Careptin^®

CAREPTIN ^® is an anticancer medicine containing platinum which is indicated in the treatment of:

– ovarian carcinoma of epithelial origin
– small cell lung carcinoma.

­ hypersensitivity to the active substance or to any of the excipients

­ patients with severe myelosuppression

­ patients with pre­existing severe renal impairment (with creatinine clearance of < 30 ml per minute) unless in the judgment of the physician and patient, the possible benefits of treatment outweigh the risks

­ patients with bleeding tumors

­ concomitant use with yellow fever vaccine

­ patients with a history of severe allergic reaction to carboplatin or other platinum containing compounds

-Dosage adjustment may allow use in the presence of mild renal impairment

Myelosuppression: which may be severe, is dose related; may result in infection (due to neutropenia) or bleeding (due to thrombocytopenia). Anemia (which is cumulative) may require blood transfusion. The median nadir typically occurs at day 21 for single-agent CAREPTIN^® and day 15 in patients receiving CAREPTIN^® in combination with other chemotherapeutic agents. Patients who have received prior myelosuppressive therapy and patients with renal dysfunction are at increased risk for bone marrow suppression.

–Allergic Reactions: As with other platinum­-based drugs, allergic reactions appearing most often during administration may occur and necessitate discontinuation of infusion. Patients should be observed carefully and an appropriate symptomatic treatment (including antihistamines, adrenaline and/or glucocorticoids) must also be initiated in such cases. Cross reactions, sometimes fatal, have been reported with all the platinum compounds.
-Renal Toxicity: In patients with impaired renal function, the effect of CAREPTIN^® on the hematopoietic system is more pronounced and longer acting than in patients with normal renal function. In this risk group, therapy with CAREPTIN^® must be performed with special caution. Dosage reduction or discontinuation of therapy is required in the presence of severe alteration in renal function test.

Precautions:

-CAREPTIN^® should only be administered under the supervision of a qualified physician who is experienced in the use of chemotherapeutic agents. Diagnostic and treatment facilities should be readily available for management of therapy and possible complications.
-Peripheral blood counts, renal and hepatic function tests should be monitored closely. Blood counts should be performed prior to commencement of CAREPTIN^® therapy and at weekly intervals thereafter. -The drug should be discontinued if abnormal depression of the bone marrow or abnormal renal or hepatic function is seen. In general, single intermittent courses of CAREPTIN^® should not be repeated until leukocyte, neutrophil, and platelet counts have returned to normal. Lowest levels of platelets are generally seen between days 14 and 21 of initial therapy. A greater reduction is seen in patients who previously received extensive myelosuppressive chemotherapy. Lowest levels of white cells occur generally between days 14 and 28 of initial therapy. If neutrophil levels fall below 2000
cells/mm or platelets are less than 100,000 cells/mm then postponement of CAREPTIN^® therapy until bone barrow recovery is evident, should be considered. This recovery usually takes 5 to 6 weeks. Transfusions may be necessary and dosage reductions recommended for subsequent treatment. Anaemia is frequent and cumulative, however rarely requires a transfusion. Haemolytic anaemia, with the presence of serologic drug induced antibodies, has been reported in patients treated with CAREPTIN^®. This event can be fatal.

-Acute promyelocytic leukaemia and myelodysplastic syndrome (MDS) / acute myeloid leukaemia (AML) have been reported years after therapy with CAREPTIN^® and other antineoplastic treatments.

-Haemolytic-uremic syndrome (HUS) is a life-threatening side effect. CAREPTIN® should be discontinued at the first signs of any evidence of micro­angiopathic haemolytic anaemia, such as rapidly falling haemoglobin with concomitant thrombocytopenia, elevation of serum bilirubin, serum creatinine, blood urea nitrogen, or LDH. Renal failure may not be reversible with discontinuation of therapy and dialysis may be required.

-Neurologic Toxicity: Although peripheral neurologic toxicity is generally common and mild, limited to paresthesia and decreases in osteotendinous reflexes, its frequency is increased in patients older than 65 years and/or in patients previously treated with cisplatin. Monitoring and neurological examinations should be carried out at regular intervals. Visual disturbances, including loss of vision, have been reported after the use of CAREPTIN^® in doses higher than those recommended in patients with renal impairment. Vision appears to recover totally or to a significant extent within weeks of stopping these high doses.

-Cases of Reversible Posterior Leukoencephalopathy Syndrome (RPLS) have been reported in patients receiving CAREPTIN^® in combination chemotherapy. RPLS is a rare, reversible (after treatment discontinuation), rapidly evolving neurological condition, which can include seizure, hypertension, headache, confusion, blindness, and other visual and neurological disturbances. Diagnosis of RPLS is based upon confirmation by brain imaging, preferably MRI (Magnetic Resonance Imaging).

– Geriatric Use: Renal function is often decreased in the elderly, so they are more likely to develop severe thrombocytopenia than younger patients. Renal function should be considered when determining dosage.

