Zolta Zoledronic acid concentrate for solution for infusion 4mg/5ml fl №1

Zolta Zoledronic acid concentrate for solution for infusion 4mg/5ml fl №1

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Composition active substance: zolendronic acid (zoledronic acid) 5 ml of the concentrate containing 4 mg of zoledronic acid anhydrous that meets of 4.26 mg of zoledronic acid monohydrate; auxiliary substances: mannitol (E 421), sodium (E 331), water for injection. Dosage form Concentrate for preparation of solution for infusions. Basic physico-chemical properties: transparent colorless liquid. Pharmacological group Means affecting the structure and mineralization of the bones. Bisphosphonates. Code ATH M05V A08. Pharmacological properties Pharmacological. Alendronova acid belongs to a class of bisphosphonates specifically act on bone tissue. It's an inhibitor of bone resorption osteoclasts. The selective effect of bisphosphonates on bone is based on their high affinity with mineralized bone tissue, but the molecular mechanism leading to inhibition of osteoclasts of activity, today is not clarified. Animal studies have shown that Zometa inhibits bone resorption without adversely affecting bone formation, mineralization and mechanical properties. In addition to inhibiting bone resorption osteoclasts, Zometa has a direct antitumor effect, which can contribute to improving the overall effectiveness in the treatment of bone metastatic disease. The following properties have been demonstrated in preclinical studies: in vivo - inhibition of bone resorption osteoclasts, which acts on the structure of microcrystalline bone matrix, reduces tumor growth, antiangiogenic effect (impact on blood vessels, which leads to a decrease in tumor blood supply), analgesic effect; in vitro inhibition osteoblast proliferation, direct cytostatic effect, proapoptotic effect on tumour cells, synergistic cytostatic effect with other anti-tumor drugs, anti-adhesive and antiinvasive action. Pharmacokinetics. Pharmacokinetics data for bone metastases obtained after a single and repeated 5 - and 15-minute infusion of 2, 4, 8 and 16 mg of zoledronic acid in 64 patients. Pharmacokinetic characteristics do not depend on the dose. After the onset of infusion of zoledronic acid plasma concentrations of the drug increase rapidly, reaching a peak at the end of the infusion, then there is a rapid decrease in the concentration to<10% of the peak value after 4:00 and to<1% of the peak value after 24 hours with a sequentially prolonged period of low concentrations do not exceed 0.1% of the peak before the introduction of the second infusion on the 28th day. Zometa, administered intravenously, is excreted by the kidneys in 3 stages: a rapid two-phase removal of the drug from the systemic circulation with a half-life period t ?? = 0,24 hours and t ?? = 1,87 hours, followed by a long phase of elimination with a final half-life period t ?? = 146 hours. No cumulation of zoledronic acid in plasma was observed with repeated injections every 28 days. Alendronova acid is not metabolized and is excreted by the kidneys unchanged. During the first 24 hours 39 ± 16% of the administered dose is detected in the urine. The rest of the drug is associated with bone tissue. Then slowly there is the reverse release of zoledronic acid from bone tissue into the systemic bloodstream and its excretion by the kidneys. The total clearance in the body is 5,04 ± 2,5 l/h and does not depend on the dose, sex, age, race and body weight of the patient. An increase in the duration of infusion from 5 to 15 minutes leads to a decrease in the concentration of zoledronic acid by 30% at the end of the infusion, but does not affect the curve of concentration versus time in blood plasma (AUC). The variability of pharmacokinetic parameters of zoledronic acid in different patients was high, as in the case of other bisphosphonates. Data on the pharmacokinetics of zoledronic acid in patients with hypercalcemia and liver failure are not available. According to the data obtained in in vitro studies , alendronova acid inhibits the enzyme P450 human and not biotransformation. According to experimental studies conducted on animals, less than 3% of the administered dose is excreted with feces, which suggests that the state of liver function does not affect the pharmacokinetics of zoledronic acid. Renal clearance of zoledronic acid correlates with creatinine clearance, renal clearance is 75 ± 33% creatinine clearance, reaching an average of 84 ± 29 ml/min (range 22 - 143 ml/min) in 64 cancer patients participating in the study. The analysis showed that in patients with creatinine clearance 20 ml/min (acute renal failure) and 50 ml/min (average renal failure) relative clearance of zoledronic acid - 37% and 72%, respectively. However, data from such in patients with acute renal failure (creatinine clearance<30 ml/min) are limited. Discovered low affinity of zoledronic