Consumer medicine information

Sensipar

Cinacalcet

BRAND INFORMATION

Brand name

Sensipar

Active ingredient

Cinacalcet

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Sensipar.

What is in this leaflet

This leaflet answers some common questions about Sensipar. It does not contain all the available information. It does not take the place of talking to your doctor, nurse or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Sensipar against the benefits he/she expects it will have for you.

If you have any concerns about taking Sensipar, ask your doctor, nurse or pharmacist.

Read this leaflet carefully before you start Sensipar and keep it with the medicine. You may need to read it again.

What Sensipar is used for

Sensipar is used to treat:

  • a condition called secondary hyperparathyroidism (high-per-para-THIGH-royd-izm) in people with kidney disease who require dialysis treatment.
  • a condition called primary hyperparathyroidism when surgical removal of the parathyroid gland is not a treatment option.
  • high blood calcium levels in people with cancer of the parathyroid gland.

Secondary hyperparathyroidism
Kidney disease can cause a condition called secondary hyperparathyroidism, which can have a big impact on your health. Four small glands located behind the thyroid gland in your neck are called parathyroid glands. They make a hormone called parathyroid hormone (PTH). Normally, PTH makes sure you have just enough calcium and phosphorus in your blood to keep your bones, heart, muscles, nerves and blood vessels working well. When your kidneys are working properly, PTH keeps your calcium and phosphorus levels normal by moving the right amounts of calcium and phosphorus in and out of your bones.

When your kidneys aren't working properly, the calcium and phosphorus balance in your body is upset, and your parathyroid glands send out too much PTH to your body. This condition is called secondary hyperparathyroidism, and it can cause bone disease and also may be a risk factor for heart disease and abnormal calcium deposits in blood vessels and other parts of the body. Sensipar lowers PTH by telling your parathyroid glands to stop releasing too much PTH into your blood. It also lowers your calcium and phosphorus levels.

Primary hyperparathyroidism/Cancer of the parathyroid gland
An overactive parathyroid gland results in a condition called primary hyperparathyroidism, which can impact your health. Four small glands located behind the thyroid gland in your neck are called parathyroid glands. They make a hormone called parathyroid hormone (PTH). When your parathyroid glands are working normally, PTH keeps your calcium levels normal by moving the right amounts of calcium in and out of your bones.

Primary hyperparathyoidism is caused by an enlargement of one or more of the parathyroid glands occasionally due to cancer of the parathyroid gland. In primary hyperparathyroidism, your parathyroid glands send out too much PTH to your body and your blood level of calcium becomes high. Sensipar lowers PTH by telling your parathyroid glands to stop releasing too much PTH into your blood. It also lowers your blood calcium levels.

Your doctor may have prescribed Sensipar for another reason. Ask your doctor if you have any questions about why Sensipar has been prescribed for you.

Before you take Sensipar

When you must not take Sensipar

Do not take Sensipar if you are allergic to the active ingredient or any of the ingredients in Sensipar listed at the end of this leaflet.

Symptoms of an allergic reaction may include:

  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • skin rash, itching or hives.

Talk to your doctor, nurse or pharmacist if you have any questions about this information.

Do not give Sensipar to a child. There is not enough information at present to recommend use of Sensipar in children.

Do not take Sensipar after the expiry date (Exp.) stamped on the pack. If you take this medicine after the expiry date has passed, it may not work as well.

Do not take Sensipar if the packaging is torn or shows signs of tampering or if the tablets do not look quite right.

Before you start to take Sensipar

Tell your doctor if:

  1. you have or have had any medical conditions, including:
  • seizures (sometimes called fits or convulsions, see 'Side effects' section).
  • heart failure (or a heart condition, see 'Side effects' section).
  • intolerance to sugars (sometimes called lactose intolerance, see 'Ingredients' section).
  • ulcers (stomach or intestinal), serious vomiting, inflammation of the stomach and swallowing tube.
  1. you are pregnant or intend to become pregnant.
Your doctor will discuss the risks and benefits of taking Sensipar if you are pregnant.
  1. you are breastfeeding or planning to breastfeed.
It is not known whether Sensipar passes into breast milk.
  1. you are taking any other medicines, including any medicines you buy without a prescription from a pharmacy, supermarket or health food shop (for example St John's Wort).

If you have not told your doctor about any of the above, tell him/her before you take Sensipar.

Taking other medicines

Tell your doctor if you are taking ketoconazole, erythromycin, itraconazole, rifampicin, phenytoin, amitriptyline, flecainide, vinblastine, thioridazine or medicines known as tricyclic antidepressants. Some of these medicines can affect how Sensipar works, while others are affected by Sensipar.

Driving and using machines

Dizziness and seizures have been reported by patients taking Sensipar. If you experience these side effects, do not drive or operate machines.

How to take Sensipar

Sensipar must be taken orally either with, or shortly after food. The tablets must be taken whole and are not to be divided.

Follow all directions given to you by your doctor, nurse and pharmacist carefully. They may differ from the information in this leaflet.

If you do not understand the instructions below, ask your doctor, nurse or pharmacist for help.

How much Sensipar to take

If you are being treated for secondary hyperparathyroidism

The usual starting dose for Sensipar is 30 mg (one tablet) once per day. Your doctor will take regular blood samples to measure how you are responding to Sensipar and will adjust your dose as necessary in order to control your parathyroid hormone, calcium and phosphate levels.

Once your condition is under control, your doctor will continue to regularly check your blood and your dose may be adjusted further in order to maintain long-term control of your parathyroid hormone, calcium and phosphate levels.