– Cases of hepatic venoocclusive disease (sinusoidal obstruction syndrome) have been reported, some of which were fatal. Patients should be monitored for signs and symptoms of abnormal liver function or portal hypertension which do not obviously result from liver metastases.

– Tumour lysis syndrome (TLS) may occur after treatment with CAREPTIN^®. Patients at high risk of TLS, such as patients with high proliferative rate, high tumour burden, and high sensitivity to cytotoxic agents, should be monitored closely and appropriate precaution taken.

– Other: Auditory defects have been reported during CAREPTIN^® therapy. Ototoxicity may be more pronounced in children and is more likely seen in patients previously treated with cisplatin. Cases of hearing loss with a delayed onset have been reported in pediatric patients. A long-term audiometric follow-up in this population is recommended. Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including CAREPTIN^® may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving CAREPTIN®. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

The recommended dose of CAREPTIN^® in previously untreated adults with normal renal function is 400 mg/m², given as a single short term intravenous infusion over 15 to 60 minutes. Alternatively, the Calvert formula (Dose (mg) = target AUC (mg/ml x min) x [GFR ml/min + 25]) may be used to determine dosage:

-Therapy should not be repeated until 4 weeks after the previous CAREPTIN® course and/or until the neutrophil count is at least 2,000 cells/mm³ and the platelet count is at least 100,000 cells/mm³.Initial dosage should be reduced by 20-25% in patients with risk factors such as previous myelosuppressive therapy and/or poor performance status (ECOG-­Zubrod 2­4 or Karnofsky below 80).
-Determination of hematologic nadir by weekly blood counts during initial courses is recommended for future dosage adjustment and scheduling of CAREPTIN^®.

-Some subgroups of patients (i.e., age 40-59, BMI 20-25) are at particular risk of undertreatment if GFR is estimated using Cockroft Gault Formula. Being an accurate estimation of GFR crucial for treatment with curative intent, in such cases GFR determination using a measured standard method (inulin, 51Cr-EDTA, 99mTc-DTPA, 125I-iothalamate or iohexol) should be preferred when feasible.

-Needles or intravenous sets containing aluminum parts that may come in contact with CAREPTIN^® injection should not be used for preparation or administration. Aluminum reacts with CAREPTIN^® injection causing precipitate formation and/or loss of potency.

-The safety measures for dangerous substances are to be complied with preparation and administration. Preparation must be carried out by personnel who have been trained in the safe use while wearing protective gloves, face mask and protective clothes.

Impaired renal function: In patients with impaired renal function, dosage of CAREPTIN^® should be reduced (refer to Calvert formula) and hematological nadirs and renal function monitored. Patients with creatinine clearance values below 60 ml/min are at increased risk of severe myelosuppression. The frequency of severe leukopenia, neutropenia, or thrombocytopenia has been maintained at about 25% with the following

dosage recommendations:

Insufficient data exist on the use of CAREPTIN^® injection in patients with creatinine clearance of 15 ml/min or less to permit a recommendation for treatment. All of the above dosing recommendations apply to the initial course of treatment. Subsequent dosages should be adjusted according to the patient’s tolerance and to the acceptable level of myelosuppression.

Combination Therapy

The optimal use of CAREPTIN^® in combination with other myelosuppressive agents requires dosage adjustments according to the regimen and schedule to be adopted.

Elderly population

In patients of more than 65 years of age, adjustment of the CAREPTIN^® dose to the general condition is necessary during the first and the subsequent therapeutic courses.

Pediatric population

There is insufficient information to support a dosage recommendation in the pediatrics population. CAREPTIN^® injection should be used by the intravenous route only.

Percentages reported with single-agent therapy.
– >10%:Central nervous system: Pain (23%), endocrine & metabolic: Hyponatremia (29% to 47%), hypomagnesemia (29% to 43%), hypocalcemia (22% to 31%), hypokalemia (20% to 28%), Gastrointestinal: Vomiting (65% to 81%), abdominal pain (17%), nausea (without vomiting: 10% to 15%) Hematologic & oncologic: Bone marrow depression (dose related and dose limiting; nadir at ~21 days with single-agent therapy), anemia(71% to 90%; grades 3/4: 21%), leukopenia (85%; grades 3/4: 15% to 26%), neutropenia (67%; grades 3/4: 16% to 21%), thrombocytopenia (62%; grades 3/4: 25% to 35%) Hepatic: Increased serum alkaline phosphatase (24% to 37%), increased serum AST (15% to 19%) Hypersensitivity: Hypersensitivity (2% to 16%) Neuromuscular & skeletal: Weakness (11%) Renal: Decreased creatinine clearance (27%), increased blood urea nitrogen (14% to 22%)

