Mesnex(r) (mesna) Injection
Mesnex(r) (mesna) Tablets
Mesnex(r) is a detoxifying agent to inhibit the hemorrhagic cystitis induced by ifosfamide (IFEX(r)). The active ingredient mesna is a synthetic sulfhydryl compound designated as sodium-2- mercaptoethane sulfonate with a molecular formula of C2H5NaO3S2 and a molecular weight of 164.18. Its structural formula is as follows: HS-CH2-CH2SO3-Na+ Mesnex Injection is a sterile, nonpyrogenic, aqueous solution of clear and colorless appearance in clear glass multidose vials for intravenous administration. Mesnex Injection contains 100 mg/mL mesna, 0.25 mg/mL edetate disodium and sodium hydroxide for pH adjustment. Mesnex Injection multidose vials also contain 10.4 mg of benzyl alcohol as a preservative. The solution has a pH range of 7.5 - 8.5. Mesnex Tablets are white, oblong, scored biconvex film coated tablets with the imprint M4. They contain 400 mg mesna. Excipients include lactose, microcrystalline cellulose, calcium phosphate, corn starch, povidone, magnesium stearate, hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide, and simethicone.
Mesnex was developed as a prophylactic agent to reduce the risk of hemorrhagic cystitis induced by ifosfamide. Analogous to the physiological cysteine-cystine system, mesna is rapidly oxidized to its major metabolite, mesna disulfide (dimesna). Mesna disulfide remains in the intravascular compartment and is rapidly eliminated by the kidneys. In the kidney, the mesna disulfide is reduced to the free thiol compound, mesna, which reacts chemically with the urotoxic ifosfamide metabolites (acrolein and 4-hydroxy-ifosfamide) resulting in their detoxification. The first step in the detoxification process is the binding of mesna to 4- hydroxy-ifosfamide forming a nonurotoxic 4-sulfoethylthioifosfamide. Mesna also binds to the double bonds of acrolein and to other urotoxic metabolites. In multiple human xenograft or rodent tumor model studies of limited scope, using i.v. or i.p. routes of administration, mesna in combination with ifosfamide (at dose ratios of up to 20-fold as single or multiple courses) failed to demonstrate interference with antitumor efficacy.
At doses of 2-4 g/m2, the terminal elimination half-life of ifosfamide is about 4-8 hours. As a result, in order to maintain adequate levels of mesna in the urinary bladder during the course of elimination of the urotoxic ifosfamide metabolites, repeated doses of Mesnex are required.
IV-IV-IV regimen
After intravenous administration of an 800 mg dose, the half-lives of mesna and dimesna in the blood are 0.36 hours and 1.17 hours, respectively. Approximately 32% and 33% of the administered dose was eliminated in the urine in 24 hours as mesna and dimesna, respectively. The majority of the dose recovered was eliminated within 4 hours. Mesna has a plasma clearance of 1.23 L/hour/kg.
IV-oral-oral regimen
The half-life of mesna ranged from 1.2 to 8.3 hours after administration of intravenous plus oral doses of Mesnex, as recommended in the DOSAGE AND ADMINISTRATION section. The urinary bioavailability of oral mesna ranged from 45-79% of intravenously administered mesna. Food does not affect the urinary availability of orally administered mesna. Approximately 18-26% of the combined intravenous and oral mesna dose appears as free mesna in the urine. When compared to intravenously administered mesna, the intravenous plus oral dosing regimen increases systemic exposures (150%) and provides more sustained excretion of mesna in the urine over a 24- hour period. Approximately 5% of the mesna dose is excreted during the 12-24 hour interval, as compared to negligible amounts in patients given the i.v. regimen. The fraction of the administered dose of mesna excreted in the urine is independent of dose. Protein binding of mesna is in a moderate range (69-75%).
Gender effect
An analysis was conducted in four male and four female volunteers; no differences in plasma pharmacokinetics were detected.
Pediatrics and Geriatrics
Pharmacokinetic data of Mesnex in pediatric and geriatric patients are not available.