If you are being treated for primary hyperparathyroidism/ cancer of the parathyroid gland

The usual starting dose for Sensipar is 30 mg (one tablet) twice per day. Your doctor will take regular blood samples to measure how you are responding to Sensipar and will adjust your dose as necessary in order to control your calcium levels. Once your condition is under control, your doctor will continue to regularly check your blood and your dose may be adjusted further in order to maintain long-term control of your calcium levels.

If you forget to take Sensipar

If you have forgotten a dose of Sensipar, you should take your next dose as normal.

If you take more Sensipar than you should (overdose)

If you take more Sensipar than you should you must contact your doctor, nurse or pharmacist immediately.

While you are taking Sensipar

Things you must do

Always follow your doctor's instructions carefully. If you are about to start using a new medicine, tell your doctor, nurse and pharmacist that you are taking Sensipar.

If you become pregnant while you are taking Sensipar, tell your doctor.

Things you must not do

Do not take Sensipar to treat any other complaint unless your doctor says so.

Do not give Sensipar to anyone else, even if their symptoms seem similar to yours.

Side effects

Tell your doctor as soon as possible if you have any problems while taking Sensipar, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

Like other medicines, Sensipar may cause side effects. Some side effects may be serious and need medical attention. Other side effects are minor and are likely to be temporary.

Sensipar lowers your calcium level. If calcium levels become too low, you may have signs of low calcium. Signs of low calcium may include numbness or tingling around the mouth, muscle aches or cramps and seizures. If you have any of these symptoms, you should tell your doctor straight away. People with kidney disease not requiring dialysis are at increased risk of developing hypocalcaemia.

Ask your doctor, nurse or pharmacist to answer any questions you may have.

If any of the following happens, stop taking Sensipar and go straight to the hospital, as you may need urgent medical attention:

  • Allergic reaction
  • Skin rash over a large area of the body
  • Swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing
  • Shortness of breath
  • Wheezing
  • Faintness, rapid pulse or sweating.

Tell your doctor, nurse or pharmacist immediately if you notice any of the following:

  • Nausea and vomiting.
People taking Sensipar have a greater chance of developing nausea and /or vomiting. If nausea or vomiting is making it difficult to take your medicines or is of any concern to you, you should tell your doctor.
  • Seizure (also known as a fit or convulsion).
The risk of having seizures is greater in people who have had seizures before. Lowering the calcium level too much may also increase the risk of having a seizure. If you have a seizure you should tell your doctor straight away.
  • Dizziness or light headedness, or worsening of a heart condition.
Sensipar may cause low blood pressure or affect the heart's function in people who have a heart condition (heart failure). If you know you have a heart condition, tell your doctor.
  • Rash.
Pinkish, itchy swellings on the skin, also called hives or nettle rash. Itchy rash.
  • Bleeding from the stomach or intestines.
Bleeding from the stomach or intestines may occur in some patients. You may experience severe pain or tenderness in the stomach, vomit blood or material that looks like coffee grounds, or have black or tar-like stools.

Tell your doctor, nurse or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may occur in some people.

After taking Sensipar

Storage

Keep your Sensipar in a cool place, under 30 degrees C.

The expiry date (Exp.) for Sensipar is stamped on the outer box and the blister label. Do not take Sensipar after this date, the last day of the month shown.

As with all medicines, you should keep Sensipar out of the reach and sight of children.

Product description

What it looks like

Sensipar is a light green film-coated tablet. They are oval-shaped and have "30", "60" or "90" marked on one side and "AMG" on the other side. Each tablet contains 30 mg, 60 mg or 90 mg of cinacalcet. They come in blister packs.

Ingredients

Active ingredient
The active ingredient in Sensipar is cinacalcet hydrochloride.

Other ingredients
The other ingredients of Sensipar are pre-gelatinised maize starch, microcrystalline cellulose, povidone, crospovidone, colloidal anhydrous silica, magnesium stearate and water.

The tablets are coated with: Carnauba wax,
Opadry green (containing lactose monohydrate, hypromellose, titanium dioxide (E171), glycerol triacetate, FD&C Blue (E132), iron oxide yellow (E172)) and Opadry clear (containing hypromellose, macrogol).

If you have been told by your doctor that you have an intolerance to certain sugars (for example, lactose), tell your doctor before taking Sensipar.

Sponsor

Sensipar is supplied in Australia by:

Amgen Australia Pty Ltd
Level 7, 123 Epping Road
North Ryde
NSW 2113
ABN 31 051 057 428

Australian Registration Numbers

Sensipar 30 mg in a blister pack AUST R 98399

Sensipar 60 mg in a blister pack AUST R 98404

Sensipar 90 mg in a blister pack AUST R 98407

(R) Registered Trademark

This leaflet was prepared in February 2020.

Published by MIMS April 2020

BRAND INFORMATION

Brand name

Sensipar

Active ingredient

Cinacalcet

Schedule

S4

 

1 Name of Medicine

Cinacalcet hydrochloride.

2 Qualitative and Quantitative Composition

Each tablet contains either 30 mg, 60 mg or 90 mg of cinacalcet as the free base equivalent (corresponding to 33 mg, 66 mg and 99 mg as the hydrochloride salt, respectively).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film-coated tablet.
Sensipar 30 mg tablets: light green, film-coated, oval-shaped tablets marked with "AMG" on one side and "30" on the opposite side.
Sensipar 60 mg tablets: light green, film-coated, oval-shaped tablets marked with "AMG" on one side and "60" on the opposite side.
Sensipar 90 mg tablets: light green, film-coated, oval-shaped tablets marked with "AMG" on one side and "90" on the opposite side, packaged in blister packs of 28 tablets.

