INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CARBOPLATIN-TEVA (CARBOPLATIN-TEVA)

Composition:

Active substance: carboplatin;

1 ml of concentrate contains 10 mg of carboplatin;

Excipients: mannitol (E 421), water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physico-chemical properties: colorless or pale yellow solution.

Pharmacotherapeutic group.

Antineoplastic agents. Platinum compounds. ATC code L01XA02.

Pharmacological Properties

Pharmacodynamics

Carboplatin-Teva is an inorganic complex compound of a heavy metal containing a central platinum atom. It is an analogue of cisplatin. Carboplatin has demonstrated antitumor activity comparable to that of cisplatin against a broad spectrum of tumors, regardless of their localization. Studies using DNA alkaline elution methods and DNA binding assays have demonstrated qualitative similarities in the mechanisms of action of carboplatin and cisplatin. Like cisplatin, carboplatin induces changes in the superhelical conformation of DNA, associated with the "DNA condensation effect." It also causes the formation of intrastrand and predominantly interstrand cross-links, which alter DNA structure and inhibit DNA synthesis.

Pharmacokinetics

Following a single intravenous dose administered over one hour, plasma concentrations of total platinum and free platinum decline in a biphasic manner, following first-order kinetics. For free platinum, the initial elimination half-life is approximately 90 minutes. The terminal phase half-life is approximately 6 hours. Elimination of total platinum shows a similar initial half-life, while the late phase half-life of total platinum may exceed 24 hours. With repeated daily dosing over 4 consecutive days, no accumulation of platinum in plasma is observed.

Carboplatin-Teva is primarily eliminated via the kidneys. Drug excretion occurs mainly within the first 6 hours after administration, with 50 to 70% of the administered dose excreted within 24 hours; 32% of the dose is excreted unchanged. Dose reduction is recommended for patients with impaired renal function. Protein binding of Carboplatin-Teva is lower than that of cisplatin.

Initial protein binding is low, with up to 29% of carboplatin bound to proteins within the first 4 hours. After 24 hours, protein binding increases to 85–89%.

Clinical characteristics.

Indications.

As monotherapy or in combination with other antineoplastic agents for the treatment of epithelial ovarian cancer and small cell lung cancer.

Contraindications.

• Hypersensitivity to the components of the medicinal product or to other platinum compounds;
• Previous severe renal impairment (creatinine clearance <30 mL/min), except in cases where, in the opinion of the physician and patient, the potential benefit outweighs the risk;
• Severe myelosuppression;
• Recent significant bleeding;
• Bleeding tumors;
• Concomitant use with yellow fever vaccine;
• Hearing impairment.

Special precautions.

Like other antineoplastic agents, Carboplatin-Teva must be reconstituted by trained personnel. Reconstitution should be performed in a specially designated area (preferably in a laminar flow cabinet for handling cytotoxic substances).

When handling Carboplatin-Teva, protective gowns, masks, gloves, and eye protection should be worn. In case of accidental contact of the solution with skin or mucous membranes, the affected area must be immediately and thoroughly rinsed with soap and water.

Handling cytotoxic agents such as Carboplatin-Teva during pregnancy is prohibited.

Any remaining medicinal product or waste must be disposed of in accordance with local requirements.

Interaction with other medicinal products and other types of interactions.

Patients with oncological diseases have an increased risk of thrombosis, so anticoagulant therapy is often used. High individual variability in coagulation during the disease and possible interactions between anticoagulants and antineoplastic agents may require monitoring of oral anticoagulants and increased frequency of INR (International Normalized Ratio) testing.

Concomitant use is contraindicated:

• with yellow fever vaccine: risk of generalized vaccine disease leading to fatal outcomes.

Concomitant use is not recommended:

• with live attenuated vaccines (except yellow fever vaccine): risk of systemic disease, potentially fatal outcome. This risk is increased in patients who already have immunosuppression due to the underlying disease. Inactivated vaccines should be used if available (e.g., poliomyelitis);
• with phenytoin, fosphenytoin: risk of seizure exacerbation due to reduced phenytoin absorption in the gastrointestinal tract associated with cytotoxic drug use, and risk of increased toxicity or loss of cytotoxic effect of the drug due to enhanced hepatic metabolism induced by phenytoin.