Hepatic and Renal Insufficiency
No clinical studies were conducted to evaluate the effect of hepatic impairment or renal impairment on the pharmacokinetics of Mesnex.
No clinical drug interaction studies have been conducted with Mesnex.
Hemorrhagic cystitis produced by ifosfamide is dose dependent (Table 1). At a dose of 1.2 g/m2 ifosfamide administered daily for 5 days, 16-26% of the patients who received conventional uroprophylaxis (high fluid intake, alkalinization of the urine, and the administration of diuretics) developed hematuria (>50 RBC/hpf or macrohematuria) (Morgan, Einhorna Costanzi). In contrast, none of the patients who received Mesnex Injection together with this dose of ifosfamide developed hematuria (Einhorna,b). In two randomized studies, (Fukuoka, Scheef), higher doses of ifosfamide, from 2 to 4 g/m2 administered for three to five days, produced hematuria in 31 to 100% of the patients. When Mesnex was administered together with these doses of ifosfamide, the incidence of hematuria was less than 7%.
Table 1
Percent of Mesnex Patients Developing Hematuria (3 50 RBC/hpf or macrohematuria)
Study
Uncontrolled Studies
Conventional
Uroprophylaxis
(number of patients)
Standard Mesnex
IV regimen
(number of patients)
MORGAN *
16% (7/44) -
COSTANZI *
26% (11/43) -
EINHORNa *
18% (7/38) 0% (0/21)
EINHORNb *
- 0% (0/32)
Controlled Studies
FUKUOKA * *
31% (14/46) 6% (3/46)
SCHEEF * *
100% (7/7) 0% (0/8)
* Ifosfamide dose 1.2 g/m2 d x 5
* * Ifosfamide dose 2 to 4 g/m2 d x 3-5
Clinical studies comparing recommended intravenous and oral mesna dosing regimens demonstrated incidences of grade 3-4 hematuria of <5% in both arms when used in conjunction with ifosfamide 1.2-2.0 gm/m2 for 3-5 days. Study D07093-0018 was an open label, randomized, two-way crossover study comparing three i.v. doses with an initial i.v. dose followed by two oral doses of mesna in patients with cancer treated with ifosfamide at a dose of 1.2-2.0 g/m2 for 3-5 days. Study MED504 was a randomized, multicenter study in cancer patients receiving ifosfamide at 2.0 g/m2 for 5 days. In both studies, development of grade 3 or 4 hematuria was the primary efficacy endpoint. The percent of patients developing hematuria in each of these studies is presented in Table 2.
Table 2
Percent of Mesnex Patients Developing Grade 3 or 4 Hematuria
Mesnex Dosing Regimen
S
tudy Standard IV regimen
IV + Oral regimen
(number of patients)
D07093-0018
0% (0/30) 3.6% (1/28)
MED504
3.7% (1/27) 4.3% (1/23)
A cross over pharmacokinetic study supports the low incidence of grade 3 or 4 hematuria with the recommended intravenous and oral mesna dosing regimens used in the two controlled studies.
Mesnex is indicated as a prophylactic agent in reducing the incidence of ifosfamide-induced hemorrhagic cystitis.
Mesnex is contraindicated in patients known to be hypersensitive to mesna or other thiol compounds.
Allergic reactions to mesna ranging from mild hypersensitivity to systemic anaphylactic reactions have been reported. Patients with autoimmune disorders who were treated with cyclophosphamide and mesna appeared to have a higher incidence of allergic reactions. The majority of these patients received mesna orally. Mesnex has been developed as an agent to reduce the risk of ifosfamide induced hemorrhagic cystitis. It will not prevent or alleviate any of the other adverse reactions or toxicities associated with ifosfamide therapy. Mesnex does not prevent hemorrhagic cystitis in all patients. Up to 6% of patients treated with mesna have developed hematuria (>50 RBC/hpf or WHO grade 2 and above). As a result, a morning specimen of urine should be examined for the presence of hematuria (microscopic evidence of red blood cells) each day prior to ifosfamide therapy. If hematuria develops when Mesnex is given with ifosfamide according to the recommended dosage schedule, depending on the severity of the hematuria, dosage reductions or discontinuation of ifosfamide therapy may be initiated. In order to reduce the risk of hematuria, Mesnex must be administered with each dose of ifosfamide as outlined in the DOSAGE AND ADMINISTRATION section. Mesnex is not effective in reducing the risk of hematuria due to other pathological conditions such as thrombocytopenia. Because of the benzyl alcohol content, the multidose vial should not be used in neonates or infants and should be used with caution in older pediatric patients.