4 Clinical Particulars

4.1 Therapeutic Indications

Sensipar may be used to treat the biochemical manifestations of secondary hyperparathyroidism (HPT) in patients with end stage renal disease, receiving dialysis (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Sensipar should be used as adjunctive therapy.
Sensipar is indicated for the treatment of hypercalcaemia in patients with parathyroid carcinoma.
Sensipar may be used to treat the biochemical manifestations of primary HPT in patients for whom parathyroidectomy is not a treatment option.

4.2 Dose and Method of Administration

Dosage (dose and interval).

Patients with end stage renal disease receiving dialysis.

Sensipar reduces parathyroid hormone (PTH) while simultaneously lowering Ca x P, calcium and phosphorus levels in patients receiving dialysis.
The recommended starting dose for adults is 30 mg once per day.
Sensipar should be titrated every 2 to 4 weeks to a maximum dose of 180 mg once daily to achieve a target PTH between 1.5 to 5 times the upper limit of normal.
In chronic kidney disease (CKD) patients, PTH levels should be assessed at least 12 hours after dosing with cinacalcet.
During dose titration, serum calcium levels should be monitored frequently and if serum calcium levels decrease below the normal range, appropriate steps should be taken to increase serum calcium levels (see Section 4.4 Special Warnings and Precautions for Use).

Parathyroid carcinoma and primary HPT for whom parathyroidectomy is not a treatment option.

The recommended starting dose of Sensipar for adults is 30 mg twice daily.
The dosage of Sensipar should be titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, 90 mg twice daily, and 90 mg three or four times daily as necessary to normalise serum calcium.

Method of administration.

Sensipar is administered orally. It is recommended that Sensipar be taken with food or shortly after a meal. Tablets should be taken whole and should not be divided.

Dosage adjustment.

Geriatric patients.

Age does not alter the pharmacokinetics of cinacalcet; no dosage adjustment is required for geriatric patients.

Renal impairment.

Renal impairment does not alter the pharmacokinetics of cinacalcet; no dosage adjustment is necessary for renal impairment.

Hepatic impairment.

Moderate to severe hepatic impairment (Child-Pugh classification) increases cinacalcet drug concentrations by approximately 2 to 4 fold. In patients with moderate-severe hepatic impairment, PTH and serum calcium concentrations should be closely monitored during dose titration of cinacalcet.

4.3 Contraindications

Sensipar is contraindicated in patients with hypersensitivity to any component(s) of this product.

Hypocalcaemia.

Sensipar treatment should not be initiated if serum calcium is less than the lower limit of the normal range (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Serum calcium.

Cinacalcet treatment should not be initiated in patients with CKD receiving dialysis if serum calcium is less than 8.4 mg/dL [2.1 mmol/L]. Since cinacalcet lowers serum calcium, patients should be monitored for the occurrence of hypocalcaemia.
Life threatening events and fatal outcomes associated with hypocalcaemia have been reported in patients treated with cinacalcet including in paediatric patients. Decreases in serum calcium can prolong the QT interval, potentially resulting in ventricular arrhythmia. Cases of QT prolongation and ventricular arrhythmia secondary to hypocalcaemia have been reported in patients treated with cinacalcet. Manifestations of hypocalcaemia may also include paraesthesias, myalgias, cramping, tetany, and seizures.
Serum calcium should be measured within 1 week after initiation or dose adjustment of cinacalcet. Once the maintenance dose has been established, serum calcium should be measured approximately monthly. If serum calcium falls below 8.4 mg/dL [2.1 mmol/L] but remains above 7.5 mg/dL [1.88 mmol/L], or if symptoms of hypocalcaemia occur, calcium containing phosphate binders and/or vitamin D sterols can be used to raise serum calcium. If hypocalcaemia persists, reduce the dose or discontinue administration of cinacalcet. If serum calcium falls below 7.5 mg/dL [1.88 mmol/L], or if symptoms of hypocalcaemia persist and the dose of vitamin D cannot be increased, withhold administration of cinacalcet until serum calcium levels reach 8.0 mg/dL [2.0 mmol/L] and/or symptoms of hypocalcaemia have resolved. Treatment should be reinitiated using the next lowest dose of cinacalcet (see Section 4.2 Dose and Method of Administration).
In the 6 month registrational trials of patients with CKD on dialysis, 66% of patients receiving cinacalcet compared with 25% of patients receiving placebo developed at least one serum calcium value < 8.4 mg/dL [2.1 mmol/L]. In CKD patients receiving dialysis who were administered cinacalcet, 29% of patients in the 6 month registrational trials and 21% and 33% of patients (within the first 6 months and overall, respectively) in the EVOLVE clinical trial, had at least one serum calcium value less than 7.5 mg/dL [1.88 mmol/L]. In the EVOLVE clinical trial, 1.1% of patients in the cinacalcet group and 0.1% in the placebo group permanently discontinued study drug due to hypocalcaemia.
Cinacalcet is not indicated for CKD patients not receiving dialysis. Investigational studies have shown that CKD patients not receiving dialysis treated with cinacalcet have an increased risk of hypocalcaemia (serum calcium levels less than 8.4 mg/dL [2.1 mmol/L]) compared with cinacalcet treated CKD patients receiving dialysis, which may be due to lower baseline calcium levels and/or the presence of residual kidney function.

