimp caps; 1 bottle in a cardboard box.
• 5 ml (500 mg) in ampoule with amber glass; 5 ampoules in a cardboard box.
• 10 ml (1000 mg) in ampoule with amber glass; 1 ampoule or 5 ampoules in a cardboard box.

Pharmacies

Pharmacological.

Methotrexate – a derivative of folic acid, belongs to the cytotoxic drugs of the class of antimetabolites. It acts during the S-phase of the cell cycle and competitively inhibits the enzyme dihydrofolate reductase, thus preventing the reduction of dihydrofolate to tetrahydrofolate, which is necessary for DNA synthesis and cell replication. Actively proliferating tissues such as malignancies, bone marrow, fetal cells, oral and intestinal mucosa, and bladder cells are usually more sensitive to methotrexate.Since the proliferation of malignant tissues is faster than normal, methotrexate can disrupt their development without causing irreparable damage to normal tissues.

Pharmacokinetics.

Approximately 50% of methotrexate binds to blood plasma proteins. After distribution, methotrexate accumulates mainly in the liver, kidneys and spleen in the form of polyglutamate, which can be contained for weeks or months. When used in low doses, a minimum amount of methotrexate penetrates into the cerebrospinal fluid.The terminal half-life of methotrexate varies widely (3-17 hours) and averages 6-7 hours. In patients with a third distribution chamber (hydrothorax, ascites), the half-life of methotrexate can be up to 4 times longer.

Approximately 10% of the dose taken is metabolized in the liver. The main metabolite of methotrexate is 7-hydroxymethotrexate.

Methotrexate is excreted mainly unchanged by the kidneys (by filtration in the glomeruli and active secretion in the proximal tubules).

Approximately 5-20% methotrexate and 1-5% 7-hydroxymethotrexate are excreted in the bile. The available expressed enterohepatic recirculation of methotrexate.

In patients with impaired renal function, the elimination of methotrexate is much slower. It is not known whether abnormal liver function affects the excretion of methotrexate.

Readings

Oncological diseases (in particular acute lymphocytic leukemia, non-Hodgkin’s lymphoma, breast cancer, choriocarcinoma).

Contraindications

Hypersensitivity to methotrexate or other components of the drug.

Significant liver dysfunction (bilirubin level> 85.5 μmol / l).

Alcohol abuse.

Renal dysfunction (creatinine clearance <20 ml / min).

Existing disorders of the hematopoietic system (in particular, bone marrow hypoplasia, leukopenia, thrombocytopenia or severe anemia).

Severe, acute or chronic infections (eg tuberculosis or HIV).

Stomatitis, ulcers of the mucous membrane of the mouth or digestive tract.

The period of pregnancy and lactation (see section “Use during pregnancy or lactation”)

Vaccination with live vaccines during treatment with methotrexate.

Special instructions

Since methotrexate “Ebeve” does not contain preservatives, only one-time withdrawal of the drug from the ampoule is allowed, and unused solutions must be disposed of.

Methotrexate “Ebeve” must not be mixed with other medicinal products in the same infusion bag or bottle.

When handling the drug, the rules for handling cytotoxic substances must be observed. Measures must be taken to prevent the contact of methotrexate solutions on the skin and mucous membranes. Wear protective gloves and goggles. If the drug nevertheless gets on the skin or mucous membranes, the affected area should be immediately washed with plenty of water.

To eliminate temporary burning sensation, you can use a softening hand cream. If there is a threat of absorption of a large amount of methotrexate, regardless of the route of absorption, treatment with leucovorin is necessary.

Pregnant women should not work with the drug.

Remains of the drug and all instruments and materials that were used to prepare the solution for infusion and administer the drug should be destroyed in accordance with the approved procedure for the disposal of cytotoxic substances waste.

In case of outpatient use, do not pour the remains of the drug down the drain or throw them away with other waste.

Interaction with other medicinal products and other forms of interaction.

Alcohol, hepatotoxic and hematotoxic drugs

The risk of the hepatotoxic effect of methotrexate increases in the case of regular use of alcohol or concomitant use of other hepatotoxic drugs. When treating with methotrexate patients taking other hepato- and hematotoxic drugs (eg, leflunomide, metamizole), special care is required.With the simultaneous use of etretinate and methotrexate, the concentration of the latter in the blood plasma may increase and severe hepatitis may develop. With combination therapy with methotrexate and leflunomide, the incidence of pancytopenia and hepatotoxic effects increases.

Oral antibiotics

Oral antibiotics (in particular tetracycline, chloramphenicol and broad-spectrum antibiotics, are not absorbed) can affect enterohepatic circulation due to inhibition of intestinal microflora or inhibition of bacterial metabolism.

Antibiotics

Antibiotics such as penicillins, glycopeptides, sulfonamides, ciprofloxacin and cephalothin can rarely reduce the renal clearance of methotrexate, as a result of which its concentration in the blood serum may increase and the toxic effect on the hematopoietic system and the gastrointestinal tract may increase.

Probenecid, weak organic acids, pyrazoles and nonsteroidal anti-inflammatory drugs

Probenecid, weak organic acids (for example, loop diuretics) and pyrazoles (phenylbutazone) can slow down the excretion of methotrexate, as a result of which its concentration in the blood serum may increase and hematological toxicity may increase.The risk of toxic effects also increases with the combined use of low-dose methotrexate and non-steroidal anti-inflammatory drugs or salicylates.

Drugs that have an adverse effect on the bone marrow

With the simultaneous use of drugs that can cause side effects on the bone marrow (for example, sulfonamide, trimethoprim / sulfamethoxazole, chloramphenicol, pyrimethamine), the possibility of developing more pronounced hematological disorders (in rare cases, acute pancytopenia) should be considered.

Drugs causing folate deficiency

With the simultaneous use of drugs that cause folate deficiency (for example, sulfonamides, trimethoprim / sulfamethoxazole), the toxic effect of methotrexate may increase. Special care is also required when treating patients with existing folate deficiency in the body. Conversely, concomitant administration of folic acid may reduce the effectiveness of methotrexate therapy.

Other anti-inflammatory drugs

When combined with other antirheumatic drugs (for example, gold salts, penicylamine, hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine), the toxic effect of methotrexate is usually not enhanced.

Sulfasalazine

Although, when combined with sulfasalazine, the effect of methotrexate can be potentiated due to inhibition of folic acid synthesis by sulfasalazine (as a result of which the frequency of side effects may increase), however, in several clinical studies, such effects were observed only in isolated cases.

Proton pump inhibitors

With the simultaneous use of methotrexate and proton pump inhibitors (for example, omeprazole or pantoprazole), an interaction may occur.Omeprazole can reduce the renal clearance of methotrexate, and pantoprazole can inhibit the renal elimination of the metabolite 7-hydroxymethotrexate, which in one case was accompanied by the development of myalgia and tremor.

Beverages containing caffeine and theophylline

During treatment with methotrexate, it is necessary to avoid excessive consumption of drinks containing caffeine (coffee, sugary drinks containing caffeine, black tea) and theophylline, since the effectiveness of methotrexate may decrease.

Vinca alkaloids can increase intracellular concentrations of methotrexate and polyglutamate methotrexate.

Bound to plasma proteins, methotrexate can be replaced by salicylates, sulfonamides, phenytoin, tetracyclines, chloramphenicol, sulfazole, doxorubicin, cyclophosphamide and barbiturates. High plasma levels of unbound methotrexate lead to increased toxicity. Salicylates, phenylbutazone, phenytoin, barbiturates, tranquilizers, oral contraceptives, tetracycline, amidopyrine derivatives, sulfonamides and raminobenzoic acid displace methotrexate through bonds with serum albumin, as a result of which the bioavailability of the latter increases (indirectly).

It is necessary to take into account the pharmacokinetic interaction between methotrexate and flucloxacilin (while the area under the pharmacokinetic curve for methotrexate decreases), anticonvulsants (the concentration of methotrexate in the blood decreases) and 5-fluorouracil (half-life of 5-fluorouracil). After the use of methotrexate together with oxacillin and omeprazole, in some cases, a significant increase in the concentration of methotrexate in the blood serum was noted. An interaction between leflunomide and methotrexate has been reported (with the development of liver cirrhosis, musculoskeletal infections and a decrease in platelet count).It is necessary to use methotrexate with caution in combination with immunomodulators during orthopedic surgery when the vulnerability to infection increases.

In the case of simultaneous use with other cytostatics, the clearance of methotrexate may decrease.

Nitric oxide anesthetics can enhance the effects of methotrexate on the metabolic conversion of folic acid, resulting in unpredictable high-grade bone marrow suppression and stomatitis.To reduce the intensity of such phenomena, it is necessary to introduce calcium folinate.

Cholestyramine can enhance extrarenal excretion of methotrexate by interfering with the process of hepatic circulation.

When using methotrexate in combination with other drugs of cytostatic action, slow excretion of methotrexate should be taken into account.