When used concomitantly, the following should be considered:

• cyclosporine (may also apply to tacrolimus and sirolimus): excessive immunosuppression with risk of lymphoproliferative disorders;
• aminoglycosides: cumulative nephrotoxic and ototoxic effects, especially in patients with renal insufficiency;
• loop diuretics: cumulative nephrotoxic and ototoxic effects.

Combination therapy with Carboplatin-Teva and other myelosuppressive agents may require dose reduction to prevent cumulative toxic effects.

Concomitant use of carboplatin with other nephrotoxic and/or ototoxic agents (vancomycin, capreomycin) increases the risk of nephrotoxic and/or ototoxic effects, as carboplatin induces changes in the renal clearance of these substances.

Carboplatin should not be administered simultaneously with products containing chelating agents, as they may theoretically reduce the antitumor activity of carboplatin.

Carboplatin-Teva interacts with components of needles, syringes, catheters, and intravenous infusion sets containing aluminum, resulting in the formation of a black precipitate; therefore, such devices should not be used for administering Carboplatin-Teva.

Special precautions for use.

Carboplatin-Teva should be administered only under the constant supervision of an oncologist experienced in the use of chemotherapeutic agents, and only in a hospital setting. Appropriate facilities and equipment for the management of potential complications must be available.

Carboplatin-Teva should be used with caution in patients with varicella, herpes, other acute infectious diseases, ascites, or exudative pleuritis.

Caution is required when administering carboplatin to patients who have undergone a course of radiation therapy.

Prior to and during treatment, renal and hepatic function, peripheral blood counts, neurological status, and audiometry should be monitored regularly. Treatment with the drug should be discontinued in cases of excessive myelosuppression or significant impairment of renal or hepatic function. Biochemical parameter changes may occur, including increased serum urea and creatinine levels, and decreased concentrations of magnesium, potassium, and calcium.

Hematological toxicity

Cases of hemolytic anemia associated with serologically detectable drug-induced antibodies have been reported in patients receiving carboplatin; such anemia may be fatal.

Leukopenia, neutropenia, and thrombocytopenia are dose-dependent and dose-limiting factors. Weekly monitoring of peripheral blood cell counts is recommended, with appropriate dose adjustments. In the event of hematological toxicity, peripheral blood cell counts should be monitored regularly until recovery. The median nadir day is 21 in patients receiving carboplatin as monotherapy and 15 in patients receiving carboplatin in combination with other chemotherapeutic agents.

Single intermittent courses of carboplatin should not be repeated until leukocytes, neutrophils, and platelets have returned to normal levels. Carboplatin administration should not be repeated earlier than 4 weeks after the previous course and/or until neutrophil count reaches at least 2,000 cells/mm³ and platelet count reaches at least 100,000 cells/mm³. Anemia is common and cumulative, but rarely requires transfusion therapy.

The severity of myelosuppression increases in patients who have previously undergone chemotherapy, particularly with cisplatin, and/or who have impaired renal function. Initial doses of carboplatin injections for these patient groups should be appropriately reduced, and their effects should be carefully monitored through regular blood tests between cycles. Combination therapy with carboplatin and other myelosuppressive treatments should be carefully planned regarding doses and timing to minimize the risk of additive adverse effects.

Myelosuppressive effects may be additive to those of concomitant chemotherapy. Patients with severe and persistent myelosuppression are at high risk of infectious complications, including fatal outcomes. If any of these events occur, carboplatin treatment should be discontinued, and dose adjustment or discontinuation of therapy should be considered. Transfusion therapy may be required to reduce the severity of hematological adverse effects.

Acute promyelocytic leukemia and myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) have been reported several years after treatment with carboplatin and other antineoplastic agents.

Hemolytic-uremic syndrome

Hemolytic-uremic syndrome (HUS) is a life-threatening adverse reaction. Carboplatin administration should be discontinued at the first signs of microangiopathic hemolytic anemia, such as a rapid decline in hemoglobin levels accompanied by thrombocytopenia, increased serum bilirubin and creatinine levels, elevated blood urea nitrogen, and increased blood LDH (lactate dehydrogenase) levels. Renal failure may be irreversible after discontinuation of therapy and may require dialysis.