Co-administration with other products.

Administer cinacalcet with caution in patients receiving any other medications known to lower serum calcium. Closely monitor serum calcium levels in patients receiving other medications known to lower serum calcium.

Laboratory tests.

Patients with CKD and secondary hyperparathyroidism.

Serum calcium should be measured within 1 week and the intact PTH (iPTH) should be measured 1 to 4 weeks after initiation or dose adjustment of cinacalcet. Once the maintenance dose has been established, serum calcium should be measured approximately monthly, and PTH every 1 to 3 months (see Section 4.2 Dose and Method of Administration). Either the iPTH or bio-intact PTH (biPTH) may be used to measure PTH levels; treatment with cinacalcet does not alter the relationship between iPTH and biPTH.

Patients with parathyroid carcinoma and patients with primary hyperparathyroidism for whom parathyroidectomy is not a treatment option.

Serum calcium should be measured within 1 week after initiation or dose adjustment of cinacalcet. Once maintenance dose levels have been established, serum calcium should be measured every 2 to 3 months (see Section 4.2 Dose and Method of Administration).

Seizures.

In clinical studies, seizures (primarily generalised or tonic-clonic) were observed in 1.4% (43/3,049) of cinacalcet-treated patients and 0.7% (5/687) of placebo-treated patients. While the basis for the reported difference in seizure rate is not clear, the threshold for seizures is lowered by significant reductions in serum calcium levels.

Hypotension and/or worsening heart failure.

In postmarketing safety surveillance, isolated, idiosyncratic cases of hypotension and/or worsening heart failure have been reported in patients with impaired cardiac function, in which a causal relationship to cinacalcet could not be completely excluded and may be mediated by reductions in serum calcium levels. Clinical trial data showed hypotension occurred in 7% of cinacalcet treated patients, 12% of placebo treated patients and heart failure occurred in 2% of patients receiving cinacalcet or placebo.

Upper gastrointestinal bleeding.

Cases of gastrointestinal bleeding, mostly upper gastrointestinal bleeding, have occurred in patients using calcimimetics, including Sensipar, from postmarketing and clinical trial sources. The exact cause of GI bleeding in these patients is unknown.
Patients with risk factors for upper GI bleeding (such as known gastritis, oesophagitis, ulcers or severe vomiting) may be at increased risk for GI bleeding when receiving Sensipar treatment. Monitor patients for worsening of common GI adverse reactions of nausea and vomiting associated with Sensipar (see Section 4.8 Adverse Effects (Undesirable Effects)) and for signs and symptoms of GI bleeding and ulcerations during Sensipar therapy. Promptly evaluate and treat any suspected GI bleeding.

Adynamic bone.

In CKD patients receiving dialysis adynamic bone may develop if PTH levels are suppressed below 100 picogram/mL (10.6 picomol/L). If PTH levels decrease below the recommended target range in patients treated with cinacalcet, the dose of vitamin D sterols and/or cinacalcet should be reduced or therapy discontinued.

Testosterone levels.

Testosterone levels are often below the normal range in patients with endstage renal disease. In a clinical study of CKD patients on dialysis, free testosterone levels decreased by a median of 31.3% in the cinacalcet treated patients and by 16.3% in the placebo treated patients after 6 months of treatment. The clinical significance of these reductions in serum testosterone is unknown. An open label extension of this study showed no further reductions in free and total testosterone concentrations over a period of 3 years in cinacalcet treated patients.

Neoplastic events.

In EVOLVE, a randomised, double blind, placebo controlled clinical study of 3,883 dialysis patients, neoplastic events were reported in 2.9 and 2.5 patients per 100 patient years in cinacalcet and placebo treatment groups, respectively. A causal relationship to cinacalcet has not been established.

Use in hepatic impairment.

Due to the potential for 2 to 4 times higher plasma levels of cinacalcet in patients with moderate to severe hepatic impairment, physicians should closely monitor these patients when initiating cinacalcet (see Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

Of the 1,136 patients enrolled in the cinacalcet phase 3 clinical programme, 26% were over 65 years old, and 9% were over 75 years old. No differences in the safety and efficacy of cinacalcet were observed in patients greater or less than 65 years of age (see Section 4.2 Dose and Method of Administration, Geriatric patients).

Paediatric use.

The safety and efficacy of cinacalcet in paediatric patients have not been established. Cinacalcet is not indicated for use in paediatric patients. A fatal outcome was reported in a paediatric clinical trial patient with severe hypocalcaemia (see Section 4.4 Special Warnings and Precautions for Use, Serum calcium; Section 5.2 Pharmacokinetic Properties, Paediatric patients).

Effects on laboratory tests.

None known.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effect of cinacalcet on other drugs.

Drugs metabolised by the enzyme cytochrome P450 2D6 (CYP2D6). Cinacalcet is an inhibitor of CYP2D6. Therefore, dose adjustments of concomitant medications may be required when cinacalcet is administered with medications that are predominantly metabolised by this enzyme (e.g. metoprolol) and particularly those with a narrow therapeutic index (e.g. flecainide, vinblastine, thioridazine and most tricyclic antidepressants).

Desipramine.

Concurrent administration of 90 mg cinacalcet with 50 mg desipramine, a tricyclic antidepressant metabolised primarily by CYP2D6, increased desipramine exposure approximately 3.6 times in CYP2D6 extensive metabolisers.

Amitriptyline.

