Active ingredients: Cinacalcet
Mimpara 30 mg film-coated tablets
Mimpara 60 mg film-coated tablets
Mimpara 90 mg film-coated tablets
Indications Why is Mimpara used? What is it for?
Mimpara works to control your body's levels of parathyroid hormone (PTH), calcium and phosphorus. It is used to treat diseases caused by problems with organs called the parathyroid glands. The parathyroid glands are four small glands found in the neck. , near the thyroid gland and which produce parathyroid hormone (PTH).
Mimpara is used:
- to treat secondary hyperparathyroidism in patients with severe kidney disease who need dialysis to purify their blood of waste products.
- to reduce high levels of calcium in the blood (hypercalcaemia) in patients with parathyroid cancer.
- to reduce high levels of calcium in the blood (hypercalcaemia) in patients with primary hyperparathyroidism, when removal of the glands is not possible.
In "primary and secondary hyperparathyroidism," an excessive amount of PTH is produced by the parathyroid glands. "Primary" means that "hyperparathyroidism is not caused by any other condition and" secondary "means that" hyperparathyroidism is caused by "another condition, such as kidney disease. Both primary and secondary hyperparathyroidism can cause calcium loss. from bone, which can cause bone pain and fractures, blood and heart vessel problems, kidney stones, mental disorders and coma.
Contraindications When Mimpara should not be used
Do not use Mimpara:
- If you are allergic to cinacalcet or any of the other ingredients of this medicine (listed in section 6).
Precautions for use What you need to know before taking Mimpara
Talk to your doctor, pharmacist or nurse before using Mimpara.
Before taking Mimpara, tell your doctor if you have or have ever had:
- fits (sometimes called fits or fits). The risk of having seizures is higher if you have previously had seizures;
- liver problems;
- cardiac compromise.
In patients treated with Mimpara, life-threatening events and fatal outcomes associated with low calcium levels (hypocalcaemia) have been reported.
Low calcium levels can have an effect on heart rhythm. Tell your doctor if, while taking Mimpara, you experience an unusually fast or racing heartbeat, have heart rhythm problems, or take medicines known to cause heart rhythm problems.
For additional information see section 4.
During treatment with Mimpara, tell your doctor:
- if you have started or stopped smoking as this may affect how Mimpara works.
Children and adolescents
Children under the age of 18 should not take Mimpara.
Interactions Which drugs or foods may change the effect of Mimpara
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines.
Tell your doctor if you are taking the following medicines.
Medicines that as such can have an effect on the action of Mimpara:
- medicines used to treat skin infections or fungal infections (ketoconazole, itraconazole and voriconazole);
- medicines used to treat bacterial infections (telithromycin, rifampicin and ciprofloxacin);
- a medicine used to treat HIV and AIDS infections (ritonavir);
- a medicine used to treat depression (fluvoxamine).
Mimpara may affect the action of the following medicines:
- medicines used to treat depression (amitriptyline, desipramine, nortriptyline and clomipramine);
- a medicine used to relieve cough (dextromethorphan);
- medicines used to treat changes in heart rate (flecainide and propafenone);
- a medicine used to treat high blood pressure (metoprolol).
Learn with food and drink
Mimpara must be taken with or shortly after meals.
Warnings It is important to know that:
Pregnancy, breastfeeding and fertility
If you are pregnant, planning to become pregnant, or are breast-feeding, ask your doctor or pharmacist for advice before taking this medicine.
Mimpara has not been tested in pregnant women. If you are pregnant, your doctor may decide to change your treatment, as Mimpara could harm your unborn baby.
It is not known whether Mimpara is excreted in human milk. Your doctor will discuss with you whether breastfeeding or treatment with Mimpara should be discontinued.
Driving and using machines
No studies on the ability to drive and use machines have been performed. Dizziness and convulsions have been reported in patients taking Mimpara. If you experience these symptoms, your ability to drive may be affected.
Mimpara contains lactose
If you have been told by your doctor that you have an "intolerance to some sugars, contact your doctor before taking this drug.
Dose, Method and Time of Administration How to use Mimpara: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If you are not sure, consult your doctor or pharmacist. Your doctor will tell you how much Mimpara to take.
Mimpara should be taken orally with or shortly after meals. The tablets should be taken whole and undivided.
Your doctor will do regular blood tests during treatment to assess your response to therapy and will adjust the dose if necessary.
If you are being treated for the treatment of secondary hyperparathyroidism
The starting dose of Mimpara is 30 mg (one tablet) once a day.
If you are being treated for the treatment of parathyroid cancer or primary hyperparathyroidism
The starting dose of Mimpara is 30 mg (one tablet) twice a day.