During radiation therapy while the patient is receiving methotrexate, the risk of soft tissue and bone necrosis may increase.

Vitamin complexes and oral iron preparations containing folic acid can alter the body’s response to methotrexate therapy.

Combined treatment with methotrexate and retinoids, for example, acitretin or etretinate, increases the risk of developing hepatotoxicity.

Application features
Treatment with methotrexate should be supervised by an experienced oncologist.

Methotrexate should be used with great caution in the treatment of patients with myelosuppression, impaired renal function, peptic ulcer disease, ulcerative colitis, ulcerative stomatitis, diarrhea, poor general condition, as well as in the treatment of young children and the elderly.

In the presence of pleural exudate or ascites, drainage should be performed before starting treatment with methotrexate. If this is not possible, do not prescribe methotrexate therapy.

If symptoms of a toxic effect on the digestive tract appear (usually stomatitis first), methotrexate treatment should be suspended, since if therapy is continued, hemorrhagic enteritis and intestinal perforation may develop, which pose a threat to the patient’s life.

During therapy with methotrexate, patients should be closely monitored in order to detect early signs of possible toxic effects and side effects. Given the risk of severe or even fatal toxic reactions, patients should be informed in detail about possible complications and recommended measures.

Administration in doses exceeding 20 mg per week is associated with a significant increase in toxic effects, especially inhibition of bone marrow function.

Avoid contact of methotrexate with skin and mucous membranes. In case of contact, flush the contaminated area with plenty of water.

Recommended investigations and precautions

Before starting treatment with methotrexate or when continuing therapy after a break, it is necessary to conduct a blood test to determine the leukocyte formula and platelet count, the activity of liver enzymes, bilirubin, serum albumin, as well as an X-ray examination of the chest organs and renal functional tests.In the presence of clinical indications, prescribe studies to exclude tuberculosis and hepatitis.

During treatment with methotrexate (during the first two weeks – once a week, during the next month – every two weeks, then – depending on the number of leukocytes and the stability of the patient’s condition, at least once a month for the next 6 months and at least every 3 months in the future, with increasing doses, it is advisable to increase the frequency of examinations) conduct the following studies:

Examination of the mouth and throat to detect changes in the mucous membranes.

Blood test with determination of leukocyte formula and platelet count. Even when used in usual therapeutic doses, methotrexate can suddenly cause hematopoietic suppression. In the case of a significant decrease in the number of leukocytes or platelets, treatment with methotrexate should be stopped immediately and symptomatic supportive therapy should be prescribed. Patients should be instructed to report to their doctor immediately about any signs and symptoms suggesting an infection is progressing.With the simultaneous use of hematotoxic drugs (for example, leflunomide), it is necessary to carefully monitor the number of leukocytes and platelets in the blood. When carrying out long-term therapy with methotrexate, a bone marrow biopsy is necessary.

Functional liver function tests. Particular attention should be paid to identifying signs of liver damage. Treatment with methotrexate should not be started or should be stopped in case of any abnormalities in the results of liver function tests or liver biopsy.Usually, the indicators return to normal within two weeks, after which the treatment can be extended by the doctor’s decision. When using methotrexate for rheumatological indications, there is no reason for liver biopsy in order to monitor the hepatotoxic effect of the drug. When treating patients with psoriasis, it is necessary to assess the feasibility of performing a liver biopsy before or during treatment with methotrexate, based on current scientific recommendations. With such an assessment, it is necessary to differentiate between patients without risk factors and patients at risk (for example, previously abused alcohol, with a persistently increased level of liver enzyme activity, a history of liver disease, hereditary liver disease in a family history, patients with diabetes mellitus, overweight patients, and also those who have previously taken hepatotoxic drugs or have been in contact with hepatotoxic chemicals).

A transient increase in the level of transaminases (up to 2-3 times higher than the upper limit of normal) has been reported in some patients. In the case of a persistent increase in the activity of hepatic enzymes, it is necessary to reduce the dose or stop treatment with methotrexate.

Assays for determining the activity of enzymes do not reliably predict morphological changes due to hepatotoxic effects, that is, even at normal levels of transaminases, the existing fibrosis can only be determined by the results of histological analysis, or, less often, the existing cirrhosis of the liver.

Further studies are needed to determine whether serial liver biochemical tests or IRI collagen propeptide tests are sufficient to detect early hepatotoxicity. Such assessments should be differentiated, taking into account the absence or presence of risk factors in the patient, such as, for example, a history of alcohol abuse, persistent elevation of liver enzymes, a history of liver disease, the presence of hereditary liver diseases in family members, diabetes mellitus, obesity, and previous treatment with hepatotoxic drugs or contact with hepatotoxic chemicals, or long-term therapy with methotrexate or receiving a cumulative dose of 1.5 g or more.With a sustained increase in the activity of hepatic enzymes, the advisability of reducing the dose or canceling further therapy should be considered.

Since methotrexate has a toxic effect on the liver, other hepatotoxic drugs should not be prescribed during the treatment period unless absolutely necessary. Alcohol consumption should also be avoided or severely limited. It is especially necessary to carefully monitor the level of liver enzymes in patients receiving concomitant therapy with other hepatotoxic and hematotoxic drugs (in particular leflunomide).

Particular care is needed when treating patients with insulin-dependent diabetes mellitus, since there are reports of isolated cases of liver cirrhosis during therapy with methotrexate without prior increase in transaminase activity.

Renal function tests and urine tests. In the case of an increase in serum creatinine, a decrease in the dose of the drug is necessary. If the serum creatinine level rises to more than 2 mg / ml, further therapy with methotrexate should not be carried out.Since methotrexate is excreted mainly in the urine, an increase in the concentration of methotrexate in the blood is possible in patients with impaired renal function, which can lead to severe adverse reactions. It is necessary to carefully monitor the condition of patients who may have impaired renal function (for example, elderly patients). This is especially important in the case of concomitant therapy with drugs that reduce the excretion of methotrexate, have an adverse effect on the kidneys (in particular NSAIDs) or on the hematopoietic system.Dehydration can also increase the toxic effects of methotrexate. Recommended increase in urine alkalinity and forced increase in urination.

Study of the respiratory system. It is necessary to closely monitor the symptoms of possible development of impaired lung function and, if necessary, prescribe a pulmonary function test. Pulmonary diseases require rapid diagnosis and discontinuation of methotrexate. The appearance during treatment with methotrexate of the corresponding symptoms (especially dry, unproductive cough) or the development of nonspecific pneumonitis may indicate a potential danger of lung damage.In such cases, methotrexate should be discontinued and the patient should be carefully examined. Although the clinical picture may vary, the typical patient with pulmonary disease caused by methotrexate will have fever, choking cough, hypoxemia, and pulmonary infiltrates on x-rays. In differential diagnosis, it is necessary to exclude infectious diseases. Lung damage can develop with treatment with methotrexate at any dose. Lung disease caused by methotrexate is not always completely reversible.Lung diseases caused by methotrexate, such as pneumonitis, can start suddenly and at any stage of therapy, do not always go away completely, and were observed with the use of methotrexate at all therapeutic doses (including a low dose of 7.5 mg / week). In the case of lung disease caused by methotrexate, GCS should be started. In the future, therapy with methotrexate is not updated.

During the period of therapy with methotrexate, possible opportunistic infections, including plasma cell pneumonia, can be fatal.If a patient has symptoms of pulmonary dysfunction, primates should take into account the possibility of plasma cell pneumonia.

Because methotrexate affects the immune system, it can alter the response to vaccination and affect the results of immunological tests. Particular care is needed when treating patients with inactive, chronic infections (such as shingles, tuberculosis, hepatitis B or C) due to their possible activation. During treatment with methotrexate, you should not vaccinate with live vaccines.

Methotrexate may increase the risk of developing neoplasms (mainly lymphomas). Malignant lymphomas can also develop in patients receiving low-dose methotrexate. In such cases, the drug should be canceled. If spontaneous regression of lymphoma is not observed, therapy with cytotoxic drugs should be prescribed.

In patients with abnormal accumulation of fluid in body cavities (“third space”), such as ascites or pleural effusion, the half-life of methotrexate from blood plasma is increased.

It is necessary to eliminate pleural effusion or ascites before starting therapy with methotrexate. Disorders that cause dehydration, such as vomiting, diarrhea, stomatitis, can increase the toxic effects of methotrexate due to an increase in its concentration. In such cases, further therapy should be temporarily interrupted until such symptoms are eliminated. It is very important to identify patients with a possible increase in the concentration of methotrexate within 48 hours after administration, since otherwise the toxic effects of methotrexate may be irreversible.Diarrhea and ulcerative stomatitis can be manifestations of toxic effects and require a temporary cessation of further therapy, otherwise hemorrhagic enteritis and death through perforation of the intestinal wall are possible.

In case of vomiting with blood, black stools or the presence of blood in the stool, further therapy should be discontinued.

Vitamins and other products containing folic acid, folinic acid or their derivatives may reduce the effectiveness of methotrexate therapy.