Hypersensitivity reactions

As with other platinum-containing agents, allergic reactions to carboplatin have been reported. Allergic reactions usually occur during infusion and require immediate discontinuation of the infusion and appropriate symptomatic treatment. Anaphylactoid-type reactions may also occur. Cross-reactions with all platinum compounds have been reported, sometimes with fatal outcomes. Patients previously treated with platinum-containing drugs have an increased risk of allergic reactions, including anaphylaxis.

Cases of hypersensitivity reactions progressing to Kounis syndrome (acute allergic coronary artery spasm that may lead to myocardial infarction) have been reported (see section "Adverse reactions").

Nephrotoxicity

Carboplatin myelosuppression is closely related to its renal clearance: more severe and prolonged myelotoxicity may occur in patients with impaired renal function or those receiving other drugs with nephrotoxic potential. Therefore, renal function parameters should be carefully assessed before and during therapy. Hepatotoxic lesions associated with nephrotoxic lesions have been observed with very high-dose carboplatin therapy. In cases of moderate or severe changes in renal or hepatic function tests, the dose should be reduced or the drug discontinued.

The hematological effects of carboplatin are more pronounced and prolonged in patients with impaired renal function compared to those with normal renal function; therefore, carboplatin therapy should be administered with particular caution in this risk group.

Neurological toxicity

Continuous monitoring for potential toxic effects during carboplatin treatment is mandatory. A neurological examination should be performed before each treatment cycle to detect signs of neurotoxicity.

Although peripheral neurological toxicity is usually mild and limited to paresthesia and diminished tendon reflexes, its frequency increases in patients aged 65 years and older and/or in patients previously treated with cisplatin. Regular monitoring and neurological examinations are recommended.

Visual disturbances, including loss of vision, have been reported after administration of carboplatin injections at doses higher than recommended in patients with renal insufficiency. Vision usually recovers within several weeks, often completely or substantially, after discontinuation of high-dose carboplatin therapy.

Use in elderly patients

When using combination therapy with carboplatin and cyclophosphamide, elderly patients were more prone to develop severe thrombocytopenia compared to younger patients. Dose selection should take into account renal function parameters, as renal function often declines with age.

Reversible posterior leukoencephalopathy syndrome (RPLS)

Cases of RPLS have been reported in patients receiving carboplatin in combination with chemotherapy. RPLS is rare and resolves after discontinuation of carboplatin therapy. It is characterized by rapid onset of neurological symptoms, which may include seizures, hypertension, headache, confusion, blindness, and other visual and neurological disorders. Diagnosis of RPLS is based on brain imaging, preferably MRI.

Hepatic veno-occlusive disease

Cases of hepatic veno-occlusive disease (sinusoidal obstruction syndrome) have been reported, some of which were fatal. Patients should be monitored for signs and symptoms of impaired liver function or portal hypertension not related to metastatic liver involvement.

Tumor lysis syndrome (TLS)

In the post-marketing period, cases of tumor lysis syndrome (TLS) have been reported in patients after administration of carboplatin as monotherapy or in combination with other chemotherapeutic agents. Patients with highly proliferative tumors, high tumor burden, and high sensitivity to cytotoxic agents should be closely monitored and appropriate preventive measures implemented.

Other

Hearing disturbances have been reported during carboplatin therapy. Ototoxicity may be more pronounced in children. Cases of delayed hearing loss have been reported in this age group. Long-term audiometric monitoring is recommended in this population.

Administration of live or attenuated vaccines to patients with immunosuppression due to chemotherapy, including carboplatin, may lead to severe or fatal infections. Therefore, live vaccination should be avoided during carboplatin treatment. Inactivated or killed vaccines may be administered, although the immune response to such vaccines may be diminished.

Carboplatin may cause nausea and vomiting. Prophylactic use of antiemetic agents has been reported to reduce the frequency and intensity of these reactions. Vomiting is more likely when carboplatin injections are used in combination with other emetogenic compounds.

Renal function impairment may occur during carboplatin therapy. Although there is no clinical evidence of synergistic nephrotoxicity, combination of carboplatin with aminoglycosides or other nephrotoxic compounds should be avoided.

A relationship between transient visual disturbances and excessively high doses in patients with impaired renal function has been reported.

Studies have shown that carboplatin is mutagenic in vitro and in vivo. The carcinogenic potential of carboplatin has not been studied, but other compounds with a similar mechanism of action and mutagenicity are known to be carcinogenic.

