Terrosa 20 micrograms/80 microliters solution for injection

Removal of black triangle and assocaited wording:

This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects.

Section 2

Do not use Terrosa

• if you are allergic to teriparatide or any of the other ingredients of this medicine (listed in section 6).
• if you have high levels of calcium in your blood (pre-existing hypercalcaemia).
• if you suffer from serious kidney problems.
• if you have ever had bone cancer or if other cancers have spread (metastasised) to your bones.
• if you have certain bone diseases. If you have a bone disease, tell your doctor.
• if you have unexplained high levels of alkaline phosphatase in your blood, which means you might have Paget’s disease of bone (disease with abnormal bone changes). If you are not sure, ask your doctor.
• if you have had radiation therapy involving your bones.

• if you are pregnant or breast-feeding.

Warnings and precautions

Terrosa may increase calcium in your blood or urine.

Talk to your doctor before or while using Terrosa:

• if you have continuing nausea, vomiting, constipation, low energy, or muscle weakness. These may be signs there is too much calcium in your blood.
• if you suffer from kidney stones or have had kidney stones.
• if you suffer from kidney problems (moderate renal impairment).

Some patients get dizzy or get a fast heartbeat after the first few doses of Terrosa. For the first doses, inject Terrosa in a place where you can sit or lie down right away if you get dizzy.

The recommended treatment time of 24  months should not be exceeded.

Before inserting a cartridge in Terrosa Pen write down the batch (Lot) number of the cartridge and its first injection date on a calendar. The date of first injection should also be recorded on the outer carton of Terrosa (see the provided space on the box: {First use:}) (see section 3.).cartridge and provide this information when reporting any side effects.

Pregnancy and breast-feeding

Do not use Terrosa if you are pregnant or breast-feeding. If you are a woman of child-bearing potential, you should use effective methods of contraception during use of Terrosa. If you become pregnant while using Terrosa, Terrosa should be discontinued. Ask your doctor or pharmacist for advice before taking anythis medicine.

Terrosa contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per dosage unitdose, that is to say essentially “sodium-free”.

Section 3

Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

The recommended dose is 20 micrograms (corresponding to 80 microliters) given once a day by injection under the skin (subcutaneous injection) in the thigh or abdomen.

To help you remember to takeuse your medicine, inject it at about the same time each day. Terrosa can be injected at meal times. Inject Terrosa each day for as long as your doctor prescribes it for you. The total duration of treatment with Terrosa should not exceed 24 months. You should not receive more than one treatment course of 24 months over your lifetime.

Your doctor may advise you to takeuse Terrosa with calcium and vitamin D. Your doctor will tell you how much you should take each day.

Terrosa can be given with or without food.

Terrosa cartridges are designed to be used only with the Terrosa Pen reusable, multidose medicine delivery system and compatible pen needles. The pen and injection needles are not included with Terrosa. However, for treatment initiation a cartridge and pen pack should be used containing one inner carton of Terrosa cartridge and one inner carton of Terrosa Pen.

The pen can be used with injection needles developed according to the pen needle ISO standard of a gauge between 29 G and 31 G (diameter 0.25 – 0.33 mm) and a length between 5 mm to 12.7 mm for subcutaneous injection only.

Before the first use, insert the cartridge into the pen. For the correct use of this medicine it is very important to closely follow the detailed Instructions for Use of your pen which are provided with the pen.

Use a new injection needle for each injection to prevent contamination and safely dispose of the needle after use.

Never store your pen with the needle attached.

Never share your pen with others.

Do not use your Terrosa Pen to inject any other medicine (e.g. insulin).

The pen is customised for use with Terrosa only.

Do not refill the cartridge.

Do not transfer the medicine into a syringe.

You should inject Terrosa shortly after you take the pen with inserted cartridge out of the refrigerator. Put the pen with inserted cartridge back into the refrigerator immediately after you have used it. Do not remove the cartridge from the pen after each use. Store it in the cartridge sleeveholder during the whole 28-day treatment period.

Section 4   Possible Side Effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The most common side effects are pain in limb (whichfrequency is very common, may affect more than 1 in 10 people). Other common side effects (affecting up to 1 in 10 people) include feeling sick, headache and dizziness. If you become dizzy (light-headed) after your injection, you should sit or lie down until you feel better. If you do not feel better, you should call a doctor before you continue treatment. Cases of fainting have occuredoccurred after teriparatide use.

If you have discomfort around the area of the injection such as redness of the skin, pain, swelling, itching, bruising or minor bleeding (which can occur in up to 1 in 10 peoplecommonly), this should clear up in a few days or weeks. Otherwise tell your doctor.

Rarely,Rarely (may affect up to 1 in 1 000 people), some patients may suffer allergic reactions consisting of breathlessness, swelling of the face, rash and chest pain. These reactions usually occur soon after injection. In rare cases, serious and potentially life-threatening allergic reactions including anaphylaxis can occur.

Other side effects include:

Common (may affect up to 1 in 10 people):)

• increase in blood cholesterol levels
• depression
• nerve pain in the leg
• feeling faint
• spinning sensation
• irregular heartbeats
• breathlessness
• increased sweating
• muscle cramps
• loss of energy
• tiredness
• chest pain
• low blood pressure
• heartburn (painful or burning sensation just below the breast bone)
• vomiting
• a hernia of the tube that carries food to your stomach (hiatus hernia)
• low haemoglobin or red blood cell count (anaemia).

Uncommon (may affect up to 1 in 100 people):)

• increased heart rate
• abnormal heart sound
• shortness of breath
• piles (haemorrhoids)
• leakage of urine
• increased need to pass water
• weight increase
• kidney stones
• pain in the muscles and pain in the joints. Some patients have had severe back cramps or pain which led to admission into hospital.
• increase in blood calcium level
• increase in blood uric acid level
• increase in an enzyme called alkaline phosphatase.

Rare (may affect up to 1 in 1, 000 people):)

• reduced kidney function, including renal failure
• swelling, mainly in the hands, feet and legs.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly (see details below).via HPRA Pharmacovigilance, Website: www.hpra.ie. By reporting side effects you can help provide more information on the safety of this medicine.

United Kingdom:Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Ireland: HPRA Pharmacovigilance

Website: www.hpra.ie

Section 6

What Terrosa contains

• The active substance is teriparatide. Each dose of 80 microliters contains 20 micrograms of teriparatide. One cartridge of 2.4 mL contains 600 micrograms of teriparatide (corresponding to 250 micrograms per mL).
• The other ingredients are: glacial acetic acid, mannitol, metacresol, sodium acetate trihydrate, hydrochloric acid (for pH adjustment), sodium hydroxide (for pH adjustment), water for injections. (see section 2 “Terrosa contains sodium”).

What Terrosa looks like and contents of the pack

Terrosa is a colourless and clear solution. for injection (injection). It is supplied in a cartridge. Each cartridge contains 2.4 mL of solution, enough for 28 doses.

Terrosa 20 micrograms/80 microliters solution for injection: 1 or 3 cartridge(s)Pack sizes:1 cartridge or 3 cartridges packed in a plastic tray sealed with lid foil and packed in a carton.

Terrosa cartridge and pen pack: 1 Terrosa cartridge packed in a plastic tray sealed with lid foil and packed in aan inner carton and 1 Terrosa Pen packed into a separatein an inner carton.

This leaflet was last revised in September 202009/2021.

 

Removal of black inverted triangle and associated wording:

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

Section 3 Pharmaceutical Form

Solution for injection. (injection).

Section 4.2 Posology and method of administration 

Elderly

DosageDose adjustment based on age is not required (see section 5.2).

Method of administration

Terrosa should be administered once daily by subcutaneous injection in the thigh or abdomen.

It should be administered exclusively with the Terrosa Pen reusable, multidose medicine delivery system and the injection needles which are listed as compatible in the instructions which are provided with the pen. The pen and injection needles are not included with Terrosa. However, for the treatment initiation a cartridge and pen pack should be used containing one carton of Terrosa cartridge and one carton of Terrosa Pen. Terrosa must not be used with any other pen.

Patients must be trained to use the proper injection techniques (. For instructions of the medicinal product, before administration, see section 6.6). An instruction and IFU at the end of the package leaflet. Instructions for use which is included in the carton of the delivery systemTerrosa Pen, which are provided with the pen is also available to instruct patients on the correct use of the pen.

The date of first injection should also be written on the outer carton of Terrosa (see the provided space on the box: {First use:}).

Excipient

 

This medicinal product contains less than 1 mmol sodium (23 mg) per dosage unitdose, that is to say essentially “sodium-free”.

4.4 Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Excipient

This medicinal product contains less than 1 mmol sodium (23 mg) per dosage unitdose, that is to say essentially “sodium-free”.

4.8 Undesirable effects

The adverse reactions associated with the use of teriparatide in osteoporosis clinical trials and post-‑marketing exposure are summarised in the table belowTable 1.

The following convention has been used for the classification of the adverse reactions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1, 000 to <1/100), and rare (≥1/10, 000 to <1/1, 000).

Table 1. Adverse drug reactions

Organ System Classorgan class	Very common	Common	Uncommon	Rare
Blood and lymphatic system disorders		Anaemia
Immune system disorders				Anaphylaxis
Metabolism and nutrition disorders		Hypercholesterol-aemiaHypercholesterolaemia	Hypercalcaemia greater than 2.76 mmol/L, hyperuricaemia	Hypercalcaemia greater than 3.25 mmol/L
Psychiatric disorders		Depression
Nervous system disorders		Dizziness, headache, sciatica, syncope
Ear and labyrinth disorders		Vertigo
Cardiac disorders		Palpitations	Tachycardia
Vascular disorders		Hypotension
Respiratory, thoracic and mediastinal disorders		Dyspnoea	Emphysema
Gastrointestinal disorders		Nausea, vomiting, hiatus hernia, gastro-oesophageal reflux disease	Haemorrhoids
Skin and subcutaneous tissue disorders		Sweating increased
Musculoskeletal and connective tissue disorders	Pain in limb	Muscle cramps	Myalgia, arthralgia, back cramp/pain*
Renal and urinary disorders			Urinary incontinence, polyuria, micturition urgency, nephrolithiasis	Renal failure/impairment
General disorders and administration site condition		Fatigue, chest pain, asthenia, mild and transient injection site events, including pain, swelling, erythema, localised bruising, pruritus and minor bleeding at injection site	Injection site erythema, injection site reaction	Possible allergic events soon after injection: acute dyspnoea, oro/facial oedema, generalised urticaria, chest pain, oedema (mainly peripheral)
Investigations			Weight increased, cardiac murmur, alkaline phosphatase increased

5.1 Pharmacodynamic properties

Postmenopausal osteoporosis

The pivotal study included 1, 637 postmenopausal women (mean age 69.5  years). At baseline, ninety percent of the patients had one or more vertebral fractures, and on average, vertebral BMD was 0.82 g/cm² (equivalent to a T-score = - 2.6). All patients were offered 10001 000 mg calcium per day and at least 400 IU vitamin D per day. Results from up to 24 months (median: 19 months) treatment with teriparatide demonstrate statistically significant fracture reduction (Table 12). To prevent one or more new vertebral fractures, 11 women had to be treated for a median of 19 months.

Table 12. Fracture incidence in postmenopausal women

Fracture incidence in postmenopausal women
	Placebo (N = 544) (%)	Teriparatide (N = 541) (%)	Relative risk (95% CI) vs. placebo
New vertebral fracture (≥1) a	14.3	5.0 b	0.35 (0.22, 0.55)
Multiple vertebral fractures (≥2) a	4.9	1.1 b	0.23 (0.09, 0.60)
Non-vertebral fragility fractures c	5.5%	2.6% d	0.47 (0.25, 0.87)
Major non-vertebral fragility fracturescfractures (hip, radius, humerus, ribs and pelvis)	3.9%	1.5% d	0.38 (0.17, 0.86)

Abbreviations: N = number of patients randomly assigned to each treatment group; CI = confidence interval.

^a The incidence of vertebral fractures was assessed in 448 placebo and 444 teriparatide patients who had baseline and follow-up spine radiographs.

^b p≤0.001 compared with placebo.

^c A significant reduction in the incidence of hip fractures has not been demonstrated.

^d p≤0.025 compared with placebo.

After 19 months (median) treatment, bone mineral density (BMD) had increased in the lumbar spine and total hip, respectively, by 9% and 4% compared with placebo (p<0.001).

Post-treatment management: Following treatment with teriparatide, 1, 262 postmenopausal women from the pivotal trial enrolled in a post-treatment follow-up study. The primary objective of the study was to collect safety data of teriparatide. During this observational period, other osteoporosis treatments were allowed and additional assessment of vertebral fractures was performed.

During a median of 18 months following discontinuation of teriparatide, there was a 41% reduction (p=0.004) compared with placebo in the number of patients with a minimum of one new vertebral fracture.

In an open-label study, 503 postmenopausal women with severe osteoporosis and a fragility fracture within the previous 3 years (83% had received previous osteoporosis therapy) were treated with teriparatide for up to 24 months. At 24 months, the mean increase from baseline in lumbar spine, total hip and femoral neck BMD was 10.5%, 2.6 % and 3.9% respectively. The mean increase in BMD from 18 to 24 months was 1.4%, 1.2%, and 1.6% at the lumbar spine, total hip and femoral neck, respectively.