Health care providers should advise patients taking Mesnex to drink at least a quart of liquid a day. Patients should be informed to report if their urine has turned a pink or red color if they vomit within 2 hours of taking oral Mesnex, or if they miss a dose of oral Mesnex. See Patient Information Leaflet for Mesnex Tablets.
A false positive test for urinary ketones may arise in patients treated with Mesnex. In this test, a red- violet color develops which, with the addition of glacial acetic acid, will return to violet.
No clinical drug studies have been conducted.
Carcinogenesis
No long-term studies in animals have been performed to evaluate the carcinogenic potential of Mesnex.
Mutagenesis
Mesna was not genotoxic in the in vitro Ames bacterial mutagenicity assay, the in vitro mammalian lymphocyte chromosomal aberration assay or the in vivo mouse micronucleus assay.
Impairment of Fertility
No studies on male or female fertility were conducted. No signs of male or female reproductive organ toxicity were seen in 6 month oral rat studies (at doses up to 2000 mg/kg/day) or 29 week oral dog studies (520 mg/kg/day; both studies approximately 10-fold higher than the maximum recommended human dose on a body surface area basis).
Pregnancy Category B
. Reproduction studies have been performed in rats and rabbits at oral doses of 1000 mg/kg in rabbit and 2000 mg/kg in rat (approximately 10 times the maximum recommended total daily i.v.-oral-oral human dose on a body surface area basis) and have revealed no evidence of harm to the fetus due to mesna. There are however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
It is not known whether mesna or dimesna is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from mesna, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness of Mesnex Tablets in pediatric patients have not been established. Because of the benzyl alcohol content in Mesnex Injection, the multidose vial should not be used in neonates or infants and should be used with caution in older pediatric patients.
Clinical studies of mesna did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. However, the ratio of ifosfamide to mesna should remain unchanged.
Mesnex adverse reaction data are available from four phase I studies in which single i.v. bolus doses of 600-1200 mg Mesnex Injection without concurrent chemotherapy were administered to a total of 53 subjects and single oral doses of 600-2400 mg of Mesnex Tablets were administered to a total of 82 subjects. The most frequently reported side effects (observed in two or more patients) for patients receiving single doses of Mesnex IV were headache, injection site reactions, flushing, dizziness, nausea, vomiting, somnolence, diarrhea, anorexia, fever, pharyngitis, hyperaesthesia, influenza-like symptoms, and coughing. Among patients who received a single 1200-mg dose as an oral solution, rigors, back pain, rash, conjunctivitis, and arthralgia were also reported. In two phase I multiple- dose studies where patients received Mesnex Tablets alone or IV Mesnex followed by repeated doses of Mesnex Tablets, flatulence and rhinitis were reported. In addition, constipation was reported by patients who had received repeated doses of IV Mesnex. Because mesna is used in combination with ifosfamide or ifosfamide-containing chemotherapy regimens, it is difficult to distinguish the adverse reactions which may be due to Mesnex from those caused by the concomitantly administered cytotoxic agents. Adverse reactions reasonably associated with mesna administered i.v. and orally in four controlled studies in which patients received ifosfamide or ifosfamide containing regimens are presented in Table 3.