Before starting treatment with methotrexate “Ebeve” it is necessary to exclude pregnancy. Methotrexate has embryotoxic and teratogenic effects and can also lead to abortion. During treatment with methotrexate, spermatogenesis and oogenesis are disrupted, which can lead to impaired fertility. These effects are reversible after discontinuation of drug therapy. Women and men of reproductive age should use effective contraceptives during treatment, as well as for six months after stopping methotrexate therapy.The physician should inform patients of reproductive age and their partners about the possible adverse effects of methotrexate on the fetus.

Toxic effect on the skin. Due to the risk of developing phototoxic reactions, patients should avoid exposure to sunlight and tanning beds.

The life-threatening consequences of intrathecal administration of methotrexate are well known, therefore, in each individual case, it is necessary to assess the ratio of risk and expected benefit from therapy.When the first signs of serious side effects appear, the drug should be discontinued.

Application of the drug in high doses. When carrying out therapy with the use of methotrexate in high doses, the simultaneous administration of folic acid is necessary. Serum methotrexate concentration is an important indicator for determining the appropriate duration of folic acid administration. The residual methotrexate level should be determined 48 hours after the start of the infusion. If the residual methotrexate level is <0.5 μmol / L, further folic acid administration is not required.

Solutions for infusion with a concentration of methotrexate 0.1 mg / ml or 3 mg / ml, prepared by diluting methotrexate “Ebeve” with 0.9% sodium chloride solution, 5% glucose solution, 10% glucose solution, as well as lactate Ringer’s solution, is physically and chemically stable for at least 24 hours when stored in a dark place at a temperature of 5 ± 3 ° C or room temperature (20-25 ° C).

From a microbiological point of view, the infusion solution should be administered immediately after preparation.

Use during pregnancy or lactation

Studies have shown the teratogenic effect of methotrexate, therefore, the use of methotrexate is contraindicated during pregnancy. In women of reproductive age, pregnancy should be ruled out by appropriate methods, such as a pregnancy test before starting methotrexate treatment.

Since methotrexate is a genotoxic substance, all women planning a pregnancy are advised to contact genetic counseling centers, preferably before starting therapy, and men should consider cryopreservation of sperm prior to starting therapy.

Patients of reproductive age (both women and men) and their partners should use effective contraceptives during treatment and for at least six months after the end of therapy with methotrexate “Ebeve”. If the patient or male partner is being treated with methotrexate, but still becomes pregnant, it is necessary to consult with specialists regarding the risk of negative effects of methotrexate on the fetus.

Methotrexate is excreted in breast milk, so breastfeeding should be discontinued during treatment.

The ability to influence the reaction rate when driving vehicles or other mechanisms

Treatment with methotrexate may cause central nervous system side effects such as fatigue and confusion. Methotrexate “Ebeve” has a weak or moderate adverse effect on the ability to drive vehicles or other mechanisms.

Dosage

Treatment of adults and children with cancer

Methotrexate Ebeve 100 mg / ml can be administered by painful injection or infusion.If intrathecal, intraventricular, intramuscular or intraarterial administration is necessary, as well as the administration of low doses, drugs with a methotrexate concentration of 5 mg / ml or 10 mg / ml should be used.

Doses should be determined depending on the weight or surface area of ​​the patient’s body, except for cases of intrathecal and intraventricular administration, when the maximum dose should not exceed 15 mg, and the maximum recommended concentration is 5 mg / ml.

If the patient has hematological disorders or impaired liver or kidney function, the dose should be reduced. High doses (over 100 mg) are usually given by infusion for no more than 24 hours. A portion of the dose may be given by an initial rapid intravenous injection.

Methotrexate (as monotherapy or in combination with other cytotoxic agents, hormonal therapy, radiation therapy, and surgery) is used to treat a wide range of cancers, so doses and treatment regimens can vary significantly.After administration of methotrexate in doses of more than 150 mg / m2, prescribe calcium folinate to protect normal cells from the toxic effects of methotrexate. Doses of calcium folinate should be determined depending on the dose of methotrexate. Typically, within 12-24 hours, inject up to 150 mg of calcium folinate in distributed doses (by intramuscular injection, painful injections, intravenous infusion, or orally), and in the next 48 hours, every 6:00, inject 12-25 mg of calcium folinate intramuscularly or intravenously, or take 15 mg orally.Initiate protective therapy with Calciumfolinate usually 8-24 hours after starting the methotrexate infusion. In the case of low-dose methotrexate (less than 100 mg), one capsule (15 mg) of calcium folinate may be sufficient every 6:00 for 48-72 hours.

Below are just some of the treatment regimens used with methotrexate.

Leukemia

3.3 mg / m2 daily for 4-6 weeks in combination with other cytostatics.
2.5 mg / kg body weight every 2 weeks.
30 mg / m2 per week (maintenance therapy).
1000-12000 mg / m2 (IV over 1-6 hours) every 1-3 weeks (high-dose intensive care).
20 mg / m2 once a week in combination with other cytostatics.
Non-Hodgkin’s lymphoma

500-2000 mg / m2 at intervals of 1 or 3 weeks in combination with other chemotherapeutic agents.
7500 mg / m2 intravenously once a week.
Breast cancer

As part of a combination chemotherapy, 40 mg / m2 intravenously on the first day of the course or on the first and third days of the course, or the first and eighth days of the course, or 3 times a year.
Choriocarcinoma

15-30 mg per day for 5 days, repetition of courses at intervals of 1 week or more.
Treatment of patients with impaired renal function

Methotrexate “Ebeve” should be used with caution in patients with impaired renal function. Doses should be adjusted depending on creatinine clearance (clearance> 50 ml / min, there is no need to reduce the dose, with a clearance of 20-50 ml / min, the dose is reduced by 50%, and with a clearance of <20 ml / min, methotrexate should not be prescribed).

Treatment of patients with impaired liver function

Methotrexate “Ebeve” should be prescribed with caution, only in case of emergency, to patients with significant liver dysfunctions (present or in history, especially those caused by alcohol abuse). Methotrexate should not be used with bilirubin levels> 85.5 μmol / L.

Treatment of elderly patients

Since liver and kidney function deteriorates with age, and folate reserves decrease, it may be advisable to reduce doses for elderly patients.

Children

The drug should be used in children with acute lymphocytic leukemia and non-Hodgkin’s lymphoma, only as part of a combination therapy. It should be used very carefully in infants, as they have reduced liver and kidney function.

Overdose

Overdose symptoms. There are mainly symptoms associated with inhibition of the hematopoietic system and the digestive system. Symptoms are leukopenia, thrombocytopenia, anemia, pancytopenia, neutropenia, mucositis, stomatitis, ulcerative lesions of the oral mucosa, nausea, vomiting, ulcerative lesions of the gastrointestinal tract and gastrointestinal bleeding.In some patients, signs of overdose may be absent. There are reports of death in patients due to sepsis, septic shock, renal failure and aplastic anemia.

Treatment for overdose . The specific antidote for methotrexate is calcium folinate. It neutralizes the toxic side effects of methotrexate.

In case of accidental overdose of calcium folinate should be administered intravenously or intramuscularly at a dose equal to or higher than the dose of methotrexate, no later than 1:00 after the use of methotrexate.Then introduce several more doses of calcium folinate until the concentration of methotrexate in the blood serum falls below 10 -7 mol / l.

In case of a significant overdose, it may be necessary to hydrate the body and alkalinize the urine to prevent the precipitation of methotrexate and / or its metabolites in the renal tubules. Routine hemodialysis and peritoneal dialysis do not improve the elimination of methotrexate. Effective clearance of methotrexate can be achieved by intensive intermittent hemodialysis using high-flux dialyzers.

Side effects

The most serious side effects of methotrexate treatment are suppression of the hematopoietic system and adverse reactions from the gastrointestinal tract.

From the side of the cardiovascular system

Pericardial effusion, pericardial tamponade.

From the side of the blood and lymphatic system

bone marrow suppression (mainly manifested in the form of leukopenia, although thrombocytopenia, anemia, or their combinations are possible).Pancytopenia, severe progressive bone marrow suppression, agranulocytosis.

From the side of the nervous system

Drowsiness, headache, fatigue. When treating with low doses of methotrexate – transient minor impairment of cognitive functions, unusual sensations in the skull area.

In rare cases, visual impairment, pain, myasthenia gravis or paresthesias in the extremities, changes in taste (metallic taste in the mouth), epileptic seizures, meningismus, paralysis are possible.

From the side of the organs of vision

Blurred vision, eye irritation, conjunctivitis.

From the respiratory system, chest and mediastinal organs

Chronic interstitial pneumonitis (symptoms indicating potentially serious lung damage in interstitial pneumonitis: dry, unproductive cough, shortness of breath, fever). Epistaxis, pneumonitis, alveolitis, pleural effusion. Pulmonary fibrosis, Pneumocystis pneumonia, dyspnea, and bronchial asthma have been reported.