acid for the cellular components of blood. Binding to plasma proteins is low (about 56%) and does not depend on the concentration of zoledronic acid. children Limited pharmacokinetic data for children with severe osteogenesis disorders suggest that the pharmacokinetics of zoledronic acid in children aged 3 to 17 years is similar to those in adults when used in equivalent doses (mg/kg). Age, body weight, gender of the patient and creatinine clearance, as it turned out, do not affect the systemic exposure of zoledronic acid. Indications Prevention of symptoms associated with bone lesions (pathological fractures, compression of the vertebral column, complications after surgery and radiation therapy or hypercalcemia due to a malignant tumor) in patients with malignant tumors at late stages. Treatment of hypercalcemia caused by a malignant tumor. Contraindications Hypersensitivity to the active substance (zoledronic acid), other bisphosphonates or any auxiliary substances that are part of the drug. Pregnancy or breast-feeding. Interaction with other medicinal products and other forms of interaction In clinical studies, Zometa is often prescribed together with other drugs, particularly anticancer drugs, antibiotics, analgesics. There were no clinically significant interactions. According to the data obtained during in vitro studies , Zometa is not significantly associated with blood plasma proteins and does not inhibit enzymes of the cytochrome P450. However special clinical studies of drug interactions have not been conducted. It is recommended to exercise caution while introducing bisphosphonates and aminoglycosides, as they may exhibit an additive effect, whereby the level of calcium in the serum may remain reduced for longer than necessary. Caution should be exercised in the appointment of zoledronic acid and other potentially nephrotoxic drugs. It should also be borne in mind the possibility of the development of hypomagnesemia treatment time. In patients with multiple myeloma, no clinically significant interactions were observed in the administration of zoledronic acid in combination with talidomide. It was reported on osteonecrosis of the jaw in patients receiving concomitant treatment with Zometa and anti-angiogenic (reduce the blood supply of a tumor) drugs. Application features general Before the introduction of this drug should ensure sufficient hydration of all patients, including patients with mild to moderate renal impairment. You should avoid fluid overload in patients with risk of development of heart failure. Standard metabolic parameters associated with hypercalcemia, such as calcium, phosphate and magnesium levels, need to be carefully checked after initiation of zoledronic acid therapy. If there is hypocalcemia, hypophosphatemia or hypomagnesemia, short-term corrective therapy may be necessary. Patients with untreated hypercalcemia usually have some renal impairment, so you need to carefully monitor kidney function. Patients receiving treatment of zoledronic acid should not simultaneously take other medications containing bisphosphonates Zometa or other drugs. Violation of kidney function When deciding on the use of this drug in patients with hypercalcemia due to a malignant tumor, against the background of impaired renal function should assess the patient's condition and conclude that the predominant potential benefits of treatment over the possible risk. When deciding on the treatment of patients with bone metastases in order to prevent symptoms associated with diseases of the spine, it should be borne in mind that the effect of the drug appears after 2-3 months. There have been reports of renal dysfunction associated with the use of zoledronic acid. Factors that increase the possibility of renal impairment include dehydration, pre-existing renal impairment, multiple cycles of zoledronic acid or other bisphosphonates, as well as the use of nephrotoxic agents or infusion in a shorter time than recommended. Although with the introduction of zoledronic acid at a dose of 4 mg for at least 15 minutes, the risk decreases, renal impairment remains possible. An increase in serum creatinine levels is also observed in some patients who constantly take the drug in recommended doses to prevent the occurrence of symptoms associated with spinal diseases, although this is quite rare. Before each dose patients should be evaluated regarding the level of creatinine in the blood serum. At the beginning of treatment for patients with bone metastases and renal insufficiency of mild or moderate recommended lower doses of zoledronic acid. Patients who suffer from deterioration kidney function during treatment, the drug can be restored only when the level of creatinine returns to its original value within 10% of the initial value. Treatment with zoledronic acid is restored to the same dose, administered to discontinue treatment. Through the possible effect of zoledronic acid on kidney function due to the lack of detailed data on clinical safety in patients with severe renal insufficiency (serum creatinine ? 