Table 3
Incidence of Adverse Events and Incidence of Most Frequently Reported Adverse Events in Controlled Studies | ||
|---|---|---|
| Mesna regimen | i.v.-i.v-i.v. | i.v.-oral-oral |
| N exposed | 119 (100.0%) | 119 (100.0%) |
| Incidence of AEs | 101 (84.9%) | 106 (89.1%) |
| Most Frequently Reported Adverse Events (Preferred Terms) | ||
| Nausea | N (%) | N (%) |
| 65 (54.6) | 64 (53.8) | |
| Vomiting | 35 (29.4) | 45 (37.8) |
| Constipation | 28 (23.5) | 21 (17.6) |
| Leukopenia | 25 (21.0) | 21 (17.6) |
| Fatigue | 24 (20.2) | 24 (20.2) |
| Fever | 24 (20.2) | 18 (15.1) |
| Anorexia | 21 (17.6) | 19 (16.0) |
| Thrombocytopenia | 21 (17.6) | 16 (13.4) |
| Anemia | 20 (16.8) | 21 (17.6) |
| Granulocytopenia | 16 (13.4) | 15 (12.6) |
Table 3
Incidence of Adverse Events and Incidence of Most Frequently Reported Adverse Events in Controlled Studies | ||||
|---|---|---|---|---|
| Asthenia | 15 | (12.6) | 21 | (17.6) |
| Abdominal Pain | 14 | (11.8) | 18 | (15.1) |
| Alopecia | 12 | (10.1) | 13 | (10.9) |
| Dyspnea | 11 | (9.2) | 11 | (9.2) |
| Chest Pain | 10 | (8.4) | 9 | (7.6) |
| Hypokalemia | 10 | (8.4) | 11 | (9.2) |
| Diarrhea | 9 | (7.6) | 17 | (14.3) |
| Dizziness | 9 | (7.6) | 5 | (4.2) |
| Headache | 9 | (7.6) | 13 | (10.9) |
| Pain | 9 | (7.6) | 10 | (8.4) |
| Sweating Increased | 9 | (7.6) | 2 | (1.7) |
| Back Pain | 8 | (6.7) | 6 | (5.0) |
| Hematuria * | 8 | (6.7) | 7 | (5.9) |
| Injection Site Reaction | 8 | (6.7) | 10 | (8.4) |
| Edema | 8 | (6.7) | 9 | (7.6) |
| Edema Peripheral | 8 | (6.7) | 8 | (6.7) |
| Somnolence | 8 | (6.7) | 12 | (10.1) |
| Anxiety | 7 | (5.9) | 4 | (3.4) |
| Confusion | 7 | (5.9) | 6 | (5.0) |
| Face Edema | 6 | (5.0) | 5 | (4.2) |
| Insomnia | 6 | (5.0) | 11 | (9.2) |
| Coughing | 5 | (4.2) | 10 | (8.4) |
| Dyspepsia | 4 | (3.4) | 6 | (5.0) |
| Hypotension | 4 | (3.4) | 6 | (5.0) |
| Pallor | 4 | (3.4) | 6 | (5.0) |
| Dehydration | 3 | (2.5) | 7 | (5.9) |
| Pneumonia | 2 | (1.7) | 8 | (6.7) |
| Tachycardia | 1 | (0.8) | 7 | (5.9) |
| Flushing | 1 | (0.8) | 6 | (5.0) |
* All grades
Postmarketing Surveillance
Allergic reactions, decreased platelet counts associated with allergic reactions, hypertension, hypotension, increased heart rate, increased liver enzymes, injection site reactions (including pain and erythema), limb pain, malaise, myalgia, ST - segment elevation, tachycardia, and tachypnea have been reported as part of postmarketing surveillance.
There is no known antidote for Mesnex. Oral doses of 6.1 and 4.3 g/kg were lethal to mice and rats, respectively. These doses are approximately 15 and 22 times the maximum recommended human dose on a body surface area basis. Death was preceded by diarrhea, tremor, convulsions, dyspnea, and cyanosis.