Coadministration of 25 mg or 100 mg cinacalcet with 50 mg amitriptyline, a tricyclic antidepressant metabolised in part by CYP2D6, increased exposure to amitriptyline and its active metabolite nortriptyline by approximately 20% in extensive metabolisers of CYP2D6 enzymes. Dose reductions of amitriptyline may be required in some subjects receiving cinacalcet concurrently.
Drugs metabolised by other cytochrome P450 (CYP) enzymes. Based on in vitro data, cinacalcet is not an inhibitor of other CYP enzymes at concentrations achieved clinically, including CYP1A2, CYP2C9, CYP2C19 and CYP3A4.

Warfarin.

Multiple oral doses of cinacalcet did not affect the pharmacokinetics or pharmacodynamics (as measured by prothrombin time and the clotting factor VII) of warfarin.
The lack of effect of cinacalcet on the pharmacokinetics of R and S-warfarin, and the absence of autoinduction upon multiple dosing in patients, indicates that cinacalcet is not an inducer of CYP3A4, CYP1A2 or CYP2C9 in humans.

Midazolam.

Coadministration of cinacalcet (90 mg) with orally administered midazolam (2 mg), a CYP3A4 and CYP3A5 substrate, did not alter the pharmacokinetics of midazolam. These data suggest that cinacalcet would not affect the pharmacokinetics of those classes of drugs that are metabolised by CYP3A4 and CYP3A5, such as certain immunosuppressants, including cyclosporin and tacrolimus.

Effect of other drugs on cinacalcet.

Cinacalcet is metabolised by multiple cytochrome P450 enzymes, primarily CYP3A4, CYP1A2 and CYP2D6, which limit the potential for other drugs to increase cinacalcet concentrations.

Ketoconazole.

Cinacalcet is metabolised in part by the enzyme CYP3A4. Coadministration of ketoconazole, a strong inhibitor of CYP3A4, caused an approximate 2-fold increase in cinacalcet exposure. Dose adjustment of cinacalcet may be required if a patient receiving cinacalcet initiates or discontinues therapy with a strong CYP3A4 inhibitor (e.g. ketoconazole, erythromycin, itraconazole) or inducer (e.g. rifampicin, phenytoin, St. John's Wort) of this enzyme.

Calcium carbonate.

Coadministration of calcium carbonate (1,500 mg) did not alter the pharmacokinetics of cinacalcet.

Sevelamer HCl.

Coadministration of sevelamer HCl (2,400 mg tid) did not alter the pharmacokinetics of cinacalcet.

Pantoprazole.

Coadministration of pantoprazole (80 mg qd) did not alter the pharmacokinetics of cinacalcet.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Cinacalcet did not impair mating or fertility in rats at oral doses up to 75 mg/kg/day, with systemic exposures up to 2 times human exposure at the maximum recommended clinical dose (MRCD), based on AUC.
Studies in monkeys showed that cinacalcet depressed serum testosterone concentrations by 70-90% at oral doses 5-100 mg/kg/day, corresponding to systemic exposures 0.1-1 times the clinical exposure, on an AUC basis, at the MRCD of 360 mg/day. The highest dose also resulted in a 42% reduction in testicular weights.
(Category B3*)
Cinacalcet crossed the placental barrier in rabbits; foetal plasma cinacalcet concentrations were about 10-13% of the maternal plasma concentrations. There was no evidence of teratogenicity in rats or rabbits. Foetal body weights were decreased in rats at 50 mg/kg/day PO (approximately 2 times the clinical exposure at the MRCD, based on AUC) and increased incidences of unossified sternebrae occurred in rats at exposures 0.1-2 times the clinical exposure, with maternal toxicity.
There are no adequate and well-controlled studies of cinacalcet in pregnant women. Because animal reproduction studies are not always predictive of human response, cinacalcet should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
*Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals have shown evidence of an increased occurrence of foetal damage, the significance of which is considered uncertain in humans.
 It is not known whether cinacalcet is excreted in human milk. Cinacalcet is excreted in the milk of lactating rats with a high milk to plasma ratio. Oral administration of cinacalcet to female rats during gestation and lactation at doses of 25 mg/kg/day and above (exposures at and above 1.5 times the clinical exposure at the MRCD, based on AUC) was associated with increases in neonatal loss and reduced body weight gain of suckling rats.
Considering the rat study findings and because many drugs are excreted in breast milk, a decision should be made to discontinue nursing or discontinue cinacalcet, taking into account the importance of cinacalcet to the mother.

4.7 Effects on Ability to Drive and Use Machines

Dizziness and seizures, which may have major influence on the ability to drive and use machines, have been reported by patients taking Sensipar (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Summary of safety profile.

Studies were conducted in patients with CKD receiving dialysis, and in patients with parathyroid carcinoma or primary HPT for whom parathyroidectomy is not a treatment option. Cinacalcet was safe and generally well tolerated. However, nausea and vomiting are very common adverse reactions.
Secondary hyperparathyroidism in patients with chronic kidney disease. In 3 double blind, placebo controlled clinical trials, 1,126 CKD patients on dialysis received study drug (656 cinacalcet, 470 placebo) for up to 6 months. Adverse events reported during the studies were typical for the dialysis patient population. The most frequently reported adverse events (incidence of at least 5% in the cinacalcet group) are provided in Table 1. The most frequently reported events in the cinacalcet group were nausea and vomiting which were generally mild to moderate in severity, brief in duration and infrequently led to discontinuation of study drug. Rash and hypocalcaemia have been observed.
Seizures were observed in 1.4% (13/910) of cinacalcet treated patients and 0.7% (5/641) of placebo treated patients across all completed placebo controlled trials.
The incidence of serious adverse events (29% vs 31%) and deaths (2% vs 3%) was similar in the cinacalcet and placebo groups, respectively.