400 µmol/l, or ? 4.5 mg/DL, for patients with hypercalcemia and serum creatinine ? 265 µmol/l, or ? 3 mg/DL, for patients with cancer and bone metastases respectively) at the beginning of treatment and only limited pharmacokinetic data for patients with severe renal insufficiency at the beginning of treatment (creatinine clearance<30 ml/min) on the Stosuvannya zoledronic acid in patients with severe renal insufficiency is not recommended. Patients, especially the elderly and those who have been treated with diuretics, should be properly hydrated before taking zoledronic acid. Impaired liver function Recommendations for patients with severe hepatic insufficiency are not available, as only limited clinical data are available. the osteonecrosis of the jaw About osteonecrosis of the jaw has been reported predominantly in patients with cancer receive medicinal products that inhibit bone resorption, including Zometa. A large number of these patients also received chemotherapy and corticosteroids. Most of the reported cases were related to dental procedures such as tooth extraction. Many of the patients showed signs of local infection, including osteomyelitis. You must consider the following risk factors to estimate individual risk of developing osteonecrosis of the jaw bisphosphonate activity (greater risk for more active constituents), administration method (greater risk for parenteral administration) and cumulative dose; cancer, chemotherapy, radiotherapy, corticosteroid therapy, Smoking; history of dental diseases, insufficient oral hygiene, periodontal disease, invasive dental procedures and non-dental prosthesis. Before the start of treatment with bisphosphonates, it is necessary to examine the oral cavity with appropriate dental prevention. During therapy, these patients should avoid invasive dental procedures if possible. Patients who develop osteonecrosis of the jaw during therapy with bisphosphonates, dental surgery can worsen the condition. There is no data on patients in need of dental procedures to determine reduces the risk of osteonecrosis of the jaw discontinuation of treatment with bisphosphonates. The physician, in making a clinical assessment, should be guided by each patient's management plan, based on an individual assessment of benefit/risk. Musculoskeletal pain During post-marketing studies have reported strong, sometimes invalidusername pain in bones, joints and/or muscles of the patients who take bisphosphonates. However, such reports were isolated. This category of drugs includes Zometa. The time before the onset of symptoms varied from one day to several months from the start of treatment. In most patients, the severity of symptoms decreased after the termination of treatment. In this category, patients noted a relapse of symptoms if treatment was resumed Zometa or other bisphosphonates. Atypical femoral fracture Edwardlucas and atypical diaphyseal femur fractures were registered during therapy, bisphosphonates, primarily in patients receiving long-term treatment of osteoporosis. These transverse or short oblique fractures are possible anywhere along the femur from just below the small trochanter to just above namyslow. These fractures occur after or without a minimal injury, and some patients experience hip or groin pain, often associated with x-ray signs of a stress fracture, a few weeks or months before the occurrence of a complete hip fracture. Fractures are often bilateral; therefore patients who receive bisphosphonate therapy and have suffered a femur fracture, it is necessary to examine the second thigh. Long-term healing of these fractures has also been reported. On the basis of an individual assessment of risks and benefits should decide the issue of termination bisphosphonate the treatment of patients with suspected atypical fractures of the femur. During treatment with bisphosphonates, patients should inform the doctor about any pain in the pelvis, hip or groin, and each patient with such symptoms should be examined for incomplete fracture of the femur. hypocalcemia Hypocalcemia was reported in patients who used Zometa. Information was received about arrhythmia and neurological reactions (including epileptic seizures, numbness and tetany), secondary to severe hypocalcemia. Cases of severe hypocalcemia have been reported to require hospitalization. Sometimes hypocalcemia may be life-threatening. Use during pregnancy or lactation The drug is contraindicated during pregnancy and lactation. gestation period There is no sufficient data on the use of zoledronic acid pregnant women. The study of reproductive function in animals showed reproductive toxicity. The potential risk to humans is unknown. lactation Unknown Zometa gets into breast milk. Influence on reproductive ability The effect of zoledronic acid was assessed in