If you forget to take Mimpara
Do not take a double dose to make up for a forgotten dose.
If you have missed a dose of Mimpara, you should take the next usual dose.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
Overdose What to do if you have taken too much Mimpara
In case you use more Mimpara than you should, contact your doctor immediately. Possible signs of overdose include numbness or tingling around the mouth, muscle aches or cramps and seizures.
Side Effects What are the side effects of Mimpara
Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you start to feel numbness or tingling around your mouth, muscle aches or cramps and fits, you should tell your doctor immediately. These symptoms may indicate that calcium levels are too low (hypocalcemia).
Very common: may affect more than 1 in 10 people
- nausea and vomiting, these side effects are usually quite mild and of short duration.
Common: may affect up to 1 in 10 people
- dizziness
- numbness or tingling sensation (paraesthesia)
- loss (anorexia) or decreased appetite
- muscle pain (myalgia)
- weakness (asthenia)
- skin reactions (rash)
- reduced testosterone levels
- high levels of potassium in the blood (hyperkalaemia)
- allergic reactions (hypersensitivity)
- headache
- seizures (convulsions or fits)
- low blood pressure (hypotension)
- upper respiratory tract infection
- difficulty in breathing (dyspnoea)
- cough
- indigestion (dyspepsia)
- diarrhea
- abdominal pain, pain in the upper abdomen
- constipation
- muscle spasms
- backache
- low levels of calcium in the blood (hypocalcaemia)
Not known: frequency cannot be estimated from the available data
- Urticaria
- Swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing (angioedema).
- Unusually fast or runaway heart rate which may be associated with low blood calcium levels (QT prolongation and ventricular arrhythmia secondary to hypocalcemia).
After the administration of Mimpara, a very small number of patients with cardiac impairment had a worsening of their condition and / or low blood pressure (hypotension).
Children and adolescents
The use of Mimpara in children and adolescents has not been established. A fatal event was reported in a teenager with very low blood calcium levels (hypocalcaemia) who was participating in a clinical study.
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP.
The expiry date refers to the last day of that month.
Do not use this medicine after the expiry date which is stated on the carton and bottle. The expiry date refers to the last day of that month.
This medicinal product does not require any special storage conditions.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Deadline "> Other information
What Mimpara contains
- The active ingredient is cinacalcet. Each film-coated tablet contains 30 mg, 60 mg or 90 mg of cinacalcet (as hydrochloride).
- The other ingredients are:
- Pregelatinised maize starch
- Microcrystalline cellulose
- Povidone
- Crospovidone
- Magnesium stearate
- Anhydrous colloidal silica
- The tablet coating contains:
- Carnauba wax
- Opadry green (lactose monohydrate, hypromellose, titanium dioxide (E171), glycerol triacetate, indigo carmine (E132), yellow iron oxide (E172))
- Clear Opadry (contains hypromellose, macrogol)
What Mimpara looks like and contents of the pack
Mimpara is a light green film-coated tablet. The tablets are oval in shape and have "30", "60" or "90" debossed on one side and "AMG" on the other.
Mimpara is available in blisters containing 30 mg, 60 mg or 90 mg film-coated tablets.
Each box can contain 14, 28 or 84 tablets packed in blisters.
Mimpara is available in bottles containing 30 mg, 60 mg or 90 mg film-coated tablets in a carton. Each bottle contains 30 tablets.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT -
MIMPARA
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
Each tablet contains 30 mg of cinacalcet (as hydrochloride).
Each tablet contains 60 mg of cinacalcet (as hydrochloride).
Each tablet contains 90 mg of cinacalcet (as hydrochloride).
Excipient with known effect:
Each 30 mg tablet contains 2.74 mg of lactose.
Each 60 mg tablet contains 5.47 mg of lactose.
Each 90 mg tablet contains 8.21 mg of lactose.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Film-coated tablet (tablet).
Light green, oval, film-coated tablet with "AMG" on one side and "30" on the other side.
Light green, oval, film-coated tablet with "AMG" on one side and "60" on the other side.
Light green, oval, film-coated tablet with "AMG" on one side and "90" on the other side.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
Treatment of secondary hyperparathyroidism (HPT) in patients with end-stage renal disease (ESRD) on maintenance dialysis therapy.
Mimpara can be used as part of a treatment regimen that includes phosphate binders and / or vitamin D as needed (see section 5.1).
Reduction of hypercalcemia in patients with:
• parathyroid carcinoma.