12 month experience with cinacalcet.

Two hundred and sixty-six patients from the 2 pivotal phase 3 studies continued to receive cinacalcet or placebo treatment in a 6 month double blind extension study (12 month total treatment duration). The incidence and nature of adverse events in this study were similar in the 2 treatment groups, and comparable to those observed in the pivotal phase 3 studies.

Other clinical experience with Sensipar in secondary hyperparathyroidism.

In EVOLVE, a randomised, double blind placebo controlled study of 3,883 patients with secondary HPT and CKD receiving dialysis in which patients were treated for up to 64 months, the most frequently reported adverse reactions (incidence of ≥ 5% in the Sensipar group and ≥ 1% compared to placebo) were nausea, vomiting, diarrhoea, dyspnoea, cough, hypotension, headache, hypocalcaemia, muscle spasms, abdominal pain, abdominal pain-upper, hyperkalaemia, upper respiratory tract infection, dyspepsia, dizziness, decreased appetite, asthenia and constipation.
Additional adverse event rates for Sensipar vs placebo are as follows: seizure (2.5%, 1.6%), rash (2.2%, 1.9%), and hypersensitivity reactions (9.4%, 8.3%).
Parathyroid carcinoma and primary HPT for whom parathyroidectomy is not a treatment option. Overall, the safety profile in patients with parathyroid carcinoma or intractable (failed or contraindicated to surgery) primary HPT was similar to that seen in patients with CKD and secondary HPT; the most frequent adverse events in this patient group were nausea and vomiting.

Summary of the safety of cinacalcet in subjects with primary HPT.

The safety profile of cinacalcet was similar across the 5 studies in primary HPT. Overall, common adverse events observed in these studies included gastrointestinal events (nausea, vomiting, abdominal pain), headache, paraesthesia, anxiety, asthenia, dizziness, and arthralgia. Most adverse events were mild to moderate in severity. The most common event considered related to cinacalcet was nausea, which was also the most common adverse event leading to withdrawal. The safety profile of cinacalcet in this subject population was generally consistent with that in subjects with CKD and no unique safety concern was identified for cinacalcet in the treatment of primary HPT.
Seizures were observed in 0.7% (1/140) of cinacalcet treated patients and 0.0% (0/46) of placebo treated patients in all clinical studies.

Postmarketing data.

Spontaneous postmarketing reports have been received describing diarrhoea, myalgia, rash, seizures, gastrointestinal bleeding, chondrocalcinosis pyrophosphate and hypersensitivity reactions, including angioedema and urticaria, in association with cinacalcet HCl administration.
Isolated idiosyncratic cases of hypotension and/or worsening of heart failure have been reported in cinacalcet treated patients with impaired cardiac function in postmarketing safety surveillance.
Common: between 1% and 10%; uncommon: between 0.1% and 1%; rare: between 0.01% and 0.1%; very rare: between 0.001% and 0.01%.

Immune system disorders.

Uncommon: hypersensitivity reactions.

Skin and subcutaneous tissue disorders.

Common: rash. Very rare: angioedema and urticaria.

Gastrointestinal disorders.

Rare: diarrhoea.

Musculoskeletal and connective tissue disorders.

Rare: myalgia. Common: back pain.

Laboratory values.

Low laboratory serum calcium levels were very common in clinical studies. Serum calcium levels should be monitored in patients receiving cinacalcet (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Serum calcium).

Reporting of suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Doses titrated up to 300 mg once daily have been safely administered to patients receiving dialysis. Overdosage of cinacalcet may lead to hypocalcaemia. In the event of overdosage, patients should be monitored for signs and symptoms of hypocalcaemia and appropriate measures taken to correct serum calcium levels (see Section 4.4 Special Warnings and Precautions for Use).
Since cinacalcet is highly protein bound, haemodialysis is not an effective treatment for overdosage of cinacalcet.
In case of overdose, immediately contact the Poisons Information Centre (in Australia, call 13 11 26) for advice.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Cinacalcet is a calcimimetic agent that increases the sensitivity of the calcium sensing receptor to extracellular calcium. Cinacalcet reduces PTH while simultaneously lowering Ca x P, calcium and phosphorus levels in chronic kidney disease in patients receiving dialysis.
Secondary HPT is a progressive disease, which occurs in patients with CKD and manifests as increases in PTH levels and derangements in calcium and phosphorus metabolism. Increased PTH stimulates osteoclastic activity resulting in cortical bone resorption and marrow fibrosis. The calcium sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH secretion. Cinacalcet directly lowers PTH levels by increasing the sensitivity of the calcium sensing receptor to extracellular calcium. The reduction in PTH is associated with a concomitant decrease in serum calcium levels.
In CKD patients with uncontrolled secondary HPT, reductions in PTH were associated with a favourable impact on bone specific alkaline phosphatase (BALP), N-telopeptide (N-Tx), bone turnover, bone fibrosis and incidence of bone fracture.
Studies in a rat model of chronic renal insufficiency (CRI) (5/6 nephrectomy) assessed the effects of cinacalcet treatment on parathyroid gland hyperplasia. Cinacalcet treatment reduced PTH and parathyroid cell proliferation to levels comparable to vehicle treated, non-nephrectomised animals, demonstrating that cinacalcet prevented the development of secondary HPT.

Pharmacodynamics.