A 24-month, randomised, double-blind, comparator-controlled Phase 4 study included 1, 360 postmenopausal women with established osteoporosis. 680 subjects were randomised to teriparatide and 680 subjects were randomised to oral risedronate 35 mg/week. At baseline, the women had a mean age of 72.1 years and a median of 2 prevalent vertebral fractures; 57.9% of patients had received previous bisphosphonate therapy and 18.8% took concomitant glucocorticoids during the study. 1, 013 (74.5%) patients completed the 24-month follow-up. The mean (median) cumulative dose of glucocorticoid was 474.3 (66.2) mg in the teriparatide arm and 898.0 (100.0) mg in the risedronate arm. The mean (median) vitamin D intake for the teriparatide arm was 14331 433 IU/day (14001 400 IU/day) and for the risedronate arm was 11911 191 IU/day (900 IU/day). For those subjects who had baseline and follow-up spine radiographs, the incidence of new vertebral fractures was 28/516 (5.4%) in teriparatide- and 64/533 (12.0%) in risedronate-treated patients, relative risk (95% CI) = 0.44 (0.29-0.68), p<0.0001. The cumulative incidence of pooled clinical fractures (clinical vertebral and non ‑vertebral fractures) was 4.8% in teriparatide and 9.8% in risedronate-treated patients, hazard ratio (95% CI) = 0.48 (0.32-0.74), p=0.0009.

Male osteoporosis

437 patients (mean age 58.7 years) were enrolled in a clinical trial for men with hypogonadal (defined as low morning free testosterone or an elevated FSH or LH) or idiopathic osteoporosis. Baseline spinal and femoral neck bone mineral densityBMD mean T-scores were -2.2 and -2.1, respectively. At baseline, 35% of patients had a vertebral fracture and 59% had a non-vertebral fracture.

All patients were offered 10001 000 mg calcium per day and at least 400 IU vitamin D per day. Lumbar spine BMD significantly increased by 3 months. After 12 months, BMD had increased in the lumbar spine and total hip by 5% and 1%, respectively, compared with placebo. However, no significant effect on fracture rates was demonstrated.

5.2 Pharmacokinetic properties

Elderly

No differences in teriparatide pharmacokinetics were detected with regard to age (range 31 to 85 years). DosageDose adjustment based on age is not required.

6.5 Nature and contetnes of container

3 mL cartridge (siliconised Type I glass), with a plunger stopper and disc seal (aluminium and rubber liner seals), packed in a plastic tray sealed with lid foil and packed in a carton.

Each cartridge contains 2.4 mL of solution corresponding to 28 doses of 20 micrograms (per 80 microliters).

Pack sizes:

Terrosa 20 micrograms/80 microliters solution for injection:

1 cartridge or 3 cartridges.

Terrosa cartridge and pen pack:

1 inner carton of Terrosa cartridge (containing 1 cartridge) and 1 inner carton of Terrosa Pen (containing 1 pen).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling 

Terrosa solution for injection is supplied in a cartridge. Terrosa cartridges are to be used in Terrosa Pen reusable, multidose pen device exclusively and . Terrosa cartridges must not be used with any other pen. NoThe pen and injection needles are suppliednot included with this medicinal product. However, for the treatment initiation a cartridge and pen pack should be used containing one carton of Terrosa cartridge and one carton of Terrosa Pen.

Each cartridge and pen should be used by only one patient. The pen can be used with compatible pen injection needles. These are listed in developed according to the instructionpen needle ISO standard of a gauge between 29 G and 31 G (diameter 0.25 – 0.33 mm) and a length between 5 mm to 12.7 mm for use for the pen. subcutaneous injection only.

A new, sterile pen needle must be used for every injection.

The expiry date on the cartridge label must always be checked before inserting the cartridge into Terrosa Pen. To avoid medication errors, make sure that the date when starting to use a new cartridge is at least 28 days before its expiry date.

The date of first injection should also be written on the outer carton of Terrosa (see the provided space on the box: {First use:}).

Before using the pen device for the first time, the patient should read and understand the instructions on how to use the pen which are provided with the pen.

After each injection, the pen should be returned to the refrigerator. After the first use, the cartridge should not be removed from the pen during the 28 days of usage.

Each cartridge should be properly disposed of after 28 days of first use, even if it is not completely empty.

Terrosa solution for injection must not be transferred to a syringe.

Empty cartridges must not be refilled.

Terrosa should not be used if the solution is cloudy, coloured or contains visible particles.

Any unused product or waste material should be disposed of in accordance with local requirements.

10. Date of revision of the text

17 September 2020

16/09/2021