animals for potential adverse effects on reproductive function and F1 generation. This led to an increase in the considered pharmacological effects associated with inhibition of calcium mobilization from bones, resulting in perinatal mortality due to hypocalcemia, specific effects of bisphosphonates, pathological delivery and early termination of the study. Thus, these results exclude the determination of the final effect of zoledronic acid on human reproductive ability. The ability to influence the reaction rate when driving motor transport or operating other mechanisms Adverse reactions of the drug, such as dizziness and somnolence may affect the ability to drive vehicles or other mechanisms, so care is needed when driving vehicles or work with machinery during the period of use of zoledronic acid. Method of application and doses The drug Zolta is administered only by doctors with experience in the administration of bisphosphonates. Before the introduction of 4 mg concentrate diluted in 100 ml 0.9% sodium chloride solution or 5% glucose solution. Ready solution for infusion is administered as a single infusion for at least 15 minutes. Concentrate this medicinal product must not be mixed with solutions for infusion containing calcium or other divalent cations, such as lactate ringer solution and must be administered in a single infusion through the separate infusion systems. Only a transparent, colourless, particle-free solution should be used. Any unused product or its waste must be disposed of in accordance with the requirements of local law. Prevention of symptoms associated with bone lesions in patients with malignant neoplasms at late stages Adults, including elderly patients The recommended dose of Zolta for the prevention of symptoms associated with bone lesions in patients with malignant neoplasms is 4 mg of zoledronic acid every 3 to 4 weeks. Patients also need daily administration of calcium products inside at a dose of 500 mg and 400 IU of vitamin d per day. The decision to treat patients with metastatic bone lesions for the prevention of symptoms associated with bone lesions, should take into account that the beginning of the effect of treatment occurs after 2 to 3 months. Treatment of hypercalcemia caused by a malignant tumor Adults, including elderly patients The recommended dose in hypercalcaemia (albumin corrected relative to calcium in the blood serum of ? 12.0 mg/DL or 3.0 mmol/l) is 4 mg as a single infusion. Before the introduction and during the introduction of the drug should be ensure adequate hydration of the patient. Violation of kidney function Hypercalcemia caused by a malignant tumor Treatment of hypercalcemia caused by a malignant tumor in patients with severe renal impairment is possible only after assessing the risks and benefits of such treatment. Clinical studies for patients with serum creatinine levels> 400 µmol/l, or> 4.5 mg/DL, are not available. Patients with hypercalcemia due to malignant tumor, with the creatinine level in serum<400 µmol/l or<4.5 mg/DL, dose adjustment is not required. Prevention of symptoms associated with bone lesions in patients with malignant neoplasms at late stages Starting treatment of patients with multiple myeloma or metastatic bone lesions due to solid tumors, it is necessary to determine the level of serum creatinine and creatinine clearance. KK is calculated at the level of creatinine in serum according to the formula of Cockroft-Gault. The drug Zolta not recommended for patients with existing severe renal impairment (creatinine clearance<30 ml/min). Clinical studies on the use of zoledronic acid in patients with serum creatinine levels> 265 mmol/l, or> 3 mg/DL, were not carried out. Recommended doses of the drug for patients with metastatic bone damage in violation of kidney function mild to moderate severity (creatinine clearance 30-60 ml/min): The initial creatinine clearance level (ml/min)the recommended dose of zoledronic acid (mg) * > 604 mg 50-603, 5 mg * 40-493, 3 mg * 30-393 mg * * Doses calculated with the assumption of a given AUC = 0,66 mg * h/l (creatinine clearance 75 ml/min). For patients with impaired renal function provides a dose reduction to a level at which such AUC is achieved, as in patients with creatinine clearance of 75 ml/min. After the start of therapy, the creatinine level in serum should be measured before each dose of the drug Zolta, in the case of impairment of liver function, treatment should be discontinued. In the course of studies, the deterioration of renal insufficiency was determined as follows: for patients with normal serum creatinine baseline (<1.4 mg/DL, or<124 µmol/l) - an increase of 0.5 mg/DL, or 44 µmol/l; for patients with altered serum creatinine baseline (> 1.4 mg/DL or> 124 µmol/l) - an increase of 1 mg/DL or 88 µmol/l. During the studies, Zometa therapy was restored after the return of creatinine level to the entry level within 10% of the initial value (see section "Features of application"). Zolta therapy should be restored in the same dose, which was prescribed to discontinue treatment. Instructions for preparing doses of the drug The dose of concentrate for solution for infusion in milliliters (ml), corresponding to the doses of the drug Zolta: 4.4 ml corresponds to 3.5 mg 4.1 ml corresponds to 3.3 mg 3.8 ml corresponds to 3.0 mg. The required amount of liquid concentrate should be diluted in 100 ml sterile 0.9% sodium chloride solution or 5% glucose solution for intravenous infusion. The dose is administered as a single infusion for at least 15 minutes. Children For children from 1 year to 17 years of safety and efficacy of zoledronic acid has not been established. Overdose Clinical experience in the treatment of acute overdose Zometa limited. It was reported that the erroneous use of zoledronic acid at a dose of 48 mg .Patients who used a dose that exceeds the recommended dose should be under constant control, since there may be a violation of kidney function (including renal failure), changes in the electrolyte composition of serum (including calcium, phosphate and magnesium concentrations). When hypocalcemia occurs, calcium gluconate infusion is shown to be performed according to clinical indications. Treatment is symptomatic. Adverse reaction Within three days after the drug was usually reported gastropathy reaction, symptoms of which include bone pain, fever, weakness, arthralgia, myalgia, chills and arthritis with swelling of joints. These symptoms usually disappear within a few days. In the case of the application of zoledronic acid identified the following important adverse reactions: the violation of the kidney, necrosis of the jaw, gastropathy reactions, hypocalcemia, blurred vision, atrial fibrillation, anaphylaxis. Information about the frequency of adverse reactions in the application of zoledronic acid at a dose of 4 mg is based mainly on data obtained during long-term therapy. Adverse reactions associated with the use of the drug, such as those reported in the application of other bisphosphonates, and can develop in about one third of all patients. Adverse reactions are classified by frequency of occurrence: very often (?1/10), often (?1/100,<1/10), sometimes (?1/1000,<1/100), rarely (?1/10000,<1/1000), very rarely (<1/10000), unknown (cannot be estimated from the available data). From the blood and lymphatic systems: often - anemia sometimes-thrombocytopenia, leukopenia rarely-pancytopenia. From the nervous system: often - headache; sometimes - paresthesia, dizziness, taste disorders, hypesthesia, hyperesthesia, tremor, drowsiness is very rare - epileptic seizures, numbness and tetany (secondary to hypocalcemia). Psychics: sometimes a concern, sleep disorders; rare - confusion. From the organ of vision: often-conjunctivitis; sometimes-blurred vision, scleritis and inflammation of the orbit; very rarely - uveitis, episcleritis. From the digestive system: often-nausea, vomiting, anorexia; sometimes - diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth. From the respiratory system: sometimes - shortness of breath, cough, Bronchoconstriction rarely - interstitial lung disease. From the skin and subcutaneous tissues: sometimes itching, rash (including erythematous and macular rash), increased sweating. From the side of musculoskeletal system and connective tissue: often - pain in bones, myalgia, arthralgia, generalized pain and sometimes muscle cramps, osteonecrosis of the jaw *. From the cardiovascular system: sometimes-arterial hypertension, arterial hypotension, atrial fibrillation arterial hypotension, causes fainting and circulatory collapse; rarely-bradycardia, very rarely - arrhythmia (secondary to hypocalcemia). The part of the kidney and genitourinary system : often - kidney failure; sometimes - acute renal failure, hematuria, proteinuria. From the immune system: sometimes - hypersensitivity reactions, rarely - angioedema. Common disorders and reactions at the injection site: often - fever, flu - like condition (including fatigue, chills, malaise and hot flashes) sometimes - reactions at the injection site (including pain, irritation, swelling, hardening), asthenia, peripheral edema, chest pain, weight gain, anaphylactic reactions/shock, urticaria, rare-arthritis and swelling of the joints as symptoms of gostrofaznih reaction. Deviation of laboratory parameters: very often - hypophosphatemia; often - increased creatinine and urea in the blood, sometimes hypocalcemia - hypomagnesemia, hypokalemia rare - hyperkalemia, hypernatremia. * Based on clinical trials examination of possible cases of osteonecrosis of the jaw. Violation of kidney function There is evidence that when using zoledronic acid may deteriorate kidney function. Factors that can increase the potential risk of impaired renal function include dehydration, previous impairment of renal function, multiple courses of treatment of zoledronic