For the prophylaxis of ifosfamide induced hemorrhagic cystitis, Mesnex may be given on a fractionated dosing schedule of 3 bolus intravenous injections or a single bolus injection followed by two oral administrations of Mesnex Tablets as outlined below.
Mesnex is given as intravenous bolus injections in a dosage equal to 20% of the ifosfamide dosage (w/w) at the time of ifosfamide administration and 4 and 8 hours after each dose of ifosfamide. The total daily dose of mesna is 60% of the ifosfamide dose. The recommended dosing schedule is outlined below:
| 0 Hours | 4 Hours | 8 Hours | |
| Ifosfamide Mesnex | 1.2 g/m 2 240 mg/m 2 | - 240 mg/m 2 | - 240 mg/m 2 |
Mesnex Injection is given as intravenous bolus injections in a dosage equal to 20% of the ifosfamide dosage (w/w) at the time of ifosfamide administration. Mesnex Tablets are given orally in a dosage equal to 40% of the ifosfamide dose 2 and 6 hours after each dose of ifosfamide. The total daily dose of mesna is 100% of the ifosfamide dose. The recommended dosing schedule is outlined below:
| 0 Hours | 2 Hours | 6 Hours | |
| Ifosfamide Mesnex Injection Mesnex Tablets | 1.2 g/m 2 240 mg/m 2 - | - - 480 mg/m 2 | - - 480 mg/m 2 |
Patients who vomit within two hours of taking oral mesna should repeat the dose or receive intravenous mesna. The efficacy and safety of this ratio of IV and PO mesna has not been established as being effective for daily doses of IFEXO higher than 2.0 g/m2. The dosing schedule should be repeated on each day that ifosfamide is administered. When the dosage of ifosfamide is adjusted (either increased or decreased), the ratio of Mesnex to IFEXO should be maintained.
The Mesnex multidose vials may be stored and used for up to 8 days. For i.v. administration the drug can be diluted by adding the Mesnex Injection solution to any of the following fluids obtaining final concentrations of 20 mg mesna/mL: 5% Dextrose Injection, USP 5% Dextrose and 0.2% Sodium Chloride Injection, USP 5% Dextrose and 0.33% Sodium Chloride Injection, USP 5% Dextrose and 0.45% Sodium Chloride Injection, USP 0.92% Sodium Chloride Injection, USP Lactated Ringer's Injection, USP For example: One mL of Mesnex Injection multidose vial 100 mg/mL may be added to 4 mL of any of the solutions listed above to create a final concentration of 20 mg mesna/mL. Diluted solutions are chemically and physically stable for 24 hours at 25deg C (77deg F). Mesna is not compatible with cisplatin or carboplatin. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
Mesnex(r) (mesna) Injection 100 mg/mL NDC 0015-3563-02 - 1 g Multidose Vial, Box of 1 vial of 10 mL NDC 0015-3563-03 - 1 g Multidose Vial, Box of 10 vials of 10 mL Mesnex(r) (mesna) Tablets NDC 0015-3565-12 - 400 mg scored tablets, Boxes containing 10 blisters per card Store at controlled room temperature 20deg C to 25deg C (68deg F to 77deg F). U.S. Patent Nos. : 5,262,169, 5,252,341, and 5,696,172 Distributed by:
A Bristol-Myers Squibb Company
SAPriPnceNtoun,mNebweJrersey, 08543 USA MesnexO (mesna) Injection manufactured by: MesnexO (mesna) Tablets manufactured for:
Baxter Healthcare Corporation
Deerfield, IL 60015 USA
Patient Information
Mesnex(r) (mesna) Tablets Read this information carefully before you start taking Mesnex (MES-nex) and each time you get more Mesnex. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about Mesnex, ask your doctor. Only your doctor can determine if Mesnex is right for you.
What is the most important information I should know?
It is important to drink at least a quart (4 cups) of liquid a day whenever you take Mesnex, whether it is intravenous (through a tube placed in a vein) or oral (by mouth).