Use during pregnancy or breastfeeding.

Contraception in men and women

Due to the genotoxic potential of carboplatin, women of childbearing potential should use effective contraception during treatment with carboplatin and for 6 months after completion of therapy. Men are advised to use effective contraception and avoid conception during carboplatin treatment and for 3 months after completion of therapy.

Pregnancy

Carboplatin injections may be harmful to the fetus. Carboplatin has demonstrated embryotoxic and teratogenic effects in animal studies. Controlled studies in pregnant women have not been conducted. If the drug is used during pregnancy or if pregnancy occurs during treatment, the patient should be informed of the potential risk to the fetus. Women of reproductive age are advised to avoid pregnancy during carboplatin therapy.

Breastfeeding

Carboplatin has been detected in the breast milk of treated mothers. If carboplatin therapy is required during lactation, breastfeeding must be discontinued. Carboplatin is contraindicated during breastfeeding.

Fertility

Patients receiving antineoplastic therapy may develop gonadal suppression, manifesting as amenorrhea or azoospermia. These effects are dose- and duration-dependent and may be irreversible. The prognosis regarding the degree of testicular or ovarian function impairment is complicated by the frequent use of combination therapy with multiple antineoplastic agents, making it difficult to assess the individual contribution of each drug.

Sexually mature men undergoing carboplatin therapy are advised to consider sperm cryopreservation prior to starting treatment due to the risk of developing irreversible infertility.

Ability to affect reaction speed when driving or operating machinery.

No studies on the effect on reaction speed during driving or operating machinery have been conducted. Carboplatin may cause nausea, vomiting, visual disturbances, and ototoxicity; therefore, driving and operating machinery are not recommended during treatment. Depending on individual sensitivity, carboplatin may impair the ability to drive or operate machinery.

Method of Administration and Dosage

The medicinal product should be diluted with 5% glucose injection solution or 0.9% sodium chloride injection solution to a final concentration of 0.5 mg/mL.

Carboplatin-Teva must be administered intravenously only.

Precautions for handling hazardous substances must be observed during preparation and administration. Preparation must be carried out only by personnel familiar with the safe handling of such agents, and protective gloves, a face mask, and protective clothing are required.

Needles or intravenous infusion systems containing aluminum components must not be used for the preparation and administration of the medicinal product. Aluminum reacts with carboplatin, forming a precipitate, which leads to loss of efficacy.

The dosage regimen should be individually determined based on indications, patient tolerance to Carboplatin-Teva, and the chosen cytotoxic therapy protocol.

The recommended dose for adults who have not been previously treated and who have normal renal function is 400 mg/m² as a single dose administered by short intravenous infusions (15 to 60 minutes).

The treatment course should be repeated no sooner than four weeks after the previous administration and/or until the neutrophil count reaches 2000 cells/mm³ and the platelet count reaches 100,000 cells/mm³.

For patients with risk factors, such as prior myelosuppressive therapy or poor performance status (ECOG-Zubrod 2–4 or Karnofsky index below 80%), a 20–25% reduction in the initial dose is recommended.

During initial treatment cycles with carboplatin, complete blood counts should be monitored weekly to adjust dosing in subsequent cycles.

Renal Impairment

Patients with creatinine clearance values below 60 mL/min are at increased risk of developing severe myelosuppression.

The incidence of severe leucopenia, neutropenia, or thrombocytopenia is approximately 25% when the following doses are administered:

Creatinine Clearance (mL/min) Initial Dose (Day 1)
41–59 mL/min 250 mg/m² intravenously
16–40 mL/min 200 mg/m² intravenously

There are insufficient data on the use of carboplatin in patients with creatinine clearance below 15 mL/min to provide treatment recommendations.

All dosage recommendations listed above apply to the initial treatment cycle. Subsequent doses should be adjusted based on patient tolerance and acceptable myelosuppressive effects.

In patients with impaired renal function, carboplatin doses should be reduced according to glomerular filtration rate (GFR), and frequent monitoring of hematological parameters and renal function is required.

Carboplatin doses can also be calculated using the Calvert formula based on the patient's glomerular filtration rate (GFR) and the desired area under the pharmacokinetic curve (AUC). It should be noted that doses calculated using the Calvert formula are expressed in mg, not mg/m².