In rare cases, a syndrome has been observed that is manifested by pleural pain and thickening of the pleura (when treated with high doses of methotrexate).

From the gastrointestinal tract

Intestinal disorders, stomatitis, nausea, inflammation of the mucous membranes, anorexia, dyspepsia. Diarrhea, oral ulcers, enteritis, vomiting, gastrointestinal ulcers have been reported. The action of methotrexate on the intestinal mucosa can cause the development of malabsorption syndrome or toxic megacolon; possible vomiting of blood and bleeding.

From the side of the kidneys and urinary system

Inflammation and ulcers of the urinary bladder, impaired renal function, impaired urination.

Renal failure, oliguria, anuria, electrolyte imbalance were observed.

Skin and subcutaneous tissue disorders

Exanthema, erythema, pruritus. Photosensitivity, alopecia, shingles, vasculitis, skin rash herpetiformis, urticaria, increased pigmentation were noted

Pay attention!

Description of the drug Methotrexate on this page is a simplified author’s version of the apteka911 website, created on the basis of the instructions for use.Before purchasing or using the drug, you should consult your doctor and familiarize yourself with the original manufacturer’s instructions (attached to each package of the drug).

Information about the drug is provided for informational purposes only and should not be used as a guide to self-medication. Only a doctor can decide on the appointment of the drug, as well as determine the doses and methods of its use.

instructions for use, analogs, composition, indications

Cancer

Methotrexate is administered orally and parenterally: injected intramuscularly, intravenously, intraarterially, intrathecally.The dose is calculated based on the patient’s weight or body surface area. Methotrexate is effective for a wide range of cancers, both as monotherapy and in combination with other chemotherapy drugs. Oral administration in pill form is often preferred with low doses of the drug being administered. Parenteral dosage forms should be inspected visually for particulate matter and discoloration prior to administration.

Choriocarcinoma and similar trophoblastic diseases. Methotrexate orally or intramuscularly at a dose of 15 to 30 mg daily for a five-day course. These courses are typically repeated 3 to 5 times as needed, with rest periods of one or more weeks between courses until any toxic symptoms subside. The effectiveness of therapy is usually assessed in a 24-hour quantitative urine test for human chorionic gonadotropin (hCG), which should return to normal or less than 50IU / 24 hours, usually after the third or fourth course, and usually accompanied by complete resolution of measurable lesions from 4 to 6 weeks.One to two courses of methotrexate is usually recommended after hCG has normalized. A thorough clinical evaluation is essential before each course of the drug. The benefits of cyclic combination therapy with methotrexate with other anticancer drugs have been reported.

Choriocarcinoma may precede cystic motility, and prophylactic chemotherapy with methotrexate is recommended. Destructive cystic drift is considered an invasive form of cystic drift. Methotrexate is administered for these painful conditions in doses similar to those recommended for choriocarcinoma.

Primary breast cancer with metastases to axillary lymph nodes. In combination with cyclophosphamide, methotrexate and fluorouracil are used as adjuvant therapy for radical mastectomy. The average dose of methotrexate is 40 mg / m ² on the 1st and 8th days of treatment.

Leukemia. Acute lymphoblastic leukemia in children and adolescents is the most responsive to chemotherapy to this day.In young adults and elderly patients, it is more difficult to obtain clinical remission and early relapse is more common. Methotrexate alone or in combination with steroids was used initially to induce remission of acute lymphoblastic leukemia. Corticosteroid therapy, in combination with other antileukemic agents or in cyclic combination with the inclusion of methotrexate, has been shown to induce rapid and effective remission. When used for the induction of methotrexate at a dose of 3.3 mg / m ² in combination with 60 mg / m ² prednisolone, prescribed daily, remission is observed in 50% of patients, usually within a period of 4 to 6 weeks.Methotrexate in combination with other agents is the drug of choice for maintaining drug remission.

When remission is achieved and maintenance therapy has led to an overall clinical improvement, follow-up therapy is performed as follows: Methotrexate is administered 2 times a week, either orally or intramuscularly, at a total weekly dose of 30 mg / m ² . Alternatively, it can be given in doses of 2.5 mg / kg IV every 14 days.

Various combination chemotherapy regimens have been used for induction and maintenance therapy in acute lymphoblastic leukemia.The physician should be familiar with new advances in antileukemic therapy.

Meningeal leukemia. Many patients with leukemia have CNS involvement. In all cases of lymphocytic leukemia, methotrexate can be prescribed to prevent lesions from the central nervous system. But methotrexate poorly penetrates the blood-brain barrier, therefore, it is administered intrathecally for adequate therapy. Preservative-free methotrexate is diluted to a concentration of 1 mg / ml in an appropriate sterile preservative-free medium such as 0.9% Sodium Chloride Injection.

Cerebrospinal fluid (CSF) volume is age dependent, not body surface. At birth, CSF is 40% of the adult volume and reaches adult volume after a few years.

With intrathecal administration of methotrexate at a dose of 12 mg / m ² (maximum 15 mg), there have been reports of a decrease in the concentration of methotrexate in the CSF and a decrease in efficacy in pediatric patients and high concentration and neurotoxicity in adults. The following doses of the drug are recommended, depending on age, not body surface area:

Age (years)	Dose (mg)
<1	6
one	eight
2	10
3 or older	12

In one study, this dosing regimen resulted in an appropriate concentration of methotrexate in the CSF and less neurotoxicity.

According to some studies in pediatric patients with acute lymphoblastic leukemia, compared with the regimen presented above, the drug was administered at a dose of 12 mg / m ² regardless of age or body surface area (maximum 15 mg), and this study showed a significant decrease in the rate of relapse in the CNS in the observed group compared to the age-dependent dose group.

Which scheme to choose – it is advisable for the doctor to consult the medical literature.

In patients under the age of 3 years, methotrexate is prescribed as part of a combination therapy. Usually used at weekly intervals until the cellular composition of the cerebrospinal fluid is normalized.

Since CSF volume can decrease with age, dose reduction may be indicated in elderly patients.

For the treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 to 5 days. However, taking the drug at intervals of less than 1 week can lead to an increase in subacute toxicity.Methotrexate is administered until the cerebrospinal fluid cells return to normal. At this point, one additional dose is appropriate. For the prevention of meningeal leukemia, the dosage is the same as for treatment, with the exception of the intervals of administration. In this regard, it is advisable for the doctor to consult the medical literature.

Adverse side effects can occur with any intrathecal administration and are usually neurological in nature. Large doses can cause seizures.

Methotrexate administered intrathecally appears in significant amounts in the systemic circulation and can lead to systemic toxicity. Thus, systemic antileukemic drug therapy should be appropriately adjusted, reduced, or discontinued. Central nervous system leukemia may not respond to intrathecal chemotherapy and radiation therapy is best considered.

Lymphomas. In Grade I-II Burkitt’s tumor, methotrexate leads to long-term remission in some cases.The recommended dose is 10-25 mg orally every other day for 4 to 8 days. In stage III, methotrexate is usually given concurrently with other anticancer drugs. Treatment at all stages usually consists of several courses, with intervals of 7-10 days.

Stage III lymphosarcomas can respond to combination drug therapy with methotrexate at a dose of 0.625 to 2.5 mg / kg per day. In Hodgkin’s disease, the response to methotrexate is negligible.

Fungal mycosis (cutaneous T-cell lymphoma). Treatment with methotrexate alone results in a clinical response in 50% of patients. Dosage in the early stages is usually 5 to 50 mg once a week. Dose reduction or discontinuation – guided by patient response and hematologic monitoring. Methotrexate is also given twice weekly at doses ranging from 15 to 37.5 mg in patients who respond poorly to weekly therapy. Combination chemotherapy, which involves high-dose intravenous methotrexate under the protection of calcium folinate, has been used in the later stages of the disease.

Osteosarcoma. Effective adjuvant chemotherapy requires the administration of several cytotoxic chemotherapy drugs. In addition to high doses of methotrexate protected by calcium folinate, these drugs can be doxorubicin, cisplatin, and a combination of bleomycin, cyclophosphamide and dactinomycin (BCD), doses and schedule are shown in the table below. The initial dose of methotrexate for high-dose treatment is 12 g / m ² . If this dose is not sufficient to produce peaks in serum methotrexate concentrations of 10-3 mmol / L at the end of the infusion, the dose may be increased to 15 g / m2 in subsequent treatment.If the patient is vomiting or is unable to tolerate oral medications, calcium folinate is given intravenously or intramuscularly in the same dose and regimen.