• primary hyperparathyroidism, in which parathyroidectomy would be indicated on the basis of serum calcium values (in accordance with the relevant treatment guidelines), but in which surgery is not clinically appropriate or contraindicated.
04.2 Posology and method of administration -
Secondary hyperparathyroidism
Adults and the elderly (> 65 years)
The recommended starting dose for adults is 30 mg once a day. In order to achieve parathyroid hormone (PTH) concentrations between 150 and 300 pg / ml (15.9-31.8 pmol / l) in the intact parathyroid assay (iPTH) in dialysis patients, the dose of Mimpara should be gradually increased every 2-4 weeks, up to a maximum daily dose of 180 mg. Determination of PTH levels should be done at least 12 hours after administration of Mimpara. Current treatment guidelines should be referenced.
After initiation of treatment with Mimpara or after a dose modification, PTH should be determined within 1-4 weeks. During maintenance therapy, PTH should be monitored approximately every 1-3 months. To measure PTH levels, both the intact parathyroid hormone (iPTH) and biointact parathyroid hormone (biPTH) assays can be used; treatment with Mimpara does not alter the ratio of intact PTH to biointact PTH.
During dose escalation, serum calcium levels should be measured frequently, and in any case within one week of starting treatment with Mimpara or a change in dose. After establishing the maintenance dose, serum calcium levels should be measured approximately every month.Should serum calcium levels fall below the normal range, appropriate measures should be taken, including modification of concomitant therapy (see section 4.4).
Children and adolescents
Mimpara is not indicated for use in children and adolescents due to a lack of data on safety and efficacy (see section 4.4).
Parathyroid carcinoma and primary hyperparathyroidism
Adults and the elderly (> 65 years)
The recommended starting dose of Mimpara in adults is 30 mg twice daily. The dose of Mimpara should be gradually increased every 2-4 weeks in the following dosing sequence: 30 mg twice daily, 60 mg twice daily. day, 90 mg twice a day and 90 mg three or four times a day as needed to reduce the serum calcium concentration to or below the upper limit of normal. The maximum dose used in clinical trials was 90 mg four times a day.
After initiation of treatment with Mimpara or after a change in dose, serum calcium should be determined within one week. After setting the maintenance dose, serum calcium should be measured every 2-3 months. Following titration of Mimpara to at the maximum dose, serum calcium should be monitored at periodic intervals; if a clinically relevant reduction in serum calcium cannot be maintained, "discontinuation of Mimpara therapy should be considered (see section 5.1).
Children and adolescents
Mimpara is not indicated for use in children and adolescents due to a lack of data on safety and efficacy (see section 4.4).
Hepatic impairment
There is no need to change the starting dose. Mimpara should be used with caution in patients with moderate to severe hepatic impairment and treatment should be closely monitored during dose escalation and during therapy (see sections 4.4 and 5.2).
Method of administration
For oral use. It is recommended to take Mimpara with meals or immediately after a meal, as clinical studies have shown that the bioavailability of cinacalcet is higher when taken with food (see section 5.2). The tablets should be taken whole and not divided.
04.3 Contraindications -
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use -
Serum calcium
Treatment with Mimpara should not be started in patients with calcium (corrected for albumin) lower than the lower limit of the normal range.
Life-threatening events and fatal outcomes associated with hypocalcaemia have been reported in adult and pediatric patients treated with Mimpara. Paresthesia, myalgia, cramps, tetany and convulsions are among the manifestations of hypocalcaemia. Decreases in serum calcium can also prolong the QT interval, potentially causing "ventricular arrhythmia secondary to" hypocalcaemia. Cases of QT prolongation and ventricular arrhythmia have been reported in patients treated with cinacalcet (see section 4.8). Yes caution is advised in patients with other risk factors for QT prolongation, such as patients with known congenital long QT syndrome or patients being treated with medicinal products known to cause QT prolongation.
Because cinacalcet reduces serum calcium, patients should be monitored closely for hypocalcaemia (see section 4.2). Serum calcium should be measured within one week after starting or adjusting the dose of Mimpara. Once the dose is established. maintenance dose, serum calcium should be measured approximately once a month.
In the event that serum calcium levels drop below 8.4 mg / dl (2.1 mmol / l) and / or symptoms of hypocalcemia occur, the following procedure is recommended:
Approximately 30% of patients with chronic renal impairment (CKD) undergoing dialysis given Mimpara had at least a serum calcium value below 7.5 mg / dL (1.9 mmol / L).
Cinacalcet is not indicated in chronic renal impairment patients not on dialysis. In clinical trials, in patients with chronic renal impairment not on dialysis, treated with cinacalcet, there was shown an increased risk of hypocalcaemia (serum calcium levels of renal function.
Convulsions
In clinical trials, seizures were observed in 1.4% of patients treated with Mimpara and in 0.7% of patients who received placebo. Although the reason for the different observed incidence of seizures is unclear, significant reductions in serum levels of calcium cause a lowering of the onset threshold.
Hypotension and / or worsening of cardiac impairment
Isolated, idiosyncratic cases of hypotension and / or worsening of cardiac impairment have been reported in post-marketing pharmacovigilance studies in patients with reduced cardiac function, for which a causal relationship with cinacalcet could not be completely excluded and which could be mediated by reductions in serum calcium levels. Data from a clinical study showed that hypotension occurred in 7% of patients treated with cinacalcet and 12% of patients treated with placebo, and cardiac impairment occurred in 2% of patients treated with cinacalcet or placebo.
General
If parathyroid hormone is chronically suppressed at iPTH levels approximately 1.5 times below the upper limit of normal, adynamic bone disease may develop. recommended goal, the dose of Mimpara and / or vitamin D should be reduced or treatment discontinued.
Testosterone Levels
In patients with end-stage renal impairment, testosterone levels are often below the normal range. In a clinical study, conducted in patients with ESRD undergoing dialysis, after 6 months of treatment, a median decrease in free testosterone levels of 31.3% was observed in patients treated with Mimpara and 16.3% in patients who they received placebo. An open-label extension phase of this study demonstrated no further reductions in free and total testosterone concentrations in patients treated with Mimpara over a 3-year period. The clinical relevance of these reductions in serum testosterone is unknown.
Hepatic impairment
Since plasma levels of cinacalcet may be reached 2-4 times higher in patients with moderate or severe hepatic impairment (Child-Pugh classification), Mimpara should be used with caution in these patients and the treatment should be monitored closely (see sections 4.2 and 5.2).
Lactose
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this drug.
04.5 Interactions with other medicinal products and other forms of interaction -
Effect of other medicinal products on cinacalcet
Cinacalcet is metabolised in part by the CYP3A4 enzyme. Concomitant administration of 200 mg bid of ketoconazole, a potent CYP3A4 inhibitor, resulted in an approximately 2-fold increase in cinacalcet levels. A dose adjustment of Mimpara may be required in the day. if a patient treated with Mimpara starts or stops therapy with a potent inhibitor (e.g. ketoconazole, itraconazole, telithromycin, voriconazole or ritonavir) or inducer (e.g. rifampicin) of this enzyme.
The data in vitro indicate that cinacalcet is partly metabolised by CYP1A2. Smoking induces CYP1A2; The clearance of cinacalcet was observed to be 36-38% higher in smokers than in non-smokers. The effect of potent CYP1A2 inhibitors (eg fluvoxamine, ciprofloxacin) on the plasma levels of cinacalcet has not been studied. Dose adjustment may be required if the patient starts or stops smoking, or if the patient starts smoking. or discontinuation of concomitant treatment with potent CYP1A2 inhibitors.
Calcium carbonate: Concomitant administration of calcium carbonate (a single 1500 mg dose) did not alter the pharmacokinetics of cinacalcet.
Sevelamer: Concomitant administration of sevelamer (2,400 mg t.i.d.) did not affect the pharmacokinetics of cinacalcet.
Pantoprazole: Concomitant administration of pantoprazole (80 mg once daily) did not alter the pharmacokinetics of cinacalcet.
Effect of cinacalcet on other medicinal products
Medicinal products metabolised by the enzyme P450 2D6 (CYP2D6): cinacalcet is a potent inhibitor of CYP2D6. When Mimpara is administered concomitantly with medicinal products metabolised predominantly by CYP2D6, individually titrated and with a narrow therapeutic index (eg flecainide, propafenone, metoprolol, desipramine, nortriptyline, clomipramine) dose adjustments of concomitant medications may be required.
Desipramine: Concomitant administration of 90 mg of Cinacalcet qd with 50 mg of desipramine, a tricyclic antidepressant metabolised primarily by CYP2D6, resulted in a significant 3.6-fold increase in desipramine concentration (90% CI: 3.0-4, 4) in CYP2D6 extensive metabolisers.
Dextromethorphan: Multiple doses of 50 mg cinacalcet increased the AUC of 30 mg dextromethorphan (metabolised primarily by CYP2D6) 11-fold in extensive CYP2D6 metabolisers.
Warfarin: Multiple oral doses of cinacalcet did not affect the pharmacokinetics or pharmacodynamics of warfarin (as assessed by prothrombin time and coagulation factor VII).
The lack of effect of cinacalcet on the pharmacokinetics of R-warfarin and S-warfarin and the absence of self-induction following multiple dose administration in patients indicates that cinacalcet is not an inducer of CYP3A4, CYP1A2 and CYP2C9 in humans. .
Midazolam: Co-administration of cinacalcet (90 mg) with midazolam (2 mg), a substrate of CYP3A4 and CYP3A5, by oral route, did not change the pharmacokinetics of midazolam. These data suggest that cinacalcet does not affect the pharmacokinetics of those classes of drugs that are metabolised by CYP3A4 and CYP3A5, such as some immunosuppressive drugs, including cyclosporine and tacrolimus.
04.6 Pregnancy and breastfeeding -
Pregnancy
There are no clinical data from the use of cinacalcet in pregnant women. Animal studies do not indicate direct harmful effects with respect to pregnancy, parturition or postnatal development. In studies in pregnant rats and rabbits no toxic effects were observed on the "embryo / fetus, with the exception of a reduction in fetal body weight in the rat at doses associated with maternal toxicity (see section 5.3). Mimpara should only be used during pregnancy if the potential benefits justify the potential risk to the fetus.
Feeding time
It is not known whether cinacalcet is excreted in human milk. Cinacalcet is excreted in the milk of lactating rats with a high milk / plasma ratio. After a careful benefit / risk assessment, a decision should be made to discontinue breastfeeding or treatment with Mimpara.
Fertility
There are no clinical data on the effect of cinacalcet on fertility. There are no effects on fertility in animal studies.
04.7 Effects on ability to drive and use machines -
No studies on the ability to drive and use machines have been performed. However, certain adverse reactions may affect the ability to drive and use machines (see section 4.8).
04.8 Undesirable effects -
a) Summary of the safety profile
Secondary hyperparathyroidism, parathyroid carcinoma and primary hyperparathyroidism
Based on available data from patients given cinacalcet in placebo-controlled and single-arm studies, the most commonly reported adverse reactions were nausea and vomiting. Nausea and vomiting were mild to moderate and transient in nature in most patients. Discontinuation of therapy for side effects was mainly caused by nausea and vomiting.
b) Table of adverse reactions
Adverse reactions, considered at least possibly attributable to cinacalcet treatment in placebo-controlled and single-arm studies, based on the assessment of best evidence of causality, are listed below according to the following convention: very common (≥ 1/10 ); common (≥ 1/100 to
The incidence of adverse reactions in controlled clinical trials and post-marketing experience is as follows:
† see section 4.4
* see paragraph C
c) Description of selected adverse reactions
Hypersensitivity reactions
Hypersensitivity reactions, including angioedema and urticaria, have been identified during post-marketing use of Mimpara. The frequencies of individual events, including angioedema and urticaria, cannot be calculated from the available data.
Hypotension and / or worsening of cardiac impairment
During post-marketing safety surveillance, idiosyncratic cases of hypotension and / or worsening of cardiac impairment have been reported in cinacalcet-treated patients with impaired cardiac function, the frequency of such cases cannot be calculated from the available data.
QT prolongation and ventricular arrhythmia secondary to hypocalcemia
QT prolongation and ventricular arrhythmia secondary to hypocalcaemia have been identified during post-marketing use of Mimpara, the frequencies of these events cannot be calculated from the available data (see section 4.4).
d) Pediatric population
Mimpara is not indicated for use in pediatric patients. The safety and efficacy of Mimpara in the pediatric population have not been established. A fatal event was reported in a patient with severe hypocalcaemia enrolled in a pediatric clinical study (see section 4.4).
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions that occur after authorization of the medicine is important as it allows for continuous monitoring of the benefit / risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system ( Italian Medicines Agency - Website: www.agenziafarmaco.gov.it/it/responsabili).
04.9 Overdose -
Doses up to 300 mg once daily have been administered in dialysis patients without causing safety concerns.
Overdose of Mimpara can lead to hypocalcemia. In the event of an overdose, patients should be monitored for signs and symptoms of hypocalcaemia and symptomatic and supportive treatment instituted. Since cinacalcet is largely protein bound, hemodialysis is not an effective treatment in the event of an overdose.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: calcium homeostasis, antiparathyroid preparations.
ATC code: H05BX01.
Mechanism of action
The calcium-sensitive receptor on the surface of the main cells of the parathyroid is the main regulator of parathyroid hormone (PTH) secretion.Cinacalcet is a calcimimetic which, by increasing the sensitivity of the calcium-sensitive receptor towards extracellular calcium, directly reduces PTH levels. The decrease in PTH is associated with a concomitant decrease in serum calcium levels.
The decrease in PTH levels is related to the concentration of cinacalcet.
After steady state has been reached, serum calcium concentrations remain constant over the dose interval.
Secondary hyperparathyroidism
In dialysis patients with end stage renal impairment (ESRD) and secondary, uncontrolled hyperparathyroidism, three double-blind, placebo-controlled clinical trials of 6 months duration (n = 1,136) were conducted. Demographics and baseline assessments were typical of the dialysis patient population with secondary hyperparathyroidism. Baseline intact PTH (iPTH) concentrations in the 3 studies were 733 and 683 pg / mL (77.8 and 72.4 pmol / L), respectively, for cinacalcet-treated and placebo-treated patients. At the time of starting the study, 66% of patients were treated with vitamin D and more than 90% of patients were treated with phosphate binders. Significant reductions in iPTH, serum calcium phosphorus product (Ca x P), calcium and phosphorus were observed in patients treated with cinacalcet compared to patients treated with standard therapy who received placebo; the results were comparable in all three studies. In the three studies, the primary endpoint (the percentage of patients with an iPTH concentration ≤ 250 pg / ml [≤ 26.5 pmol / l]) was achieved by 41%, 46% and 35 % of patients treated with cinacalcet and 4%, 7% and 6% of patients who received placebo. Approximately 60% of patients treated with cinacalcet achieved a ≥ 30% reduction in iPTH levels and this effect was recorded for any baseline iPTH level. The mean reductions in Ca x P product, calcium and phosphorus are were respectively 14%, 7% and 8%.
Reductions in iPTH and Ca x P product were maintained over treatments lasting up to 12 months. Cinacalcet reduced iPTH, Ca x P product, calcium and phosphorus regardless of baseline iPTH or Ca x P product and regardless of the dialysis modality (peritoneal dialysis or hemodialysis), the duration of dialysis or the possible administration of vitamin D.
The reduction in PTH was associated with a nonsignificant reduction in bone metabolism markers (bone alkaline phosphatase, N-telopeptide, bone turnover and bone fibrosis). Examining the pooled data from the 6- and 12-month clinical trials retrospectively, Kaplan-Meier estimates for bone fractures and parathyroidectomy were lower in the cinacalcet group than in the control group.
Clinical studies in patients with chronic renal impairment and secondary hyperparathyroidism, not on dialysis, indicated that cinacalcet reduced PTH levels similarly to that observed in patients with ESRD and secondary hyperparathyroidism on dialysis. However, efficacy, safety, optimal doses and treatment goals in pre-dialysis patients with renal impairment have not yet been established. These studies demonstrate that non-dialysis CKD patients treated with cinacalcet have a more high risk of hypocalcaemia compared to ESRD patients on dialysis treated with cinacalcet: this could be due to lower basal calcium levels and / or the presence of residual renal function.
EVOLVE (EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events), a randomized, double-blind study conducted to evaluate the effects of cinacalcet HCl vs placebo on reducing the risk of all-cause mortality and cardiovascular events in 3,883 patients with secondary hyperparathyroidism and CKD undergoing dialysis. The study did not meet the primary objective of demonstrating a reduction in the risk of all-cause mortality or cardiovascular events including myocardial infarction, hospitalization for unstable angina, cardiac impairment, or peripheral vascular events (HR 0.93; CI 95 %: 0.85 - 1.02; p = 0.112). In a secondary analysis, after adjustment for baseline characteristics, the HR for the composite primary endpoint was 0.88; 95% CI: 0.79 - 0.97.
Parathyroid carcinoma and primary hyperparathyroidism
In a clinical study, 46 patients (29 with parathyroid cancer, 17 with primary hyperparathyroidism and severe hypercalcaemia who had failed or had contraindications to parathyroidectomy) received cinacalcet for up to 3 years (mean 328 days for patients with parathyroid cancer and 347 days patients with primary hyperparathyroidism). Cinacalcet was administered in doses of 30 mg twice daily to 90 mg four times daily. The primary endpoint of the study was a reduction in calcium by ≥ 1 mg / dL (≥ 0.25 mmol / L). In patients with parathyroid cancer, mean calcium decreased from 14.1 mg / dL to 12.4 mg / dl (from 3.5 mmol / l to 3.1 mmol / l) while in patients with primary hyperparathyroidism the calcium decreased from 12.7 mg / dl to 10.4 mg / dl (3.2 mmol / l 2.6 mmol / L) Eighteen of 29 patients (62%) with parathyroid carcinoma and 15 of 17 patients (88%) with primary hyperparathyroidism achieved a reduction in blood calcium of ≥ 1 mg / dL (≥ 0.25 mmol / L).
In a 28-week placebo-controlled study, 67 patients with primary hyperparathyroidism were included who were eligible for parathyroidectomy based on corrected total serum calcium> 11.3 mg / dL (2.82 mmol / L) but ≤ 12.5 mg / dl (3.12 mmo / l) who could not undergo parathyroidectomy. Cinacalcet was initially administered at a dose of 30 mg twice daily then gradually increased to maintain a corrected total serum calcium concentration within the normal range. A significantly higher proportion of patients treated with cinacalcet achieved a mean corrected total serum calcium concentration ≤ 10.3 mg / dL (2.57 mmol / L) and a decrease from baseline ≥ 1 mg / dL (0.25 mmol / l), of the mean corrected total serum calcium concentration compared to patients treated with placebo (75.8% vs 0% and 84.8% vs 5.9%, respectively).
05.2 "Pharmacokinetic properties -
Absorption
After oral administration of Mimpara, the maximum plasma concentration of cinacalcet is achieved in approximately 2-6 hours. Based on comparisons between studies, cinacalcet was estimated to have an absolute bioavailability in fasted subjects of approximately 20-25%. Administration of Mimpara with meals results in an increase in the bioavailability of cinacalcet by approximately 50-80%. The increases in plasma concentrations of cinacalcet are similar regardless of the fat content of the foods.
Absorption is saturated at doses above 200 mg, possibly due to poor solubility.
Distribution
The volume of distribution is large (approximately 1,000 liters), indicating "wide distribution. Cinacalcet is approximately 97% bound to plasma proteins and very little distributed in erythrocytes.
After absorption, cinacalcet concentrations decline in a biphasic manner, with an "initial half-life of approximately 6 hours and a" terminal half-life of 30-40 hours. Steady state levels of Cinacalcet are reached within 7 days, with accumulation The pharmacokinetics of cinacalcet do not vary over time.
Biotransformation
Cinacalcet is metabolised by several enzymes, mainly CYP3A4 and CYP1A2 (the contribution of CYP1A2 has not yet been characterized clinically). Major circulating metabolites are inactive.
The data in vitro show that cinacalcet is a potent inhibitor of CYP2D6, but at concentrations clinically achieved with therapeutic doses it does not inhibit other CYP enzymes including CYP1A2, CYP2C8, CYP2C9, CYP2C19 and CYP3A4 or inducers of CYP1A2, CYP2C19 and CYP3A4.
Elimination
Following administration of a radioactively labeled 75 mg dose to healthy volunteers, cinacalcet was rapidly and extensively metabolised by oxidation and subsequent conjugation. Renal excretion of metabolites was the predominant route of elimination of radioactivity. Approximately 80% of the dose was recovered in the urine and 15% in the faeces.
Linearity / non-linearity
The AUC and Cmax of cinacalcet increase approximately linearly over the dose range of 30 to 180 mg once daily.
Pharmacokinetic / pharmacodynamic relationship (s)
The PTH begins to decrease soon after administration, reaching the nadir approximately 2-6 hours later, corresponding to the Cmax of cinacalcet. Thereafter, as cinacalcet levels decrease, PTH levels increase for up to 12 hours after administration, PTH suppression then remains approximately constant until the end of the daily dose interval. In clinical studies of Mimpara i PTH levels were measured at the end of the interval between one dose and the next.
Senior citizensThere are no clinically relevant differences in the pharmacokinetics of cinacalcet due to age.
Renal impairment: The pharmacokinetic profile of cinacalcet in patients with mild, moderate and severe renal impairment and in those on hemodialysis or peritoneal dialysis is similar to that seen in healthy volunteers.
Hepatic impairment: Mild hepatic impairment did not particularly affect the pharmacokinetics of cinacalcet. Compared to subjects with normal hepatic function, the mean AUC of cinacalcet was approximately 2 times higher in subjects with moderate impairment and about 4 times higher in subjects with severe impairment. In patients with moderate and severe hepatic impairment the mean half-life cinacalcet is 33% and 70% longer, respectively. Protein binding of cinacalcet is not affected by hepatic impairment. As the dose is titrated for each subject based on safety and efficacy parameters, no further dose adjustment is required in patients with hepatic impairment (see sections 4.2 and 4.4).
Sex: The clearance of cinacalcet in women may be lower than in men. Since the dose is individually titrated, no further dose adjustments are required due to gender.