Calvert formula should not be used for dose calculation if the patient has received intensive prior therapy (mitomycin C, nitrosourea, combination doxorubicin/cyclophosphamide/cisplatin, combination of 5 or more agents, radiation therapy ≥4500 rad delivered to a field of 20×20 cm or applied to more than one site).

Thrombocytopenia and neutropenia

For patients who did not experience signs of hematologic toxicity at the previous dose (e.g., platelet and neutrophil counts remained above 100,000 cells/mm³ and 2,000 cells/mm³, respectively), the dose of carboplatin as monotherapy or in combination (e.g., with cyclophosphamide) may be increased by 25%. For patients who experienced only mild or moderate hematologic toxicity at the previous dose (platelet and neutrophil counts of 50,000–100,000 cells/mm³ or 500–2,000 cells/mm³, respectively), dose adjustment of carboplatin as monotherapy or in combination therapy is not required. For patients who experienced moderate or severe hematologic toxicity at the previous dose (platelet and neutrophil counts below 50,000 cells/mm³ or 500 cells/mm³, respectively), a 25% dose reduction of carboplatin as monotherapy or in combination therapy should be considered.

Combination therapy

Optimal use of carboplatin with other myelosuppressive agents requires dose adjustments depending on the dosing regimen and treatment protocol being used.

In the treatment of elderly patients (over 65 years of age), carboplatin doses during the first and subsequent treatment cycles should be adjusted according to the patient's overall health status.

Children.

There is no clinical experience with the use of carboplatin in children.

Overdose.

There is no specific antidote for carboplatin. In case of overdose, severe myelosuppression, hearing impairment, as well as liver and kidney dysfunction may be expected. Administration of carboplatin at doses exceeding the recommended ones has been associated with loss of vision. Treatment is symptomatic and supportive. Blood transfusions and bone marrow transplantation may be effective in managing hematological adverse effects.

Adverse reactions

The frequency of adverse effects was determined based on data from 1893 patients who received carboplatin injections as monotherapy, as well as post-marketing experience.

Adverse reactions are listed by MedDRA system organ class, and the frequency of adverse reactions is classified as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), and not known (cannot be estimated from the available data).

• Fatal outcome in <1%, fatal cardiovascular events in <1%, including heart failure, embolism, and stroke.

From post-marketing data.

Hematologic disorders

Myelosuppression is a dose-limiting toxic effect of carboplatin therapy and may be enhanced when combined with other myelosuppressive compounds or treatment modalities. In patients with normal baseline parameters, thrombocytopenia with platelet counts below 50,000 cells/mm³ occurs in 25% of patients, neutropenia with granulocyte counts below 1,000 cells/mm³ in 18%, and leukopenia with white blood cell counts below 2,000 cells/mm³ in 14%. The median nadir day in patients receiving carboplatin is day 21.

Myelotoxicity is more pronounced in patients who have undergone extensive prior treatment (especially with cisplatin) or in patients with impaired renal function. Patients with poor general health status receiving carboplatin injections have shown increased frequency of leukopenia and thrombocytopenia. These adverse effects, although usually reversible, led to infectious and hemorrhagic complications in 4% and 5% of patients receiving carboplatin injections, respectively. These complications resulted in death in less than 1% of patients.

Anemia with hemoglobin levels below 8 g/dL was observed in 15% of patients with normal baseline parameters. The incidence of anemia increased with higher cumulative doses of carboplatin.

Gastrointestinal disorders

Carboplatin may cause vomiting in 65% of patients (severe in one-third of them) and nausea in an additional 15%. These symptoms usually resolve within 24 hours after carboplatin administration and can be managed or prevented with antiemetics. Vomiting occurs more frequently in patients previously treated with cisplatin or in those receiving carboplatin in combination with other emetogenic agents.

Other gastrointestinal complaints include pain in 8% of patients, diarrhea and constipation (6%), and mucosal disorders.

Neurological disorders

Peripheral neuropathy (mainly paresthesia and decreased deep tendon reflexes) occurred in 4% of patients receiving carboplatin injections. Patients at increased risk of neurological complications include those aged 65 years or older, patients previously treated with cisplatin, or those undergoing prolonged carboplatin therapy. Clinically significant sensory disturbances (i.e., visual and taste disturbances) occurred in 1% of patients; optic neuritis has been reported. The incidence of neurological adverse effects was higher in patients receiving carboplatin as part of combination therapy, which may be related to cumulative effects.

Otototoxicity

The drug may cause ototoxic effects. Audiometric studies revealed high-frequency hearing loss (4000–8000 Hz) in 15% of patients. Tinnitus, hearing loss, and very rare cases of hypoacusis have been reported.

In patients with pre-existing hearing impairment due to cisplatin, further deterioration of auditory function may occur during carboplatin therapy.

Renal disorders

With standard dosing, renal function impairment is uncommon, despite the fact that carboplatin is administered without hydration using large fluid volumes and/or forced diuresis. Increased serum creatinine levels occurred in 6% of patients, increased blood urea nitrogen in 14%, and increased serum uric acid in 5%. These effects were usually mild and reversible in approximately half of the patients. Creatinine clearance proved to be the most sensitive indicator of renal function in patients receiving carboplatin injections: in 27% of patients with a baseline creatinine clearance of 60 mL/min or higher, a decrease in creatinine clearance occurred during carboplatin therapy.

Cases of hematuria and edema have been reported.

Electrolytes

Patients experienced decreased levels of serum sodium (29%), potassium (20%), calcium (22%), and magnesium (29%). Cases of early-onset hyponatremia have also been reported. Electrolyte losses were minor, and the condition resolved without clinical symptoms.

Hepatobiliary disorders

Liver function abnormalities were observed in patients with normal baseline parameters, including increased total bilirubin levels in 5% of patients, serum glutamic-oxaloacetic transaminase (SGOT) in 15%, and alkaline phosphatase in 24%. Most abnormalities were mild and reversible in approximately half of the patients.

In a limited number of patients receiving very high doses of carboplatin and undergoing autologous bone marrow transplantation, significant abnormalities in liver function parameters occurred.

After administration of high-dose carboplatin, cases of acute fulminant hepatic necrosis have been reported.

Allergic reactions

Anaphylactic-type reactions, sometimes fatal, may occur within minutes after drug injection: facial swelling, dyspnea, tachycardia, hypotension, urticaria, anaphylactic shock, bronchospasm, and angioedema.

Other adverse reactions

Secondary acute malignant neoplasms have been reported after combination chemotherapy containing carboplatin. Alopecia, fever and chills, mucositis, asthenia, malaise, and influenza-like syndrome, as well as dysgeusia, have occasionally been observed.

Hemolytic-uremic syndrome has been observed in isolated cases.

Isolated cases of cardiovascular adverse events (heart failure, embolism), hemorrhagic complications, and isolated cases of stroke and hypertension have been reported.

Local reactions

Cases of injection site reactions (burning, pain, erythema, swelling, urticaria, and necrosis associated with extravasation) have been reported.

Reporting of suspected adverse reactions. All suspected adverse reactions and lack of drug efficacy should be reported via the following link: https://aisf.dec.gov.ua

Shelf life. 2 years.

After dilution with 5% glucose solution or 0.9% sodium chloride solution for injection, the infusion solution is physically and chemically stable for 24 hours when stored at 2–8 °C (in a refrigerator) and for 3 hours when stored at room temperature (15–25 °C) in a light-protected environment. From a microbiological standpoint, the diluted solution should be used immediately. If not used immediately, the user is responsible for storage duration and conditions, which should not exceed 24 hours at 2–8 °C, provided reconstitution was performed under controlled and validated aseptic conditions.

The vial with ready-to-use solution is intended for single use only.

Storage conditions.

Store in the original packaging to protect from light at temperatures not exceeding 25 °C. Keep out of reach of children.

Incompatibilities.

Since aluminum may react with carboplatin, leading to precipitate formation or loss of drug activity, needles and other intravenous administration equipment containing aluminum components are not recommended for the preparation and administration of Carboplatin-Teva solution. Do not mix with other drugs in the same container.

Packaging.

5 mL, 15 mL, 45 mL, or 60 mL in a vial; 1 vial per carton.

Prescription status. Prescription only.

Manufacturer.

Farmahem B.V.

Manufacturer's address and location of business operations.

Svensweg 5, 2031 GA Haarlem, The Netherlands.