Means	Dose	Treatment weeks after surgery
Methotrexate Calcium folinate	12 g / m 2 IV over 4 hours (initial dose) 15 mg orally every 6 hours for 60 hours, i.e.i.e. 10 doses in total, starting 24 hours after the start of the methotrexate infusion	4, 5, 6, 7, 11, 12, 15, 16, 29, 30, 44
Doxorubicin as the only remedy	30 mg / m 2 per day, intravenously, for 3 days	8, 17
Doxorubicin Cisplatin	50 mg / m 2 IV 100 mg / m 2 intravenous	20, 23, 33, 3620, 23, 33, 36
Bleomycin Cyclophosphamide Dactinomycin	15 U / m 2 intravenous, within 2 days 600 mg / m 2 intravenous, for 2 days 0.6 mg / m 2 intravenously, for 2 days	2, 13, 26, 39, 422, 12, 26, 39, 422, 12, 26, 39, 42

If these high doses of methotrexate are to be administered, the following safety precautions must be observed.

Guidelines for Covered Methotrexate Calcium Folinate

1. The use of methotrexate should be postponed until recovery if:

• the number of leukocytes is less than 1500 / μl;

• the number of neutrophils is less than 200 / μl;

• the number of platelets is less than 75,000 / μl;

• a serum bilirubin level of more than 1.2 mg / dL;

• ALT level exceeds 450 U;

• mucositis is present until there is evidence of recovery;

• there is persistent pleural fluid.Drainage must be performed prior to infusion.

2. Normal renal function must be clinically proven:

but. Serum creatinine should be normal and creatinine clearance should be greater than 60 ml / min before starting therapy.

b. Serum creatinine should be measured prior to each subsequent course of therapy.

3. Patients should be well hydrated and should receive sodium bicarbonate to alkalize urine.

but. Inject 1000 ml / m ² intravenous fluid within 6 hours before starting the methotrexate infusion. Continue hydration at 125 ml / m ² / hour (3 liters / m ² / day) during the methotrexate infusion and for 2 days after the end of the infusion.

b. Alkalinize urine to maintain pH above 7.0 during methotrexate infusion and calcium folinate therapy. This can be achieved by administering sodium bicarbonate orally or by incorporating it into a separate solution for intravenous administration.

4. Serum serum creatinine and methotrexate should be re-evaluated within 24 hours of starting methotrexate therapy and at least once daily until methotrexate levels are at least 5×10 ^-8 mol / L (0.05 micromolar).

Patients suffering from delayed elimination of methotrexate will develop irreversible oliguric renal failure. In addition to appropriate calcium folinate therapy, these patients require constant hydration, alkalinization of urine, and careful monitoring of fluid and electrolyte balance until serum methotrexate levels fall below 0.05 micromolar and renal failure resolves.When needed, acute short-term hemodialysis with high dialyzer flow may also be beneficial in these patients.

5. Some patients have significant abnormalities in the elimination of methotrexate or renal impairment after administration of methotrexate. These disorders may or may not be associated with significant clinical toxicity. If no significant toxicity is observed, calcium folinate therapy should be extended for an additional 24 hours (14 doses in total over 84 hours) in subsequent courses of therapy.The possibility that the patient is taking other drugs that interact with methotrexate (for example, drugs that can interfere with the binding of methotrexate to serum albumin) should always be reassessed, even if laboratory abnormalities are not observed.

ATTENTION: DO NOT USE CALCIUM FOLINATE INTRATEKALLY!

Psoriasis, rheumatoid arthritis and juvenile rheumatoid arthritis.

Adults.Rheumatoid Arthritis – Recommended starting dosage:

1. Once inside, 7.5 mg, once a week.

2. 3 divided oral doses of 2.5 mg, with a 12 hour interval, as a course once a week.

Parenteral route of administration: The recommended starting dose is 7.5 mg of methotrexate once a week, administered subcutaneously, intramuscularly or intravenously. Depending on the patient’s illness and the patient’s tolerability of the drug, the initial dose can be gradually increased by 2.5 mg per week.A weekly dose of 25 mg should not be exceeded. A response to treatment can be expected in 4-8 weeks. After achieving a therapeutic effect, the dose should be gradually reduced to the last necessary to maintain the effect of the drug.

Dosage for children under 16 years of age with polyarthritic juvenile idiopathic arthritis: The recommended dose is 10-15 mg / m ² per week. In case of insufficient effect, the weekly dose can be increased to 20 mg / m ² per week.In this group of patients, the drug is used intramuscularly.

For any adult patient with rheumatoid arthritis (RA) or patients with juvenile rheumatoid arthritis (JRA), the dosage can be gradually adjusted to achieve an optimal response. Limited experience has shown a significant increase in the frequency and severity of serious toxic reactions, especially bone marrow suppression, at doses exceeding 20 mg per week in adults. Although there is experience with doses up to 30 mg / m ^{2 90 390 per week in children, there is still too little published data to assess the effects of dosages greater than 20 mg / m 2 90 390 per week, which can lead to serious toxicity in children.Experience suggests, however, that children receiving 20 to 30 mg / m 2 90 390 per week (0.65 to 1.0 mg / kg per week) may have better absorption and fewer gastrointestinal side effects if methotrexate is administered either intramuscularly or subcutaneously.}

The therapeutic response usually begins at 3 to 6 weeks, and the patient’s condition may continue to improve for an additional 12 weeks or more.

The optimal duration of treatment is unknown.Limited data from long-term studies in adults indicate that initial clinical improvement persists for at least two years with continued therapy. When methotrexate treatment is stopped, arthritis usually worsens within 3 to 6 weeks.

The patient should be fully informed about the risks and should be under constant medical supervision.

Assessment of hematological, hepatic, renal and pulmonary functions should be carried out during the entire course of therapy, physical examination and laboratory tests – before and periodically during therapy.Appropriate measures must be taken to avoid conception during treatment with methotrexate.

All therapy schedules should be constantly reviewed and monitored, taking into account the individual characteristics of the patient. An initial test dose may be given prior to regular dosing to detect drug hypersensitivity. Maximum myelosuppression usually occurs at seven to ten days.

Psoriasis.

one.Weekly single dose, intramuscularly or intravenously: 10 to 25 mg per week until an adequate response is achieved. It is recommended that a test dose of 5-10 mg be administered parenterally 1 week prior to therapy in order to detect an idiosyncratic reaction. The recommended starting dose is 7.5 mg of methotrexate once a week, subcutaneously, intramuscularly, or intravenously. The dose should be gradually increased, but the weekly dose should not be exceeded – 30 mg of methotrexate. A response to treatment can be expected in 2-6 weeks.After achieving a therapeutic effect, the dose should be gradually reduced to the last necessary to maintain the effect of the drug.

2. Divided oral doses of 2.5 mg at 12 hour intervals for 3 doses per week.

Dosage is administered gradually until an optimal clinical response is achieved; the dose of 30 mg per week should not be exceeded.

After achieving the optimal clinical response, the dose should be reduced to the lowest possible amount of medication and the longest possible break.The use of methotrexate may permit a return to conventional topical therapy, which should be encouraged.

Methotrexate injection solution 1 g / 10 ml or 5 g / 50 ml is hypertonic and cannot be used intrathecally. A solution of 500 mg / 20 ml and 1 g / 40 ml is also not intended for intrathecal use.

Children (3 years and older) and adolescents. Caution should be exercised when using methotrexate in children and adolescents and appropriate treatment protocols should be followed.In pediatric patients with acute lymphoblastic leukemia (ALL), after administration of methotrexate at a dose of 1 g / m ² , severe neurotoxicity (damage to the nervous system) was observed, which manifested itself in the form of generalized or focal seizures of epilepsy. Symptomatic patients showed leukoencephalopathy and / or microangiopathic calcification on diagnostic imaging.

Elderly patients (over 65 years of age). Dose reduction should be considered due to folate deficiency and limited hepatic and renal function.Elderly patients should be screened for early signs of toxicity.

Preparation of drug solution

Reconstitute the contents of the vial in 1 ml (for a vial with 10 mg of lyophilized powder) or in 2 ml (for a vial with 50 mg of lyophilized powder) of 0.9% sodium chloride solution for injection. The resulting solution with a concentration of 10 mg / ml or 25 mg / ml, respectively, can be administered intravenously, intramuscularly or subcutaneously.The concentration of the solution for intrathecal administration is 1 mg / ml.

The preparation of the solution should be carried out under aseptic conditions. The drug solution must be used immediately after preparation! Before administration, the solution must be visually inspected for transparency. If a sediment is found, the product must be disposed of.

Medical personnel, when handling the drug and during its administration, must take the necessary precautions; precautions must also be taken by patients.

The preparation and handling of methotrexate solution, as well as other anticancer drugs, requires caution. Protective equipment such as goggles, mask and gloves must be worn.

If the drug or solution gets on the skin, the affected area should be immediately washed thoroughly with soap and water. If the drug or solution gets on the mucous membranes, the affected area should be immediately thoroughly rinsed with water.

City pharmacy – medicines, health products in Smolensk at competitive prices

injection

Chorionic carcinoma of the uterus, acute lymphocytic leukemia, tumors of the central nervous system (leukemoid infiltration of the meninges), breast cancer, head and neck cancer, cancer of the lungs, bladder, stomach; Hodgkin’s disease, non-Hodgkin’s lymphoma, retinoblastoma, osteosarcoma, Ewing’s sarcoma, soft tissue sarcoma; refractory psoriasis (only with an established diagnosis in case of resistance to other types of therapy), rheumatoid arthritis.

Inside, parenterally (i / m, i / v, intra-arterial, intrathecal), depending on the indication.

The dose is individualized depending on the type of tumor, the stage of the disease, the effectiveness of therapy, and tolerance.

The doses used in accordance with the treatment regimens are divided into regular (low) doses (single dose below 100 mg / m2), medium (single dose 100-1000 mg / m2) and high (single dose above 1000 mg / m2).Therapy with usual doses (without calcium folinate covering): i / v 15-20 mg / m2 2 times a week or 30-50 mg / m2 once a week, or i / m, i / v 15 mg / m2 per day for 5 days with repetition after 2-3 weeks.

Medium dose therapy: intravenous 50–150 mg / m2 (without calcium folinate cover) with repetition after 2-3 weeks or 240 mg / m2 (intravenous infusion over 24 hours under the cover of calcium folinate) with repetition after 4–7 days; or 500–1000 mg / m2 (intravenous infusion over 36–42 hours under the cover of calcium folinate), repeated after 2–3 weeks.High-dose therapy (under the cover of calcium folinate): 1000–1200 mg / m2 (intravenous infusion 1–6 h), repeated after 1–3 weeks (requires monitoring of serum methotrexate levels).

Intrathecal 0.2-0.5 mg / kg body weight or 8-12 mg / m2 every 2-3 days. The maximum dose for intrathecal administration is 15 mg / m2. After symptoms decrease, the intervals between courses of therapy are a week, then a month, until the cerebrospinal fluid indicators return to normal. Prophylactic intrathecal administration is indicated every 6–8 weeks.In severe cases of generalized refractory psoriasis, including psoriatic arthritis and other autoimmune diseases, 10-50 mg of methotrexate parenterally at weekly intervals. In case of resistant rheumatoid arthritis – 5–15 mg intramuscularly once a week, the maximum dose per week is 25 mg.
Inside (before meals). Usually the initial dose is 2.5–5 mg, then the dose is gradually increased to 7.5–25 mg per week, the weekly dose is 10–25 mg, the maximum total dose is 25 mg per week. Usually 2.5 mg of methotrexate is taken 3 times a week at 12-hour intervals and with a break of a week (Monday morning and evening, Tuesday morning, then a break until next Monday).

Hypersensitivity, immunodeficiency, anemia (including hypo- and aplastic), leukopenia, thrombocytopenia, leukemia with hemorrhagic syndrome, hepatic or renal failure.
Infectious diseases, oral and gastrointestinal ulcers, recent surgery, history of gout or renal calculi (risk of hyperuricemia), old age and children.

[C53] Malignant neoplasm of the cervix [C58] Malignant neoplasm of the placenta [C54] Malignant neoplasm of the body of the uterus [C30] Malignant neoplasm of the nasal cavity and middle ear [C81] Hodgkin’s disease [lymphogranulomatosis] [C30-C39] Malignant neoplasms of the respiratory and chest organs [C44] Other malignant neoplasms of the skin [C62] Malignant neoplasm of the testicle [C56] Malignant neoplasm of the ovary [C45-C49] Malignant neoplasms of the mesothelial and soft tissues [C34] Malignant neoplasms of the bronchi and lungs [C15-C26] Malignant neoplasms of the digestive organs [C50 Malignant neoplasms of the breast [C71] Malignant neoplasm of the brain [C31] Malignant neoplasm of the paranasal sinuses [C45] Mesothelioma [C41] Malignant neoplasm of bones and articular cartilage of other and unspecified sites (osteosarcoma, osteogenic cancer] gastric cancer) [C16] a [C00-C14] Malignant neoplasms of the lip, oral cavity and pharynx [C76.0] Malignant neoplasm of the head, face and neck [C40] Malignant neoplasm of bones and articular cartilage of the extremities [C69.2] Malignant neoplasm of the retina [C32] Malignant neoplasm of the larynx [C67] Malignant neoplasm of the urinary bladder [C49] Malignant neoplasms of other types of connective and soft fabrics

Methotrexate 15 mg syringe solution

Alexey 25.05.2019

From time to time I order medicines in your pharmacy, as there is a large assortment and fairly reasonable prices. I need hormonal injections for my joints, only here they are constantly on sale, in other pharmacies they are often not available. I always receive an order on time and with a good expiration date. Online consultants work with knowledge of their business and fully own the information. Thanks.

Alexander 07/18/2019

This is what I understand about professional customer service! When communicating, I realized that the client is appreciated here and that they are treated humanly.Thank you for your good advice and help in choosing the right tonometer, it is called OMRON S1. It is very convenient for me to use it, it is easy to use and shows everything clearly. We sent the goods, as agreed on the next day, there were no delays in shipment. Packed securely – everything came whole.

Tatiana 10/08/2019

I have been using the medicines of this pharmacy for several months, all the necessary funds are always available, the prices here are slightly lower than in other pharmacies where I went before.Another huge plus for me is the presence of a courier service, it is very convenient when there is no way to come to the pharmacy. I would also like to express my gratitude to the staff for their politeness and responsiveness. Thanks a lot.

Julianna 03/26/2020

Gout is not a death sentence if you get the right treatment. My father has had gout for three years now. We diagnosed her when his leg hurt badly, he could not stand on it, we went to the doctor on crutches, we thought it was a fracture.At first, they could not understand what had happened, it turned out according to blood tests – increased uric acid. Of course, at first they were upset, because this is already for life. But the doctor reassured us that with modern medicine it’s not so scary, we have to stick to a diet, take medicine and everything will be fine. At first he drank allopurinol, but at some point he began to help less and the pain made itself felt. We went to the doctor, he prescribed a new drug for us – Azurix. My father liked that it is convenient to drink it, one pill once a day, he will not forget.After a fairly short time, the father noticed a felt improvement, there are practically no exacerbations. Now he drinks it constantly and does not complain yet. Azurix helps.

Alexandra 04/29/2020

My doctor introduced me to these capsules a couple of years ago. Since then, I know for sure that if it starts to twist in the nose and flow out of it, then it’s time to take Antigrippin-ANVI. In 3-4 days, all symptoms go away and the disease does not play out further. An excellent option and not expensive at all.

B12 in plant foods. What Every Vegan Should Know About Vitamin B12

Function in the body

Cyanocobalamin is water-soluble, it is synthesized by the intestinal microflora. It is responsible for the level of hemoglobin, the functioning of the nervous system, reduces irritability, in combination with folic acid (B9) participates in hematopoiesis in the bone marrow, the maturation of erythrocytes.

The intake of products containing vitamin B12 stimulates carbohydrate and fat metabolism, activates the blood coagulation system, has a positive effect on the function of the nervous system and liver, stimulates the production of bile salts, which lowers cholesterol levels.

A significant amount of vitamin B12, which contains animal products, accumulates in the liver and kidneys, as well as in the spleen and muscles.

Cyanocobalamin is used for the prevention and treatment of various forms of anemia, diseases of the liver, spleen, skin, neuritis and neuralgia, exhaustion of the body, metabolic disorders, inflammation of the oral mucosa.

Vitamin B12 has a beneficial effect on the work of the heart muscle and thyroid gland, strengthens the immune system, and normalizes blood pressure.It has antiallergic, antitumor and antitoxic effect, enhances the therapeutic effect of some medications.

Products containing vitamin B12 are included in the diet to improve reproductive function (especially in men), appetite, increase tone, normalize sleep, fight depression, reduce irritability, increase the ability to concentrate, improve memory.

What is B12?

Actually B12 is not a vitamin, but a bacterium.Such bacteria live in the soil, getting on the grass and foliage of plants through the roots. Herbivores, eating grass, receive the B12 bacteria necessary for the body, through the esophagus entering the intestines of the animals and settling there, replenishing the lack of B12.

As for predators that do not consume plants for food (as we are used to thinking), they mainly get B12 by eating their herbivorous prey. Although most carnivores still prefer to eat grass and plant foods at least occasionally, this provides them with an additional source of vitamin.

B12 – where does it come from and why is it needed

Vitamin B12, in fact, is a bacterium, and has a second name – cobalamin, because of its cobalt content. It is present in all products of animal origin, while the animals themselves do not synthesize it. This substance is produced by the simplest microorganisms contained in soil and water – bacteria, fungi and blue-green algae. Bacteria from the soil enter the grass and plants that herbivores feed on. Once in the gastrointestinal tract, they begin to produce B12, which is immediately absorbed and absorbed into the tissues and organs of the animal.The largest amount is concentrated in the liver and kidneys. Least of all it accumulates in muscle tissue, in other words, in meat.

According to research, scientists have also found B12 in the mouth, nasopharynx, upper bronchi, and colon in some people.

Basic functions B12:

• normalization of the nervous system;
• an important role in the synthesis of DNA and RNA;
• influence on the formation of red blood cells;
• participation in cellular metabolism.

This irreplaceable element is involved in the creation and renewal of all body tissues. It is essential for the healthy development of the fetus during pregnancy and the growing body of children and adolescents.

Where is B12 found?

According to generally accepted norms, it is believed that meat-eaters / s receive vitamin B12 in sufficient quantities and there are no more complete sources for obtaining this vitamin. But in practice, I have not met a single non-vegan or non-vegan who would have bothered to take tests to check the amount of bacteria in the body, so I will not talk about the usefulness of the sources.I’ll just tell you how to get B12.

• Dairy and Eggs
  Vegetarians who eat milk and eggs believe they are getting enough B12. But these foods contain very little vitamin, to replenish it, you will need to eat a large number of eggs, which are allergenic and contain a large amount of cholesterol. And milk in large volumes causes fragility of bones. Learn more about the dangers of milk.
• Mushrooms
  Shiitake and, to a lesser extent, brown champignons contain a lot of the necessary vitamin.Add them to hot dishes or salads.
• Foods fortified with B12
  Vitamins are often added to soy milk and yoghurt and other plant-based milk products. Check the information on the package to be sure.
• Spirulina and nori algae
  According to some reports, algae contain a large amount of vitamin B12. But as a result of sixty years of research, it was found that they contain an inactive analogue of the vitamin, which is not absorbed by the body properly.When using this type of B12, analyzes will show vitamin reserves in sufficient quantities, although in fact the body will experience a lack of it.
• Meat and fish products
  In modern conditions, it is generally accepted that people get the necessary amount of vitamin from meat and dairy products, as well as eggs, some types of fish and seafood. But in fact, not all those who eat the above foods fully replenish their B12 supply.

Demand per day

The daily requirement for vitamin B12 is limited to micrograms and is presented in the table.

90,000

To whom

is intended

Amount, μg Infant 0.4 … 0.5 6 years 1.0 … 1.5 7 … 10 2 10 3 Pregnant 4 Breastfeeding 4

In case of excess intake, the catalyst is deposited in the liver depot, and in case of deficiency, it is removed.

However, these standards are designed for a healthy person. In some diseases, the absorption of nutrients and cyanocobalamin is impaired.

The fight against infectious agents requires increased consumption. Helminths prevent the intake of active components.

Aldehydes formed during alcohol intoxication, as well as nicotine, destroy vitamins.

Adherents of religious fasts do not consume animal food for a long time.

At this time, the vitamin is being extracted from the liver depots.In addition, there are exemptions that allow the use of fish containing B12. What vegetarians can do then is that they can replenish their B12 reserves through dietary supplements.

Children need 1-3 micrograms of vitamin daily, adults – 2 to 4 micrograms, pregnant and lactating women – up to 5 micrograms or more.

What foods contain vitamin B12?

Milk

Vitamin b12, like calcium, vitamins A and D, are found in milk in large quantities.

To get enough vitamin B12, you only need to drink one cup of milk a day.

People who are lactose intolerant can consume soy milk as an alternative.

Soy milk is also very low in calories.

And soy milk contains a lot of vitamin B12.

Yogurt is also high in vitamin B12.

One cup of milk contains approximately one microgram of vitamin B12, and only a quarter of a cup of yogurt contains approximately 1.49 micrograms of vitamin B12.

Beef

Beef, like many other foods, is an excellent source of vitamin B12.

Beef also contains other beneficial nutrients: zinc, protein, iron and phosphorus.

Iron and vitamin B12 are useful for the prevention and treatment of anemia.

Beef is generally good for maintaining the “health” of red blood cells.

It is also beneficial for your brain health and hormone production.

Beef contains 1.5 micrograms of vitamin B12, which is approximately 60% of the RDA.

Beef should be part of your diet.

However, it should be consumed in moderation, as overeating has never been good.

Eggs

Believe it or not, not only chicken eggs are good for your health, but also duck and quail eggs.

Eggs are composed of many beneficial nutrients such as protein, iron, riboflavin, and vitamin A and D.

What vitamin B12 is in eggs? The largest amount is in the yolks (also do not forget that there is a lot of cholesterol).

Cheese

Cheese contains vitamins B12, A, D and E, iron, phosphorus, calcium and protein.

There is also a wide selection of different cheeses such as mozzarella, parmesan, feta, etc.

And in any of these cheeses there is vitamin B12 in sufficient quantities.

Cheese adds a pleasant flavor to many culinary dishes.

Make pasta, pizza, or cheese sandwiches to boost vitamin B12 levels.

Fish

Vitamin B12 is quite common in food, and fish is no exception.It is high in vitamin B12 as well as other vital nutrients such as omega-3s, fatty acids, calcium and vitamin D.

There are also many different types of fish that are high in vitamin B12.

These are: salmon, tuna, mackerel, sardines and herring.

The fatty acids found in these fish are extremely beneficial for the prevention of heart disease.

Fish is also highly recommended for pregnant women, not only because of its rich “vitamin” composition, but also because of other vital nutrients.

Sardines

Sardines are high in vitamin B12 as well as vital omega-3 fatty acids. Research only confirms the fact that omega-3 fatty acids, together with vitamin B12, improve cardiovascular health, reduce inflammation in the body and help fight asthma.

Atlantic mackerel

Atlantic mackerel (not to be confused with king mackerel) is the leader on my list of healthy foods, because it contains not only a lot of vitamin B12, but also omega-3 fatty acids, and little mercury.It is considered the best food option for a healthy and healthy diet.

Nutritional yeast

Nutritional yeast is a great option for vegetarians looking for a way to increase the amount of vitamin B12 in their diet. They contain an increased amount of other vitamins of this group. Nutritional yeast is considered a complete source of protein, as it contains 9 of the 18 amino acids that the human body cannot produce.

Feta cheese

Feta cheese is an excellent source of vitamin B12 and other nutrients such as riboflavin and calcium.Traditionally, feta cheese is made from sheep milk or a mixture of sheep and goat milk. The healthiest and most nutritious feta cheese is the one made at home. Riboflavin in feta helps with headaches, reduces their frequency and intensity, helps with migraines.

Salmon

Salmon is one of the most useful and nutritious sources of protein, which contains a large amount of vitamin B12. Choose only those from natural waters to get the most of the health benefits of their meat.Salmon is simply packed with vitamins B12 and D, which are also often lacking in the human body. Studies have shown that 800 – 5000 IU of vitamin D daily improves the condition of the musculoskeletal system, naturally slows down the aging of the skeletal structure, and also reduces the number of fractures in older people over 65.

Lamb

Lamb meat is eaten everywhere, it is famous for its tenderness and a large amount of nutrients and trace elements, namely: vitamin B12, protein, iron, selenium and zinc.The last two elements are considered the main immunomodulatory substances in the human body.

Myths about B12

Very often the body does not receive the required amount of B12, although its owner is sure of the opposite. Believing in the well-established myths, many are unaware of the lack of this vitamin.

• MYTH 1. I eat meat, so I get B12
  As we have already figured out, predators replenish B12 when they eat herbivores that receive vitamin from plants. But in the meat and dairy industries, animals are fed with nutritious mixtures to get meat and milk as quickly as possible.Many of them do not even have the opportunity to walk on the grass and look at the meadows; we are not talking about feeding on fresh vegetation. Such animals themselves suffer from a lack of B12 and their meat will not be able to make up for your lack of vitamin.
• MYTH 2. B12 is synthesized in the human body
  A lot of research confirms that the human body was once able to maintain life and promote the reproduction of B12 bacteria. But in modern conditions of life in megacities, our body has lost the ability to independently generate bacteria without their input from the outside.Don’t believe me? You can check! Just do not forget to get tested regularly during the experiment, B12 deficiency is very dangerous!
• MYTH 3. I can get B12 from greens, like cows
  If ​​you are going to eat lettuce leaves and tops straight from the garden, you may be able to do something. In most cases, we still wash the greens before eating, so as not to eat bacteria worse than B12. Washing water, chemicals and other plantation treatments during plant growth kill many harmful and beneficial bacteria.The chemicals themselves are very dangerous, but it is best to wash foods before using them, getting B12 from other sources.
• MYTH 4. Plant / artificial B12 is not absorbed
  B12 is absorbed as a food supplement, but according to the results of many studies it is worse than its “natural” counterpart. Modern manufacturers take this factor into account by increasing the dose of the vitamin several times. Vitamin B12 is considered harmless, its excess is excreted from the body in the urine, so there is no maximum daily intake.Follow the instructions on the package, take breaks between courses of admission and choose methylcobalamin as the source of the vitamin instead of cyanocobalamin, which negatively affects the body in case of kidney problems. I recommend this B12 complex. To determine the amount of vitamin in the body, get tested regularly.

B12 deficiency – how to recognize it and why it is dangerous for vegetarians

A deficiency in b12 will negatively affect the functioning of the whole organism if it is not detected and prevented in time.

In both animals and humans, vitamin B12 is concentrated and deposited in the liver. When you switch to vegetarianism, these reserves can last for months and years. Vegetarians who care about their b12 levels shouldn’t rely on these supplies alone, they definitely need an additional source. Otherwise, there is a risk of an increase in homocysteine ​​in the blood, which can lead to the development of cardiovascular diseases, negatively affect the course of pregnancy.

Early manifestations of b12 deficiency:

See Also

• Digestive Disorders
• loss of energy, fatigue, drowsiness
• loss of appetite
• nausea.

With an obvious deficiency, the symptoms already become dangerous and manifest as:

• numbness or tingling in the limbs, muscle weakness
• pale and slightly yellowish skin color
• increased nervousness, aggression or depression, memory problems, hallucinations
• ringing in the ears, headaches, visual impairment, shortness of breath, heart palpitations
• ulcers in the corners of the mouth, bleeding gums, inflammation of the mucous membrane of the tongue
• diarrhea.

Of course, these signs can correspond to different diseases. Homocysteine ​​or methylmalonic acid (MMA) tests can help identify or rule out a vitamin deficiency as a cause. Currently, the indicators of these substances are the most accurate markers in determining the content of B12. A homocysteine ​​test can also help detect hidden b12 deficiency that is asymptomatic.

Causes and symptoms of deficiency

The body excretes cyanocobalamin in the bile.Its destruction takes a long time.

Lack of vitamin B12 occurs with prolonged rejection of products containing it – meat, liver, fish, milk, eggs. E200 preservative can also cause cyanocobalamin destruction.

The reason for the deficiency is a violation of its assimilation in diseases of the gastrointestinal tract – atrophic gastritis, enterocolitis, helminthic invasions.

A regular shortage for 5-6 years is the reason for the development of B12-deficiency anemia. The pathological condition disrupts the formation of deoxyribonucleic acid, the exchange of fatty acids, reduces the level of erythrocytes and hemoglobin, affects the gastrointestinal tract, the central nervous system.This type of anemia causes diseases of the liver, kidneys, blood.

Other causes of B12-deficiency anemia – taking medications for seizures, contraception, excessive consumption of foods containing yeast.

Diseases of the stomach, biliary tract, intestines cause secondary vitamin deficiency due to a decrease in the production of cyanocobalamin by the intestinal microflora.

Even with a sufficient intake of foods containing vitamin B12, it is poorly absorbed if the body does not produce enough internal factor (Castle factor) – an enzyme that interacts with the inactive form of cyanocobalamin supplied with food and converts it into an active (digestible) form.

In old age, the Castle factor is practically not produced due to a reduced synthesis of acids in the body. In this case, the doctor prescribes injections instead of cyanocobalamin tablets. The inclusion in the diet of acidic plant foods – berries, fruits, vegetables – helps to maintain the required level of acid production in the body.

Some vitamins are antagonists. Therefore, vitamins B12 and B1, B2, B6, ascorbic acid cannot be mixed in one syringe – they are destroyed by the cobalt ion, which the cyanocobalamin molecule contains.

Vitamin B12 deficiency is indicated by the following symptoms:

• Increased fatigue, drowsiness, depression;
• headache, dizziness;

90,019 irritability;

• lack of appetite;
• numbness of the limbs;
• weakening and loss of hair;
• grayish or yellowish complexion.

Vitamin complexes

It is very important to periodically monitor the content of this beneficial substance in the body.In case of its deficiency, you urgently need to purchase a complex with it in any form at the pharmacy.

Known sources of vitamin B12:

• Cyanocobalamin ampoules. They should be injected intramuscularly every day. You will have enough packaging for a course of ten days.
• Vitamin complex in tablets, for example, “Neurovitan” or “Neurobion”. Take it one pill after meals once or twice a day for 10 days.

Do not consume more vitamin than is required according to the instructions.It is best if you balance your diet and ensure that you have enough of this substance in your diet. You can also take an additional vitamin complex, but you should choose one. In case of an excess of cyanocobalamin and the occurrence of hypervitaminosis, the following symptoms may appear:

• nervous excitement;
• heart pains;

90,019 rash;

90,019 pulmonary edema;

• blockage of blood vessels;
• arrhythmia.

Foods for vegetarians with B12 content

Scientific research over the past decades has proven that plants do not contain a useful form of vitamin B12 for humans.Eggs, milk and its derivatives, contrary to popular belief, are not a reliable source of the vitamin.

Where B12 is found in sufficient quantity:

1. Vitamin-enriched breakfast cereals (cereals), nutritional and brewer’s yeast, vegetable milk.
2. Vitamin supplements. As a rule, vegetarians get vitamin B12 from them, as from the most reliable source.

Some of the vitamin may be contained in the following foods:

• tofu cheese, tempeh bread, miso paste, provided that the bacteria that produce cobalamin were involved in the preparation process.
• natural farm vegetables, fruits, berries and herbs grown on cobalt-containing soil, without chemical treatment.

The presence of the vitamin in seaweed is often questioned or considered negligible. Many of them contain an inactive form of the vitamin, which is not actually absorbed, but affects the quantitative indicators of its level when analyzed.

Useful properties

Thiamine increases the speed of the brain, improves intellectual abilities and memory.It improves mood and affects the work of the entire central nervous system. It is directly involved in water-salt, protein, carbohydrate and energy metabolism, including in the processes of hematopoiesis. A pronounced antioxidant that slows down the aging of the body. Essential for maintaining good muscle tone in the digestive system and blood vessels. For good health, 1-2 mg per day is enough.

Harm of cobalamin

It is extremely difficult to harm the body with vitamin B12.It is non-toxic even at high doses. At the same time, it dissolves well in water, because the excess substance is simply excreted along with the urine.

However, in rare cases, an overdose of the body still happens (for example, with the abuse of drugs with cobalamin). In this case, the patient may complain of the following health problems:

• Headache.
• Dizziness.
• Tachycardia.
• Soreness in the region of the heart.
• Diarrhea.
• Pulmonary edema.
• The appearance of blood clots in the vessels.
• Congestive heart failure.
• Urticaria.
• Anaphylactic shock (extremely rare).

Supplementary intake of vitamin B12 preparations is prohibited in the following situations:

• For thromboembolism.
• Threat of blood clots.
• With erythremia, erythrocytosis.
• During pregnancy.
• During lactation.
• If you are allergic to B12.

Precautions for taking vitamin B12

If you are deficient in vitamin B12 and decide to take supplements with it, it is worth knowing and considering that it can interact with certain medications. Be sure to talk to your doctor if you are currently taking any medication or have a chronic medical condition.

Drugs that reduce the level of vitamin B12 in the human body include:

• Antiepileptic drugs
• Bile acid sequestrants
• Chemotherapy drugs (especially methotrexate)
• Colchicine
• h3 blockers
• Metformin (glucophage)
• Proton pump inhibitors, including esomeprazole (Nexium), lansprazole (Prevacid), omeprazole (Prilosec) and rabeprazole (Aciphex)
• Antibiotics, especially tetracycline

Vitamin B12 (cyanocobalamin) injections are also a great way to replenish vitamin deficiencies.

Should You Take Vitamin B12 Supplements?

Vitamin B12 supplements are recommended for people who are at risk of vitamin B12 deficiency. These include the elderly, pregnant or lactating women, vegetarians and vegans, people with bowel problems, and those who have had stomach surgery.

Vitamin B12 found in fortified foods and supplements is synthetically manufactured, making it suitable for vegans (16). Vitamin B12 supplements can be found in many forms.You can swallow, chew, drink, inject them intramuscularly, or place them under your tongue.

Studies have shown that vitamin B12, taken orally and injected intramuscularly, is equally effective in restoring its level in the bodies of people with a deficiency (40, 41, 42).

In fact, a study found that people with low vitamin B12 levels replenished their stores to normal levels after 90 days of either supplementation or injection (41).

Output:

Vitamin B12 supplements are recommended for people who avoid animal products or have problems absorbing it.They can be found in various forms and doses range from 150 to 2000 mcg.

Summarize

• Vitamin B12 is a key nutrient your body needs for many important functions.
• It can be found in large quantities in animal products, fortified foods and food additives. Some of the richest sources are liver, beef, sardines, shellfish, and dairy.
• If you are looking to increase your vitamin B12 stores or prevent vitamin B12 deficiency, these foods can significantly improve your overall health.

Sources of

• https://www.silazdorovya.ru/v-kakix-produktax-soderzhitsya-vitamin-b12/
• https://greenvegan.ru/zdorove/vitamin-b12-gde-soderzhitsya-kak-prinimat-defitsit-b12-u-veganov/
• https://myvegan-club.ru/posts/article/vitamin-b12-dlya-vegetariancev
• https://PolzaVsVred.ru/medicina/v12-vitamin-produkty.html
• https://WomFit.com/pitanie/dobavki/produkty-soderzhashhie-vitamin-v12.