A small number of patients who take Mesnex get blood in their urine (hematuria). Therefore, it is important that your doctor check your urine in the laboratory each day that you get Mesnex. The laboratory test can find low levels of blood in the urine that you cannot see just by looking at it.
If you notice that your urine has turned a pink or red color, contact your doctor as soon as possible. Certain prescription medicines and foods, such as red beets, may also cause your urine to change color. A laboratory test of your urine will show if the source of the color is due to one of these causes or hematuria.
You need to take your Mesnex Tablets at the exact times your doctor tells you. If you miss a dose, take it as soon as you remember, and contact your doctor for more instructions. Do not double your dose to make up for the missed dose.
If you vomit within 2 hours of taking oral Mesnex, contact your doctor right away.
What is Mesnex?
Mesnex reduces the chance of your getting one of the side effects of another medicine, IFEXO (ifosfamide) for Injection. IFEX is used to treat certain types of cancers. Mesnex should only be given with IFEX. Mesnex reduces the chance of your getting hemorrhagic cystitis from IFEX. This condition causes bloody urine from damage to the bladder lining. The damage to the bladder may show up as blood in your urine (hematuria). If a very small amount of blood is in your urine, you may not be able to see it, but your doctor or nurse can test for it in the laboratory. If there is a larger amount of blood in your urine, you will see that the urine has turned a pink or red color. Mesnex does not reduce the chance of getting other side effects of cancer chemotherapy. When IFEX is given without Mesnex, hematuria occurs in a large number of patients. Therefore, it is very important to always take Mesnex when getting IFEX treatment.
Who should not take Mesnex?
Do not take Mesnex if you have had an allergic reaction to Mesnex or other medicines that contain sulfur. Before beginning treatment with Mesnex, check with your doctor if you are:
Pregnant. You and your doctor should discuss if Mesnex is right for you.
Breast feeding. Your doctor may advise you to stop breast-feeding or not to use Mesnex.
Have an autoimmune disorder such as rheumatoid arthritis, systemic lupus erythematosis (SLE), or nephritis (a type of kidney problem). You may be more likely to get an allergic reaction from Mesnex.
How should I take Mesnex?
Take Mesnex at the exact times in the exact amounts your doctor tells you to.
If your first dose is intravenous and the other doses are oral, you will get the intravenous dose at the same time as the IFEX. You should take the tablets 2 and 6 hours after the IFEX.
The dose of Mesnex depends on the amount of the IFEX dose. Pay careful attention to the number of tablets your doctor instructs you to take. You may need to take half tablets for your dose. Each tablet has a groove in the middle that makes it easy to break the tablets in half. For more information about how to take Mesnex, see the section "What is the most important information I should know about Mesnex?"
What are the most common side effects of Mesnex?
The most common side effects reported for Mesnex Tablets are headache; digestive symptoms such as nausea (feeling sick to your stomach), vomiting (throwing up), diarrhea (frequent or watery stools or bowel movements), stomach pain and low or no appetite; flu-like symptoms including dizziness, flushing, and fever; sensitive skin; sleepiness; coughing; sore throat; cold-like symptoms; injection site reactions. Some patients may get allergic reactions, rash, constipation, paleness, fluid retention (water stays in your body), and decreased blood pressure. These are not all the possible side effects of Mesnex. For a complete list, ask your doctor.
If you suspect that someone may have taken more than the prescribed dose of Mesnex, contact your local poison control center or emergency room right away. Storage
Store Mesnex Tablets in a cool, dry place protected from excess moisture and heat. If possible do not store in the kitchen or bathroom. Throw away any unused portion after the expiration date.
General advice about prescription medicines
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Mesnex for a condition for which it was not prescribed. Do not give Mesnex to other people, even if they have the same symptoms you have. It may harm them. This leaflet summarizes the most important information about Mesnex. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Mesnex that is written for health professionals. IFEX is a registered trademark of Bristol-Myers Squibb Company This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration. MesnexO (mesna) Tablets manufactured for:
Baxter Healthcare Corporation
Deerfield, IL 60015 USA SAP Number Issue date