Reductions in PTH levels correlate with cinacalcet concentrations. Nadir PTH occurs approximately 2 to 6 hours postdose, corresponding with cinacalcet Cmax. After steady state is reached, serum calcium concentrations remain constant over the dosing interval.

Clinical trials.

Secondary hyperparathyroidism in patients with chronic kidney disease.

Three 6 month, multicentre, randomised, double blind, placebo controlled clinical studies were conducted in CKD patients receiving dialysis with uncontrolled secondary HPT (n = 665 on cinacalcet, 471 on placebo). The patient population consisted of both recently established and long standing dialysis patients, with a range of 1 to 359 months. Cinacalcet was administered either alone or in combination with vitamin D sterols; 34% of patients were not receiving vitamin D sterols at study entry. The majority (more than 90%) of patients were receiving phosphate binders. Dose adjustments in phosphate binder therapy were permitted throughout the study. Vitamin D doses remained constant unless the patient developed hypercalcaemia, hypocalcaemia or hyperphosphataemia. Patients continued on their previously prescribed drugs including: calcium channel blockers, ACE inhibitors, beta-blockers, hypoglycaemics, and lipid lowering agents. Cinacalcet (or placebo) was initiated at a dose of 30 mg and titrated every 3 or 4 weeks to a maximum dose of 180 mg once daily to achieve an iPTH of 10.6 to 26.5 picomol/L (1.5 to 4 times the upper limit of normal). The severity of secondary HPT ranged from mild to severe (iPTH values of 28.8 to 969.5 picomol/L), with mean (SE) baseline iPTH concentrations across the 3 studies of 77.8 (2.2) and 72.5 (2.0) picomol/L for the cinacalcet and placebo groups, respectively. Significant reductions in iPTH, serum calcium-phosphorus product (Ca x P), calcium, and phosphorus were observed in the cinacalcet treated patients compared with placebo treated patients receiving standard of care, and the results were consistent across the 3 studies (Table 2).
Mean iPTH and Ca x P by treatment group for the overall study population during the 6-month treatment period are presented in Figure 1 and Figure 2.
In patients receiving cinacalcet, reductions in iPTH and Ca x P occurred within 2 weeks and were maintained for at least 12 months of treatment (n = 99 on cinacalcet, 111 on placebo).
Cinacalcet decreased iPTH and Ca x P levels regardless of disease severity (i.e. baseline iPTH value), dialysis modality (PD vs HD), duration of dialysis, and whether or not vitamin D sterols were administered. Approximately 60% of patients with mild (iPTH from 31.8 to 53.0 picomol/L), moderate (iPTH between 53.0 and 84.8 picomol/L) or severe (iPTH above 84.8 picomol/L) secondary HPT achieved at least a 30% reduction in iPTH levels. Cinacalcet treatment also reduced iPTH and Ca x P in patients with elevated Ca x P levels.
The impact of cinacalcet on bone disease, including the risk of adynamic bone disease, has not been conclusively evaluated.
The pivotal clinical studies were designed to evaluate the effect of cinacalcet on biochemical parameters, including PTH, serum calcium and phosphorus. Clinical outcomes such as quality of life, rate of parathyroidectomy, symptomatic bone disease, hospitalisation, or mortality were not prespecified endpoints and were not evaluated within individual studies. The pivotal efficacy and safety studies in patients with secondary hyperparathyroidism of chronic kidney disease, requiring dialysis did not examine quality of life benefits. There were no differences between cinacalcet and placebo treated patients in terms of statistically significant differences in self reported cognitive functioning scale scores during the efficacy assessment phase.
EVOLVE (EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events) was a randomised, double blind clinical study evaluating cinacalcet HCl vs. placebo for the reduction of the risk of all cause mortality and cardiovascular events in 3,883 patients with secondary HPT and CKD receiving dialysis. The study did not meet its primary objective of demonstrating a reduction in risk of all cause mortality or cardiovascular events including myocardial infarction, hospitalisation for unstable angina, heart failure or peripheral vascular event (HR 0.93; 95% CI: 0.85, 1.02; p = 0.112). Because the primary composite endpoint did not reach statistical significance, secondary endpoints were not tested for statistical significance. Primary and secondary endpoints are shown in Table 3.

Parathyroid carcinoma.

Twenty-nine patients with parathyroid carcinoma were enrolled in an open label study. Parathyroid carcinoma and severe hypercalcaemia in these patients was persistent despite previous parathyroidectomy and bisphosphonate therapy. The study consisted of two phases, a dose titration phase and a maintenance phase. Cinacalcet was administered at doses ranging from 30 mg twice daily to 90 mg four times daily, and mean serum calcium declined from 3.53 to 3.10 mmol/L across the titration phase (up to 16 weeks). Sixty-two percent of patients (18 of 29) achieved a reduction in serum calcium of at least 0.25 mmol/L.

Primary HPT for whom parathyroidectomy is not a treatment option.

Seventeen patients with primary HPT for whom parathyroidectomy was not a treatment option were enrolled in an open label study. The study consisted of two phases, a dose titration phase and a maintenance phase. Cinacalcet was administered at doses ranging from 30 mg twice daily to 90 mg four times daily, and mean serum calcium declined from 3.18 to 2.60 mmol/L across the titration phase (up to 16 weeks). Eighty-eight percent of patients (15 of 17) achieved a reduction in serum calcium of at least 0.25 mmol/L.
An additional 114 patients with primary HPT and hypercalcaemia, including 25 patients with recurrent primary HPT after parathyroidectomy, were enrolled in 3 controlled studies and one open label study. In one study of 45 patients with primary HPT, including 12 patients with recurrent primary HPT after parathyroidectomy cinacalcet normalised serum calcium in approximately 80% of patients, and this was sustained for up to 3 years.