Pediatric population: the pharmacokinetics of cinacalcet were studied in 12 pediatric patients (6-17 years) with CKD undergoing dialysis who received a single oral dose of 15 mg. Mean AUC and Cmax values (23.5 (range 7.22-77.2) ng * hr / mL and 7.26 (range 1.80-17.4) ng / mL, respectively) were approximately within 30% of the mean values for AUC and Cmax observed in a single study in healthy adults who received a single dose of 30 mg (33.6 (range 4.75-66.9) ng * hr / ml and 5 , 42 (range 1.41-12.7) ng / mL, respectively). Due to the limited data available in pediatric subjects, the possibility of higher exposures in lighter / younger subjects than in heavier / older subjects cannot be excluded. Pharmacokinetics in pediatric subjects after multiple doses have not been studied.
Smoke: clearance of cinacalcet is higher in smokers than in non-smokers, possibly due to the induction of CYP1A2-mediated metabolism. The fact that a patient starts or stops smoking could affect the plasma levels of cinacalcet and therefore require correction of the dose.
05.3 Preclinical safety data -
Cinacalcet was not teratogenic in rabbits following administration of doses which, based on AUC, were 0.4 times the maximum human dose for the treatment of secondary hyperparathyroidism (180 mg per day). Based on AUC data, the non-teratogenic dose in the rat was 4.4 times higher than the maximum dose for the treatment of secondary hyperparathyroidism. No effects on male or female fertility were detected following exposures up to 4 times higher than the dose of 180 mg / day used in humans (the safety margins in the small population of patients treated with a maximum therapeutic dose of 360 mg / day would be approximately half of those indicated above).
A slight decrease in body weight and food intake at the highest dose was observed in pregnant rats. In rats, a reduction in fetal weight was observed at doses for which the mothers had severe hypocalcaemia. Cinacalcet has been shown to cross the placental barrier in rabbits.
Cinacalcet did not show any genotoxic or carcinogenic potential. Safety margins observed in toxicology studies are narrow due to dose-limiting hypocalcaemia observed in experimental animal models. Cataract and lens opacity were observed in repeated dose toxicology and carcinogenicity studies performed in rodents, but not in dogs. either in monkeys or in clinical trials where cataract formation was monitored In rodents, cataracts are known to occur following hypocalcemia.
In studies in vitro, the CI50 values for the serotonin transporter and for the KATP channels were 7 and 12 times higher than the EC50 for the calcium-sensitive receptor, respectively, obtained under the same experimental conditions. The clinical relevance is unknown, however, the possibility that cinacalcet acts on these secondary targets cannot be completely ruled out.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Core of the tablet
Pregelatinised maize starch
Microcrystalline cellulose
Povidone
Crospovidone
Magnesium stearate
Anhydrous colloidal silica
Tablet coating
Carnauba wax
Opadry II green: (Lactose monohydrate, hypromellose, titanium dioxide [E171], glycerol triacetate, indigo carmine [E132], yellow iron oxide [E172])
Clear Opadry: (Hypromellose, macrogol)
06.2 Incompatibility "-
Not relevant.
06.3 Period of validity "-
Blister: 5 years.
Bottle: 5 years.
06.4 Special precautions for storage -
This medicinal product does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package -
Aclar / PVC / PVAc / aluminum blister containing 14 tablets. Packs of 1 blister (14 tablets), 2 blisters (28 tablets) or 6 blisters (84 tablets) per box.
High density polyethylene bottle with a cotton spiral and a child resistant polypropylene cap with induction seal, packed in a cardboard box. Each bottle contains 30 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling -
No special instructions for disposal.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
Amgen Europe B.V.
Minervum 7061
4817 ZK Breda
Netherlands
08.0 MARKETING AUTHORIZATION NUMBER -
EU / 1/04/292/001 - box of 14 tablets
EU / 1/04/292/002 - box of 28 tablets
EU / 1/04/292/003 - box of 84 tablets
EU / 1/04/292/004 - bottle of 30 tablets
EU / 1/04/292/005 - box of 14 tablets
EU / 1/04/292/006 - box of 28 tablets
EU / 1/04/292/007 - box of 84 tablets
EU / 1/04/292/008 - bottle of 30 tablets
EU / 1/04/292/009 - box of 14 tablets
EU / 1/04/292 / 010- box of 28 tablets
EU / 1/04/292/011 - box of 84 tablets
EU / 1/04/292/012 - bottle of 30 tablets
036598011
036598047
036598086
036598023
036598050
036598098
036598035
036598062
036598100
036598124
036598074
036598112
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
Date of first authorization: 22 October 2004
Date of most recent renewal: 23 September 2009
10.0 DATE OF REVISION OF THE TEXT -
December 2016