– 1% to 10%: Central nervous system: Peripheral neuropathy (4% to 6%), neurotoxicity (5%)
Dermatologic: Alopecia (2% to 3%) Gastrointestinal: Constipation (6%), diarrhea (6%), dysgeusia (1%), mucositis (≤1%), stomatitis (≤1%) Hematologic & oncologic: Bleeding complications (5%), hemorrhage (5%) Hepatic: Increased serum bilirubin (5%) Infection: Infection (5%) Ophthalmic: Visual disturbance (1%) Otic: Ototoxicity (1%) Renal: Increased serum creatinine (6% to 10%)

– <1%, post-marketing, and/or case reports (Limited to important or life-threatening): Anaphylaxis, anorexia, bronchospasm, cardiac failure, cerebrovascular accident, dehydration, embolism, erythema, febrile neutropenia, hemolytic anemia (acute), hemolytic-uremic syndrome,
hypertension, hypotension, injection site reaction (pain, redness, swelling), limb ischemia (acute), malaise, metastases, pruritus, skin rash, tissue necrosis (associated with extravasation), urticaria, vision loss.

– Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (www.adr.ttac.ir).

– CAREPTIN^® may interact with aluminum to form a black precipitate. Needles, syringes, catheters or IV administration sets that contain aluminum parts which may come into contact with CAREPTIN^®, should not be used for the preparation or administration of the drug.

– Due to the increase of thrombotic risk in cases of tumoral diseases, the use of anticoagulative treatment is frequent. The high intra-individual variability of the coagulability during diseases, and the possibility of interaction between oral anticoagulants and anticancer chemotherapy, may require an increase in frequency of INR monitoring if a patient is treated with oral anticoagulants.

Concomitant use contraindicated: yellow fever vaccine: risk of generalized disease mortal.

Concomitant use not recommended:

– Live attenuated vaccines (except yellow fever): Risk of systemic, possible fatal disease. This risk is increased in subjects who are already immunosuppressed by their underlying disease. Use an inactivated vaccine where this exist. (poliomyelitis).

– Phenytoin, fosphenytoin: Risk of exacerbation of convulsions (resulting from the decrease of phenytoin digestive absorption by the cytotoxic drug), risk of toxicity enhancement or loss of efficacy of the cytotoxic drug (due to increased hepatic metabolism by phenytoin).

Concomitant use to take into consideration

– Ciclosporin (and by extrapolation tacrolimus and sirolimus): Excessive immunosuppression with risk of lymph proliferation.

– Concurrent therapy with nephrotoxic or ototoxic drugs such as aminoglycosides, vancomycin, capreomycin and diuretics, may increase or exacerbate toxicity, particularly in renal failure patients, due to CAREPTIN^® induced changes in renal clearance.

– Loop diuretics: The concomitant use of CAREPTIN^® with loop diuretic should be approached with caution due to the cumulative nephrotoxicity and ototoxicity.

– Combination therapy with other myelosuppressive agents may require dose changes or rescheduling of doses in order to minimize the additive myelosuppressive effects.

Pregnancy

CAREPTIN^® can cause fetal harm when administered to a pregnant woman. CAREPTIN^® has been shown to be embryotoxic and teratogenic in rats receiving the drug during organogenesis. No controlled studies in pregnant women have been conducted. Safe use of CAREPTIN^® in pregnancy has not been established. Both men and women receiving CAREPTIN^® should be informed of the potential risk of adverse effects on reproduction. Women of childbearing potential should be fully informed of the potential hazard to the foetus should they become pregnant during CAREPTIN^® therapy. CAREPTIN^® should not be used in pregnant women or women of childbearing potential who might become pregnant unless the potential benefits to the mother outweigh the possible risks to the foetus.

Breast feeding

It is not known whether CAREPTIN^® is excreted in breast milk. To avoid possible harmful effects in the infant, breastfeeding must be stopped during CAREPTIN^® therapy.

Fertility

Gonadal suppression resulting in amenorrhea or azoospermia may occur in patients receiving antineoplastic therapy. These effects appear to be related to dose and length of therapy and may be irreversible. Prediction of the degree of testicular or ovarian functional impairment is complicated by the common use of combinations of several antineoplastics, which makes it difficult to assess the effects of individual agents. Men of sexually mature age treated with CAREPTIN^® are advised not to father a child during treatment and up to 6 months afterwards. Male patients should seek advice about sperm preservation prior to initiation of the therapy because of the possibility of irreversible infertility due to therapy with CAREPTIN^®.

–  Keep vial in the outer carton in order to protect from light.

– Store the medicine at temperatures below 30° C and stored away from light and moisture. Do not refrigerate or freeze.

– Keep the medicine out of the reach of children and pets.

– From a microbiological point of view, the solution for infusion should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2° C to 8°C unless dilution has taken place in controlled and validated aseptic condition.

After dilution

In use: Chemical and physical in-use stability has been demonstrated for 24 hours at room temperature and 30 hours at 2-8°C.