acid or other bisphosphonates, as well as the simultaneous use of other nephrotoxic drugs or reduce the recommended time of infusion. Cases of deterioration of renal function, progression of renal failure and the need for hemodialysis in patients after the first or one-time use of zoledronic acid at a dose of 4 mg. the osteonecrosis of the jaw Cases of osteonecrosis (primarily of the jaw) has been reported predominantly in patients with cancer treated with drugs inhibiting bone destruction, such as Zometa. Many of these patients had symptoms of local infection, including osteomyelitis, and most cases were related to dental procedures, such as tooth extraction. Jaw osteonecrosis has many established risk factors, in particular cancer, concomitant therapy (e.g. chemotherapy, radiation therapy, corticosteroids) and concomitant diseases (e.g. anemia, coagulopathy, infections, existing diseases of the oral cavity) are diagnosed. Although a causal relationship has not been established, it is recommended to avoid invasive dental procedures. atrial fibrillation In the case of the use of zoledronic acid in a dose of 5 mg once a year for the treatment of postmenopausal osteoporosis (PTI) the overall frequency of occurrence of atrial fibrillation in patients receiving 5 mg of zoledronic acid and placebo was 2.5% (96 out of 3862) and 1, 9% (75 out of 3852), respectively. The incidence of atrial fibrillation as a serious adverse event in patients receiving 5 mg of zoledronic acid and placebo was 1.3% (51 of 3862) and 0.6% (22 of 3852), respectively. This difference in frequency, which was observed in this study, was not noted in other studies of the use of zoledronic acid, including studies of the use of zoledronic acid at a dose of 4 mg every 3-4 weeks in patients with malignant neoplasms. The mechanism underlying the increased frequency of atrial fibrillation in this separate clinical study is not known. gastropathy reaction These adverse reactions include the following symptoms: fever, myalgia, headache, limb pain, nausea, vomiting, diarrhea and arthralgia, which can begin in the first 3 days after the infusion of zoledronic acid. Atypical fractures of the femur During the period of post approval marketing applications have rarely been reported following reactions: acute edwardlucas and diaphyseal femur fractures (adverse reactions to bisphosphonates). hypocalcemia Hypocalcemia was reported in patients who used this drug. Information was received about arrhythmia and neurological reactions (including epileptic seizures, numbness and tetany), secondary to severe hypocalcemia. Cases of severe hypocalcemia have been reported to require hospitalization. Sometimes hypocalcemia may be life-threatening. Shelf life The clogged bottle is stored for 3 years. From the microbiological point of view, dilute solution for infusion should be used immediately. If the solution has not been used immediately, the user is responsible for the duration and storage conditions when using, usually should not exceed 24 hours at a temperature of 2-8 ° C. the Cooled solution must be brought to room temperature before administration. Storage conditions Store in the original packaging at a temperature not exceeding 25 ° C out of reach of children. Packaging 5 ml in a bottle; 1 bottle in a cardboard box. Category home away from home By prescription. Manufacturer Laboratorios Normon, S. A. Laboratorios Normon, SA. Manufacturer's location and address of the place of business Ronda de Valdecarros, 6, Tres Cantos, 28760 Madrid, Spain/Ronda de Valdecarrizo, 6, Tres Cantos, 28760 Madrid, Spain. Applicant AMAKS Pharma LTD/Amaxa Pharma LTD. The location of the applicant 72 Hammersmith road, London, W14 8TH, UK/72 Hammersmith Road, London, W14 8TH, United Kingdom. DEPOSITARY THE ZOLADEX 3.6 MG The Zoladex – a drug with marked anti-tumor effect. The medication is an analogue of gonadotropin-releasing hormone. The active component of the drug in its action is aimed at reducing the concentration of testosterone and estradiol in serum in women and men. Indications for appointment Zoladex is used in the treatment of: Malignant tumors in the prostate region. If necessary, carry out in vitro fertilization. Fibroids of the uterus, malignant and benign formations in the uterine cavity. Severity of endometriosis, amenable to hormonal treatment, including the need to terminate the endometrium before ablation or resection. Cancerous tumors in the mammary glands in combination with chemotherapy. How to apply The drug has the form of capsules with prolonged action for subcutaneous injection into the abdominal wall. The active ingredient is active for 28 days after use. The duration of therapy and the number of capsules used is set by the attending physician and is used as standard for malignant tumors for a long time. In benign formations, the remedy is used for up to 6 months.

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