5.2 Pharmacokinetic Properties

Absorption.

After oral administration of cinacalcet, maximum plasma concentration is achieved in approximately 2 to 6 hours. The absolute bioavailability of cinacalcet is approximately 25%. Administration of cinacalcet with food results in an approximate 50 to 80% increase in bioavailability. Increases in plasma concentrations are similar, regardless of the fat content of the meal.
After absorption, cinacalcet concentrations decline in a biphasic fashion with an initial half-life of approximately 6 hours and a terminal half-life of 30 to 40 hours. Steady-state drug levels are achieved within 7 days with minimal accumulation. The AUC and Cmax of cinacalcet increase linearly over the once daily dose range of 30 to 180 mg. The pharmacokinetics of cinacalcet do not change over time.

Distribution.

The volume of distribution is high (approximately 1,000 L), indicating extensive distribution. Cinacalcet in plasma is approximately 97% bound to plasma proteins and in whole blood, cinacalcet distributes minimally into red blood cells.

Metabolism.

Cinacalcet is metabolised by multiple enzymes, primarily CYP3A4, CYP1A2 and CYP2D6. The major circulating metabolites are inactive. After administration of a 75 mg radiolabelled dose to healthy volunteers, cinacalcet was rapidly and extensively metabolised by oxidation followed by conjugation.

Excretion.

Renal excretion of metabolites was the prevalent route of elimination of radioactivity. Approximately 80% of the dose was recovered in the urine and 15% in the faeces.

Special populations.

Hepatic impairment.

Mild hepatic impairment did not alter the pharmacokinetics of cinacalcet. Compared to subjects with normal liver function, average AUC of cinacalcet was approximately 2 times higher in subjects with moderate impairment and approximately 4 times higher in subjects with severe impairment (see Section 4.4 Special Warnings and Precautions for Use). Because doses are titrated for each subject based on safety and efficacy parameters, no additional dose adjustment is necessary for subjects with hepatic impairment.

Renal impairment.

The pharmacokinetic profile of cinacalcet in patients with mild, moderate, and severe renal insufficiency, and those on haemodialysis or peritoneal dialysis is comparable to that in healthy volunteers. No dosage adjustment based on the degree of renal function is necessary.

Geriatric patients.

There are no clinically relevant differences due to age in the pharmacokinetics of cinacalcet. No dosage adjustment based on age is necessary.

Paediatric patients.

The safety and efficacy of cinacalcet has not been studied in children and are not established. A single dose pharmacokinetic study has been completed in paediatric patients 6-17 years of age (N = 12). The pharmacokinetic parameters following a 15 mg dose are summarised in Table 4.
Whilst a 15 mg dose of cinacalcet was used in the paediatric PK study, this dose strength is not registered.
Six of the twelve subjects experienced decreases in serum calcium below the lower limit of normal (2.23 mmol/L). In these six subjects, baseline values were in the range of 2.20 to 2.52 mmol/L and the decreased values were in the range of 2.00 to 2.22 mmol/L. In the same study, QT interval prolongation, assessed as unrelated to cinacalcet, was reported in one of the twelve subjects.
The use of multiple doses in paediatric subjects has not been studied. On the basis of these limited data, there is a potential for higher exposures and greater pharmacodynamic effects in the lighter/younger relative to the heavier/old paediatric subjects when treated with identical doses of cinacalcet (see Section 4.4 Special Warnings and Precautions for Use, Serum calcium).

5.3 Preclinical Safety Data

Genotoxicity.

Cinacalcet was negative in the Ames assay, Chinese Hamster Ovary HGPT forward mutation assay, in vitro chromosome aberration assay and the mouse micronucleus assay. These tests indicate that cinacalcet is unlikely to pose a genotoxic risk to humans.

Carcinogenicity.

Cinacalcet, administered orally at dietary doses up to 200 mg/kg to mice and 35 mg/kg/day to rats for 104 weeks, showed no evidence of carcinogenic potential. These doses resulted in total systemic exposure (AUCs) approximately equivalent to the exposures observed in humans given the maximum dose of 360 mg/day. A decreased incidence of thyroid C-cell adenomas was observed in rats treated with cinacalcet.

6 Pharmaceutical Particulars

6.1 List of Excipients

Pregelatinised maize starch, microcrystalline cellulose, povidone, crospovidone, colloidal anhydrous silica and magnesium stearate. Tablets are coated with Opadry II complete film coating system 32K11479 green, Opadry complete film coating system YS‐1‐19025‐A ‐ clear and carnauba wax.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Sensipar 30 mg, 60 mg and 90 mg tablets are packaged in PVC/PCTFE (Aclar)/Al blister packs of 28 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Cinacalcet hydrochloride is described chemically as N-[1-(R)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-aminopropane hydrochloride and has the following structural formula:

Chemical structure.


The empirical formula of cinacalcet hydrochloride is C22H22F3N.HCl and it has a molecular weight of 393.9 g/mol (hydrochloride salt) and 357.4 g/mol (free base). It has one chiral centre having an R-absolute configuration. The R-enantiomer is the more potent enantiomer and has been shown to be responsible for pharmacodynamic activity.
Cinacalcet hydrochloride is a white to off-white, crystalline solid that is soluble in methanol or 95% ethanol and poorly soluble in water.

CAS number.

364782-34-3.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes