medication_name stringlengths 6 170 | section_title stringclasses 42 values | text stringlengths 0 47.1k |
|---|---|---|
Deponit 10 mg/24 h transdermal patch | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Concomitant treatment with other vasodilators (e.g. phosphodiesterase inhibitors such as sildenafil, vardenafil, tadalafil), calcium channel antagonists, ACE-inhibitors, monoamine oxidase inhibitors, beta-blockers, diuretics, antihypertensives, tricyclic antidepressants and major tranquillisers, as well as the consumption of alcohol, may potentiate the hypotensive effect of the preparation.
The blood pressure lowering effect of these patches will be increased if used together with phosphodiesterase inhibitors (e.g. sildenafil, vardenafil, tadalafil) which are used for erectile dysfunction (see Section 4.3). This might lead to life threatening cardiovascular complications. Patients who have recently taken phosphodiesterase inhibitors (e.g. sildenafil, vardenafil, tadalafil) therefore must not be treated with GTN. Patients who are on nitrate patch therapy therefore must not use phosphodiesterase inhibitors (e.g. sildenafil, vardenafil, tadalafil).
The use of GTN with riociguat, a soluble guanylate cyclase stimulator, is contraindicated (see section 4.3) since concomitant use can cause hypotension.
If administered concurrently, these patches may increase the blood level of dihydroergotamine and lead to coronary vasoconstriction.
The possibility that ingestion of non-steroidal anti-inflammatory drugs except Acetyl Salicylic acid might diminish the therapeutic response to the patch cannot be excluded.
Concurrent administration with Amifostine and acetyl salicylic acid may potentiate the hypotensive effect of the preparation.
Sapropterine (Tetrahydrobiopterine, BH4) is a cofactor for nitric oxide synthetase. Caution is recommended during concomitant use of sapropterine-containing medicine with all agents that cause vasodilation by affecting nitric oxide (NO) metabolism or action, including classical NO donors (e.g. glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), isosorbide 5-mononitrate (5-ISMN) and others).
4.6 |
Deponit 10 mg/24 h transdermal patch | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy and breast-feeding
Like any drug, Deponit 10 should be employed with caution during pregnancy, especially in the first 3 months.
These patches should not be used during pregnancy or lactation unless considered absolutely essential by the physician.
It is not known whether the active substance passes into the breast milk. Benefits to the mother must be weighed against risk to the child.
Fertility
Reproduction toxicity studies performed in rats and rabbits using various routes of administration did not reveal any effect on mating, fertility and general reproductive parameters. There is no data available on the effect of Deponit 10 on fertility in humans.
4.7 |
Deponit 10 mg/24 h transdermal patch | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Glyceryl trinitrate can cause postural hypotension and dizziness. Patients should not drive or operate machinery if they feel affected.
4.8 |
Deponit 10 mg/24 h transdermal patch | Clinical particulars - Undesirable effects | Undesirable effects |
Deponit 10 mg/24 h transdermal patch | Clinical particulars - Overdose | Undesirable effects frequencies are defined as: very common (≥1/10), common (≥1/100,<1/10), uncommon (≥1/1,000,<1/100), rare ≥1/10,000,<1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).
During administration of Deponit 10 the following undesirable effects may be observed:
SOC
Very common (≥1/10)
Common (≥1/100,<1/10)
Uncommon (≥1/1,000,<1/100)
Rare ≥1/10,000,<1/1,000)
Very rare (<1/10,000)
Not known (cannot be estimated from the available data)
Nervous system disorders
Headache
Dizziness (including dizziness postural), somnolence
Cardiac disorders
Tachycardia
Enhanced angina pectoris symptoms
Palpitations
Vascular disorders
Orthostatic hypotension
Circulatory collapse (sometimes accompanied by bradyarrythmia and syncope)
Flushing, hypotension
Gastrointestinal disorders
Nausea, vomiting
Heartburn
Skin and subcutaneous tissue disorders
Allergic skin reactions (e.g. rash), allergic contact dermatitis
Dermatitis exfoliative, rash generalized
General disorders and administration site conditions
Asthenia
Pruritus, pruritus at patch application site, burning, erythema, irritation
rash
Investigations
Heart rate increase
Severe hypotensive responses have been reported for organic nitrates and include nausea, vomiting, restlessness, pallor and excessive perspiration.
During the treatment with these patches, a temporary hypoxaemia may occur due to a relative redistribution of the blood flow in hypoventilated alveolar areas. Particularly in patients with coronary artery disease this may lead to a myocardial hypoxia.
Like other nitrate preparations, GTN commonly causes dose-dependent headaches due to cerebral vasodilation. These often regress after a few days despite the maintenance of therapy. If headaches persist during intermittent therapy, they should be treated with mild analgesics. Unresponsive headaches are an indication for reducing the dosage of GTN or discontinuing treatment.
A slight reflex-induced increase in heart rate can be avoided by resorting, if necessary, to combined treatment with a beta-blocker.
Upon removal of the patch, any slight reddening of the skin will usually disappear within a few hours. The application site should be changed regularly to prevent local irritation.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
By reporting side effects, you can help provide more information on the safety of this medicine.
4.9 |
Deponit 10 mg/24 h transdermal patch | Clinical particulars - Subsection 10 | Overdose
In view of the transdermal mode of delivery, an overdose of glyceryl trinitrate is unlikely to occur. However, in the unlikely event of an overdose, the symptoms could include the following:
• Fall in blood pressure ≤ 90 mmHg
• Collapse or syncope
• Paleness
• Sweating
• Weak pulse
• Reflex tachycardia
• Flushing
• Light-headedness on standing
• Headache
• Weakness
• Dizziness
• Nausea
• Vomiting
• Methaemoglobinaemia has been reported in patients receiving other organic nitrates. During glyceryl trinitrate biotransformation nitrite ions are released, which may induce methaemoglobinaemia and cyanosis with subsequent tachypnoea, anxiety, loss of consciousness and cardiac arrest. It can not be excluded that an overdose of glyceryl trinitrate may cause this adverse reaction
• In very high doses the intracranial pressure may be increased. This might lead to cerebral symptoms
General procedure:
• Since these patches are applied to the skin, removing the patch immediately stops delivery of the drug.
• General procedures in the event of nitrate-related hypotension
- Patient should be kept horizontal with the head lowered and legs raised or, if necessary, compression bandaging of the patient's legs.
- Supply oxygen
- Expand plasma volume
- For specific shock treatment admit patient to intensive care unit
Special procedure:
• Raising the blood pressure if the blood pressure is very low
• Treatment of methaemoglobinaemia
Treatment with intravenous methylene blue
- Initially 1 to 2 mg/kg, not exceeding 4 mg/kg of a 1% solution over 5 minutes.
- Repeat dose in 60 minutes if there is no response.
- Administer oxygen (if necessary)
- Initiate artificial ventilation
Treatment with methylene blue is contraindicated in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency or methaemoglobin reductase deficiency. (see also section 4.4).
Where treatment with methylene blue is contraindicated or is not effective, exchange transfusion and / or transfusion of packed red blood cells is recommended.
Resuscitation measures:
In case of signs of respiratory and circulatory arrest, initiate resuscitation measures immediately.
5. Pharmacological properties
5.1 |
Deponit 10 mg/24 h transdermal patch | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Absorption:
The transdermal absorption of glyceryl trinitrate circumvents the extensive hepatic first pass metabolism so the bioavailability is about 70% of that achieved after i.v. administration.
Distribution
The steady-state concentration in the plasma depends on the patch dosage and the corresponding rate of absorption. At a rate of absorption of 0.4 mg/h, the steady-state concentration is about 0.2 µg/l on average. Plasma protein binding is about 60%.
Metabolism
Glyceryl trinitrate is metabolized to 1,2- and 1,3-dinitroglycerols. The dinitrates exert less vasodilatory activity than glyceryl trinitrate. The contribution to the overall effect is not known. The dinitrates are further metabolized to inactive mononitrates, glyceryl and carbon dioxide. The metabolism of glyceryl trinitrate, which is effected in the liver, but also in many other cells, e.g. the red blood cells, includes the separation of one or more nitrate groups.
Elimination
The elimination half-life of glyceryl trinitrate is 2-4 min. In addition to the metabolism of glyceryl trinitrate, there is a renal excretion of the catabolites.
5.3 |
Deponit 10 mg/24 h transdermal patch | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Glyceryl trinitrate is a well-known active substance, established for more than a hundred years. Thus new preclinical studies have not been carried out with Deponit 10.
6. |
Deponit 10 mg/24 h transdermal patch | Pharmaceutical particulars - List of excipients | List of excipients
Acrylate/vinyl acetate copolymer (adhesive matrix)
Polypropylene (backing foil)
Polyethylene (siliconised release liner)
6.2 |
Deponit 10 mg/24 h transdermal patch | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Deponit 10 mg/24 h transdermal patch | Pharmaceutical particulars - Shelf life | Shelf life |
Deponit 10 mg/24 h transdermal patch | Pharmaceutical particulars - Special precautions for storage | Shelf life of the product as packaged for sale: 48 months.
6.4 |
Deponit 10 mg/24 h transdermal patch | Pharmaceutical particulars - Nature and contents of container | Special precautions for storage
Do not store above 25°C.
6.5 |
Deponit 10 mg/24 h transdermal patch | Pharmaceutical particulars - Special precautions for disposal and other handling | Nature and contents of container
Multilaminate film/foil pouch with heat-sealed edges.
28 patches per carton.
6.6 |
Deponit 10 mg/24 h transdermal patch | Pharmaceutical particulars - Subsection 7 | Special precautions for disposal and other handling
The patch should be removed from the package just before application. After removal of the protective foil, the patch should be applied to unbroken, clean and dry skin that is smooth and with few hairs. The same area of skin should not be used again for some days.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Deponit 10 mg/24 h transdermal patch | Marketing authorisation holder | Norgine Pharmaceuticals Limited
Norgine House, Widewater place,
Moorhall Road, Harefield,
Middlesex, U89 6NS, UK
8. Marketing authorisation number(s)
PL 20011/0045
9. |
Deponit 10 mg/24 h transdermal patch | Date of first authorisation/renewal of the authorisation | Date of latest renewal: 28 February 2008
10. |
Deponit 10 mg/24 h transdermal patch | Date of revision of the text | 03/2019 |
Deponit 5 mg/24 h transdermal patch | Name of the medicinal product | Deponit 5 mg/24 h transdermal patch
2. |
Deponit 5 mg/24 h transdermal patch | Qualitative and quantitative composition | One patch contains glyceryl trinitrate 18.7 mg
The average amount of glyceryl trinitrate absorbed from each patch in 24 hours is 5 mg.
For the full list of excipients, see section 6.1.
3. |
Deponit 5 mg/24 h transdermal patch | Pharmaceutical form | Transdermal patch
White, translucent square patch with convex round corners with “Deponit 5” marked on the outer face.
4. |
Deponit 5 mg/24 h transdermal patch | Clinical particulars - Therapeutic indications | Therapeutic indications
Prophylaxis of angina pectoris alone or in combination with other anti-anginal therapy.
4.2 |
Deponit 5 mg/24 h transdermal patch | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
Adults
Treatment should be initiated with one patch daily. If necessary, the dosage may be increased to two patches. The maximum daily dose is 20 mg, any increases or decreases in dose should be made gradually.
Elderly population
No specific information on use in the elderly is available, however there is no evidence to suggest that an alteration in dose is required.
Paediatric population
The safety and efficacy of Deponit patch in children has not yet been established
Method of administration
Dermal
It is recommended that the patch is applied to healthy, undamaged, relatively crease free and hairless skin. The best places to apply Deponit patches are the easily reached, fairly static areas at the front or side of the chest. However, Deponit patches may also be applied to the upper arm, thigh, abdomen or shoulder. Skin care products should not be used before applying the patch. The replacement patch should be applied to a new area of skin. Allow several days to elapse before applying a fresh patch to the same area of skin.
Tolerance may occur during chronic nitrate therapy. To avoid development of tolerance, the GTN patch should remain on the skin only for about 12-14 hours, to ensure a nitrate free interval of 10-12 hours. Additional anti-anginal therapy with drugs not containing nitro compounds should be considered for the nitrate-free interval if required.
As with any nitrate therapy, treatment with these patches should not be stopped abruptly. If the patient is being changed to another type of treatment, the two should overlap.
4.3 |
Deponit 5 mg/24 h transdermal patch | Clinical particulars - Contraindications | Contraindications
• Hypersensitivity to the active substance, to other nitro compounds or to any of the excipients listed in section 6.1
• Raised intracranial pressure including that caused by head trauma or cerebral haemorrhage
• Acute circulatory failure associated with marked hypotension (shock).
• Myocardial insufficiency due to obstruction, as in aortic or mitral stenosis or constrictive pericarditis.
• Marked anaemia
• Closed angle glaucoma
• Severe Hypotensive conditions (systolic blood pressure less than 90mmHg)
• Severe hypovolaemia
• Hypertrophic obstructive cardiomyopathy
• Aortic stenosis and mitral stenosis
• Constrictive pericarditis
• Cardiac tamponade
• Concomitant use of phosphodiesterase type-5 inhibitors. Phosphodiesterase type-5 inhibitors (e.g. sildenafil, tadalafil, vardenafil) have been shown to potentiate the hypotensive effects of nitrates, and their co-administration with nitrates or nitric oxide donors is therefore contra-indicated.
• During nitrate therapy, the soluble guanylate cyclase stimulator riociguat must not be used (see section 4.5).
4.4 |
Deponit 5 mg/24 h transdermal patch | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Warnings:
In cases of recent myocardial infarction or acute heart failure, treatment with the preparation should be carried out cautiously under strict medical surveillance and/or haemodynamic monitoring.
Removal of the patch should be considered as part of the management of patients who develop significant hypotension.
Precautions:
This patch should be used with caution in patients with
• Severe hepatic or renal impairment
• Hypothyroidism
• Hypothermia
• Malnutrition
• A recent history of myocardial infarction
• Hypoxaemia or a ventilation/perfusion imbalance due to lung disease or ischaemic heart failure.
• Arterial Hypoxaemia due to severe anaemia (including G6PD deficiency induced forms), because in such patients the biotransformation of nitroglycerin is reduced.
• Alveolar hypoventilation a vasoconstriction occurs within the lung to shift perfusion from areas of alveolar hypoxia to better ventilated regions of the lung (Von Euler–Liljestrand mechanism).
• Angina pectoris, myocardial infarction, or cerebral ischaemia frequently suffer from abnormalities of the small airways (especially alveolar hypoxia).Under these circumstances vasoconstriction occurs within the lung to shift perfusion from areas of alveolar hypoxia to better ventilated regions of the lung. As a potent vasodilator, nitroglycerin could reverse this protective vasoconstriction and thus result in increased perfusion of poorly ventilated areas, worsening of the ventilation/perfusion imbalance, and a further decrease in the arterial partial pressure of oxygen.
• Methemoglobinemia
Following treatment with GTN, methemoglobinemia has been reported. Treatment of methaemoglobinemia with methylene blue is contraindicated in patients with glucose-6-phosphate deficiency or methemoglobin-reductase deficiency (see also section 4.9).
The patch is not indicated for use in acute angina attacks. In the event of an acute angina attack, sublingual treatment such as a spray or tablet should be used.
As with all nitrate preparations withdrawal of long-term treatment should be gradual by replacement with decreasing doses of long acting oral nitrates.
Also when transferring the patient on long-term therapy to another form of medication, nitroglycerin should be gradually withdrawn and overlapping treatment started.
If the patches are not used as indicated (see Section 4.2) tolerance to the medication could develop.
Patients should be warned not to discontinue or interrupt GTN patch therapy in order to use phosphodiesterase inhibitor-containing products (e. g. sildenafil, vardenafil, tadalafil).
During treatment with GTN alcohol should be avoided as it may potentiate the hypotensive and vasodilating effect of GTN (see section 4.5).
4.5 |
Deponit 5 mg/24 h transdermal patch | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Concomitant treatment with other vasodilators (e.g. phosphodiesterase inhibitors such as sildenafil, vardenafil, tadalafil), calcium channel antagonists, ACE-inhibitors, monoamine oxidase inhibitors, beta-blockers, diuretics, antihypertensives, tricyclic antidepressants and major tranquillisers, as well as the consumption of alcohol, may potentiate the hypotensive effect of the preparation.
The blood pressure lowering effect of these patches will be increased if used together with phosphodiesterase inhibitors (e.g. sildenafil, vardenafil, tadalafil) which are used for erectile dysfunction (see Section 4.3). This might lead to life threatening cardiovascular complications. Patients who have recently taken phosphodiesterase inhibitors (e.g. sildenafil, vardenafil, tadalafil) therefore must not be treated with GTN. Patients who are on nitrate patch therapy therefore must not use phosphodiesterase inhibitors (e.g. sildenafil, vardenafil, tadalafil).
The use of GTN with riociguat, a soluble guanylate cyclase stimulator, is contraindicated (see section 4.3) since concomitant use can cause hypotension.
If administered concurrently, these patches may increase the blood level of dihydroergotamine and lead to coronary vasoconstriction.
The possibility that ingestion of non-steroidal anti-inflammatory drugs except Acetyl Salicylic acid might diminish the therapeutic response to the patch cannot be excluded.
Concurrent administration with Amifostine and acetyl salicylic acid may potentiate the hypotensive effect of the preparation.
Sapropterine (Tetrahydrobiopterine, BH4) is a cofactor for nitric oxide synthetase. Caution is recommended during concomitant use of sapropterine-containing medicine with all agents that cause vasodilation by affecting nitric oxide (NO) metabolism or action, including classical NO donors (e.g. glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), isosorbide 5-mononitrate (5-ISMN) and others).
4.6 |
Deponit 5 mg/24 h transdermal patch | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy and breast-feeding
Like any drug, Deponit 5 should be employed with caution during pregnancy, especially in the first 3 months.
These patches should not be used during pregnancy or lactation unless considered absolutely essential by the physician.
It is not known whether the active substance passes into the breast milk. Benefits to the mother must be weighed against risk to the child.
Fertility
Reproduction toxicity studies performed in rats and rabbits using various routes of administration did not reveal any effect on mating, fertility and general reproductive parameters. There is no data available on the effect of Deponit 5 on fertility in humans.
4.7 |
Deponit 5 mg/24 h transdermal patch | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Glyceryl trinitrate can cause postural hypotension and dizziness. Patients should not drive or operate machinery if they feel affected.
4.8 |
Deponit 5 mg/24 h transdermal patch | Clinical particulars - Undesirable effects | Undesirable effects |
Deponit 5 mg/24 h transdermal patch | Clinical particulars - Overdose | Undesirable effects frequencies are defined as: very common (≥1/10), common (≥1/100,<1/10), uncommon (≥1/1,000,<1/100), rare ≥1/10,000,<1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).
During administration of Deponit 5 the following undesirable effects may be observed:
SOC
Very common (≥1/10)
Common (≥1/100,<1/10)
Uncommon (≥1/1,000,<1/100)
Rare (≥1/10,000,<1/1,000)
Very rare (<1/10,000)
Not known (cannot be estimated from the available data)
Nervous system disorders
Headache
Dizziness (including dizziness postural), somnolence
Cardiac disorders
Tachycardia
Enhanced angina pectoris symptoms
Palpitations
Vascular disorders
Orthostatic hypotension
Circulatory collapse (sometimes accompanied by bradyarrythmia and syncope)
Flushing, hypotension
Gastrointestinal disorders
Nausea, vomiting
Heartburn
Skin and subcutaneous tissue disorders
Allergic skin reactions (e.g. rash), allergic contact dermatitis
Dermatitis exfoliative, rash generalized
General disorders and administration site conditions
Asthenia
Pruritus, pruritus at patch application site, burning, erythema, irritation
Rash
Investigations
Heart rate increase
Severe hypotensive responses have been reported for organic nitrates and include nausea, vomiting, restlessness, pallor and excessive perspiration.
During the treatment with these patches, a temporary hypoxaemia may occur due to a relative redistribution of the blood flow in hypoventilated alveolar areas. Particularly in patients with coronary artery disease this may lead to a myocardial hypoxia.
Like other nitrate preparations, GTN commonly causes dose-dependent headaches due to cerebral vasodilation. These often regress after a few days despite the maintenance of therapy. If headaches persist during intermittent therapy, they should be treated with mild analgesics. Unresponsive headaches are an indication for reducing the dosage of GTN or discontinuing treatment.
A slight reflex-induced increase in heart rate can be avoided by resorting, if necessary, to combined treatment with a beta-blocker.
Upon removal of the patch, any slight reddening of the skin will usually disappear within a few hours. The application site should be changed regularly to prevent local irritation.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
By reporting side effects, you can help provide more information on the safety of this medicine.
4.9 |
Deponit 5 mg/24 h transdermal patch | Clinical particulars - Subsection 10 | Overdose
In view of the transdermal mode of delivery, an overdose of glyceryl trinitrate is unlikely to occur. However, in the unlikely event of an overdose, the symptoms could include the following:
• Fall in blood pressure ≤ 90 mmHg
• Collapse or syncope
• Paleness
• Sweating
• Weak pulse
• Reflex tachycardia
• Flushing
• Light-headedness on standing
• Headache
• Weakness
• Dizziness
• Nausea
• Vomiting
• Methaemoglobinaemia has been reported in patients receiving other organic nitrates. During glyceryl trinitrate biotransformation nitrite ions are released, which may induce methaemoglobinaemia and cyanosis with subsequent tachypnoea, anxiety, loss of consciousness and cardiac arrest. It can not be excluded that an overdose of glyceryl trinitrate may cause this adverse reaction
• In very high doses the intracranial pressure may be increased. This might lead to cerebral symptoms
General procedure:
• Since these patches are applied to the skin, removing the patch immediately stops delivery of the drug.
• General procedures in the event of nitrate-related hypotension
- Patient should be kept horizontal with the head lowered and legs raised or, if necessary, compression bandaging of the patient's legs.
- Supply oxygen
- Expand plasma volume
- For specific shock treatment admit patient to intensive care unit
Special procedure:
• Raising the blood pressure if the blood pressure is very low
• Treatment of methaemoglobinaemia
Treatment with intravenous methylene blue
- Initially 1 to 2 mg/kg, not exceeding 4 mg/kg of a 1% solution over 5 minutes.
- Repeat dose in 60 minutes if there is no response.
- Administer oxygen (if necessary)
- Initiate artificial ventilation
Treatment with methylene blue is contraindicated in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency or methaemoglobin reductase deficiency (see also section 4.4).
Where treatment with methylene blue is contraindicated or is not effective, exchange transfusion and / or transfusion of packed red blood cells is recommended.
Resuscitation measures:
In case of signs of respiratory and circulatory arrest, initiate resuscitation measures immediately.
5. Pharmacological properties
5.1 |
Deponit 5 mg/24 h transdermal patch | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Absorption
The transdermal absorption of glyceryl trinitrate circumvents the extensive hepatic first pass metabolism so the bioavailability is about 70% of that achieved after i.v. administration.
Distribution
The steady-state concentration in the plasma depends on the patch dosage and the corresponding rate of absorption. At a rate of absorption of 0.4 mg/h, the steady-state concentration is about 0.2 µg/l on average. Plasma protein binding is about 60%.
Metabolism
Glyceryl trinitrate is metabolized to 1,2- and 1,3-dinitroglycerols. The dinitrates exert less vasodilatory activity than glyceryl trinitrate. The contribution to the overall effect is not known. The dinitrates are further metabolized to inactive mononitrates, glyceryl and carbon dioxide. The metabolism of glyceryl trinitrate, which is effected in the liver, but also in many other cells, e.g. the red blood cells, includes the separation of one or more nitrate groups.
Elimination
The elimination half-life of glyceryl trinitrate is 2-4 min. In addition to the metabolism of glyceryl trinitrate, there is a renal excretion of the catabolites.
5.3 |
Deponit 5 mg/24 h transdermal patch | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Glyceryl trinitrate is a well-known active substance, established for more than a hundred years. Thus new preclinical studies have not been carried out with Deponit 5.
6. |
Deponit 5 mg/24 h transdermal patch | Pharmaceutical particulars - List of excipients | List of excipients
Acrylate/vinyl acetate copolymer (adhesive matrix)
Polypropylene (backing foil)
Polyethylene (siliconised release liner)
6.2 |
Deponit 5 mg/24 h transdermal patch | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Deponit 5 mg/24 h transdermal patch | Pharmaceutical particulars - Shelf life | Shelf life |
Deponit 5 mg/24 h transdermal patch | Pharmaceutical particulars - Special precautions for storage | Shelf life of the product as packaged for sale: 48 months.
6.4 |
Deponit 5 mg/24 h transdermal patch | Pharmaceutical particulars - Nature and contents of container | Special precautions for storage
Do not store above 25°C.
6.5 |
Deponit 5 mg/24 h transdermal patch | Pharmaceutical particulars - Special precautions for disposal and other handling | Nature and contents of container
Multilaminate film/foil pouch with heat-sealed edges.
28 patches per carton.
6.6 |
Deponit 5 mg/24 h transdermal patch | Pharmaceutical particulars - Subsection 7 | Special precautions for disposal and other handling
The patch should be removed from the package just before application. After removal of the protective foil, the patch should be applied to unbroken, clean and dry skin that is smooth and with few hairs. The same area of skin should not be used again for some days.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Deponit 5 mg/24 h transdermal patch | Marketing authorisation holder | Norgine Pharmaceuticals Limited
Norgine House, Widewater place,
Moorhall Road, Harefield,
Middlesex, U89 6NS, UK
8. Marketing authorisation number(s)
PL 20011/0044
9. |
Deponit 5 mg/24 h transdermal patch | Date of first authorisation/renewal of the authorisation | Date of latest renewal: 28 February 2008
10. |
Deponit 5 mg/24 h transdermal patch | Date of revision of the text | 03/2019 |
Qarziba (Dinutuximab beta) | Introduction | 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.1. |
Qarziba (Dinutuximab beta) | Name of the medicinal product | Qarziba 4.5 mg/mL concentrate for solution for infusion
2. |
Qarziba (Dinutuximab beta) | Qualitative and quantitative composition | 1 mL of concentrate contains 4.5 mg dinutuximab beta.
Each vial contains 20 mg dinutuximab beta in 4.5 mL.
Dinutuximab beta is a mouse-human chimeric monoclonal IgG1 antibody produced in a mammalian cell line (CHO) by recombinant DNA technology.
For the full list of excipients, see section 6.1.
3. |
Qarziba (Dinutuximab beta) | Pharmaceutical form | Concentrate for solution for infusion
Colourless to slightly yellow liquid
4. |
Qarziba (Dinutuximab beta) | Clinical particulars - Therapeutic indications | Therapeutic indications
Qarziba is indicated for the treatment of high-risk neuroblastoma in patients aged 12 months and above, who have previously received induction chemotherapy and achieved at least a partial response, followed by myeloablative therapy and stem cell transplantation, as well as patients with history of relapsed or refractory neuroblastoma, with or without residual disease. Prior to the treatment of relapsed neuroblastoma, any actively progressing disease should be stabilised by other suitable measures.
In patients with a history of relapsed/refractory disease and in patients who have not achieved a complete response after first line therapy, Qarziba should be combined with interleukin-2 (IL-2).
4.2 |
Qarziba (Dinutuximab beta) | Clinical particulars - Posology and method of administration | Posology and method of administration
Qarziba is restricted to hospital-use only and must be administered under the supervision of a physician experienced in the use of oncological therapies. It must be administered by a healthcare professional prepared to manage severe allergic reactions including anaphylaxis in an environment where full resuscitation services are immediately available.
Posology
Treatment with Qarziba consists of 5 consecutive courses, each course comprising 35 days. The individual dose is determined based on the body surface area and should be a total of 100 mg/m2 per course.
Two modes of administration are possible:
• a continuous infusion over the first 10 days of each course (a total of 240 hours) at the daily dose of 10 mg/m2
• or five daily infusions of 20 mg/m2 administered over 8 hours, on the first 5 days of each course
When IL-2 is combined with Qarziba, it should be administered as subcutaneous injections of 6×106 IU/m2/day, for 2 periods of 5 consecutive days, resulting in an overall dose of 60×106 IU/m2 per course. The first 5-day course should start 7 days prior to the first infusion of dinutuximab beta and the second 5-day course should start concurrently with dinutuximab beta infusion (days 1 to 5 of each dinutuximab beta course).
Prior to starting each treatment course, the following clinical parameters should be evaluated and treatment should be delayed until these values are reached:
• pulse oximetry > 94% on room air
• adequate bone marrow function: absolute neutrophil count ≥ 500/µL, platelet count ≥ 20,000/µL, haemoglobin > 8.0 g/dL
• adequate liver function: alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) < 5 times upper limit of normal (ULN)
• adequate renal function: creatinine clearance or glomerular filtration rate (GRF) > 60 mL/min/1.73 m2
Dose modification of dinutuximab beta
Based on the physician's evaluation of the severity of adverse drug reactions to dinutuximab beta, patients may undergo a dose reduction of 50% or a temporary interruption of the infusion. As a consequence, either the infusion period is prolonged or, if tolerated by the patient, the infusion rate may be increased up to 3 mL/h (continuous infusion), in order to administer the total dose.
Recommended dose modifications for dinutuximab beta
Adverse reaction
Severity
Treatment modification
Any
Grade 1 – 2
Decrease infusion rate to 50%,
After resolution, resume infusion at original rate
Hypersensitivity reaction
e.g. hypotension
Interrupt infusion and administer supportive measures,
After resolution, resume infusion at original rate
Dilated pupils with sluggish light reflex +/- photophobia
Interrupt infusion,
After resolution, resume infusion at 50% rate
Any
Grade ≥ 3
Interrupt infusion and administer supportive measures,
Resume infusion at 50% rate if ADR resolves or improves to Grade 1 – 2,
After resolution, increase to original rate
Recurrent
Discontinue infusion,
Resume next day if ADR resolves
Hypersensitivity reaction
e.g. bronchospasm, angioedema
Interrupt infusion immediately and treat appropriately (see section 4.4),
Resume treatment for subsequent courses
Capillary leak syndrome
Interrupt infusion and administer supportive measures,
Resume at 50% rate if ADR resolves or improves to Grade 1 – 2
Central neurotoxicity
Interrupt infusion immediately, rule out other influencing factors and treat appropriately.
There is limited data available on resuming treatment and no recommendations can be made
Treatment with dinutuximab beta should be permanently discontinued if the following toxicities occur:
• grade 3 or 4 anaphylaxis
• prolonged grade 2 peripheral motor neuropathy
• grade 3 peripheral neuropathy
• grade 3 vision eye toxicity
• grade 4 hyponatremia (< 120 mEq/L) despite appropriate fluid management
• recurrent or grade 4 capillary leak syndrome (requires ventilator support)
• severe central neurotoxicity that includes grade 3 or 4 with substantial prolonged neurological deficit without any detectable reason, recurrent grade 1-3 neurotoxicity, and permanent neurological deficit
• all grades of posterior reversible encephalopathy syndrome and transverse myelitis
Renal and hepatic impairment
There are no data in patients with renal and hepatic impairment (see section 5.2).
Paediatric population
The safety and efficacy of Qarziba in children aged less than 12 months have not yet been established. No data are available.
Method of administration
Qarziba is for intravenous infusion. The solution should be administered via a peripheral or central intravenous line. Other intravenously co-administered agents should be delivered via a separate infusion line (see section 6.6).
For continuous infusions, the solution is administered at a rate of 2 mL per hour (48 mL per day) using an infusion pump.
For 8-hour daily infusions, the solution is administered at a rate of approximately 13 mL per hour.
Pre-medication should always be considered before starting each infusion (see section 4.4).
For instructions on dilution of the medicinal product before administration, see section 6.6.
4.3 |
Qarziba (Dinutuximab beta) | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Acute grade 3 or 4, or extensive chronic graft-versus-host disease (GvHD)
4.4 |
Qarziba (Dinutuximab beta) | Clinical particulars - Special warnings and precautions for use | 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.
Pain
Neuropathic pain usually occurs at the beginning of the treatment and premedication with analgesics, including intravenous opioids, prior to each infusion of dinutuximab beta is required. A triple therapy, including nonopioid analgesics (according to WHO guidelines), gabapentin and opioids, is recommended for pain treatment. The individual dose may vary widely.
Nonopioid analgesics
Nonopioid analgesics should be used permanently during the treatment, e.g. paracetamol or ibuprofen.
Gabapentin
The patient should be primed with 10 mg/kg/day, starting 3 days prior to dinutuximab beta infusion. The daily dose of gabapentin is increased to 2×10 mg/kg/day orally, the next day and to 3×10 mg/kg/day orally, the day before the onset of dinutuximab beta infusion and thereafter. The maximum single dose of gabapentin is 300 mg. This dosing schedule should be maintained for as long as required by the patient.
Oral gabapentin should be tapered off after weaning off intravenous morphine infusion, at the latest after dinutuximab beta infusion therapy has stopped.
Opioids
Treatment with opioids is standard with dinutuximab beta. The first infusion day and course usually requires a higher dose than subsequent days and courses.
• Before initiation of a continuous intravenous morphine infusion, a bolus infusion of 0.02 to 0.05 mg/kg/hour morphine should be started 2 hours before dinutuximab beta infusion.
• Subsequently, a dosing rate of 0.03 mg/kg/hour is recommended concomitantly with dinutuximab beta infusion.
• With daily infusions of dinutuximab beta, morphine infusion should be continued at a decreased rate (e.g. 0.01 mg/kg/h) for 4 hours after the end of dinutuximab beta infusion.
• With continuous infusion, in response to the patient's pain perception, it may be possible to wean off morphine over 5 days by progressively decreasing its dosing rate (e.g. to 0.02 mg/kg/hour, 0.01 mg/kg/hour, 0.005 mg/kg/hour).
• If continous morphine infusion is required for more than 5 days, treatment should be gradually reduced by 20% per day after the last day of dinutuximab beta infusion.
After weaning off intravenous morphine, in case of severe neuropathic pain, oral morphine sulphate (0.2 to 0.4 mg/kg every 4 to 6 hours) can be administered on demand. For moderate neuropathic pain, oral tramodol may be administered.
Hypersensitivity reactions
Severe infusion-related reactions, including cytokine release syndrome (CRS), anaphylactic and hypersensitivity reactions, may occur despite the use of premedication. Occurrence of a severe infusion related reaction (including CRS) requires immediate discontinuation of dinutuximab beta therapy and may necessitate emergency treatment.
Cytokine release syndrome frequently manifests itself within minutes to hours of initiating the first infusion and is characterised by systemic symptoms such as fever, hypotension and urticaria.
Anaphylactic reactions may occur as early as within a few minutes of the first infusion with dinutuximab beta and are commonly associated with bronchospasm and urticaria.
Premedication
Antihistamine premedication (e.g. diphenhydramine) should be administered by intravenous injection approximately 20 minutes before starting each dinutuximab beta infusion. It is recommended that antihistamine administration be repeated every 4 to 6 hours as required during dinutuximab infusion.
Patients should be closely monitored for anaphylaxis and allergic reactions, particularly during the first and second treatment course.
Treatment of hypersensitivity reactions
Intravenous antihistamine, epinephrine (adrenaline) and prednisolone for intravenous administration should be immediately available at the bedside during administration of dinutuximab beta to manage life-threatening allergic reactions. It is recommended that treatment for such reactions include prednisolone administered by intravenous bolus, and epinephrine administered by intravenous bolus every 3 to 5 minutes as necessary, according to clinical response. In case of bronchial and/or pulmonary hypersensitivity reaction, inhalation with epinephrine (adrenaline) is recommended and should be repeated every 2 hours, according to clinical response.
Capillary leak syndrome (CLS)
CLS is characterised by a loss of vascular tone and extravasation of plasma proteins and fluid into the extravascular space. CLS usually develops within hours after initiation of treatment, while clinical symptoms (i.e. hypotension, tachycardia) are reported to occur after 2 to 12 hours. Careful monitoring of circulatory and respiratory function is required.
Neurological disorders of the eye
Eye disorders may occur as dinutuximab beta binds to optic nerve cells. No dose modification is necessary in the case of an impaired visual accommodation that is correctable with eye glasses, as long as this is judged to be tolerable.
Treatment must be interrupted in patients who experience Grade 3 vision toxicity (i.e. subtotal vision loss per toxicity scale). In case of any eye problems, patients should be referred promptly to an ophtalmology specialist.
Peripheral neuropathy
Occasional occurrences of peripheral neuropathy have been reported with Qarziba. Cases of motor or sensory neuropathy lasting more than 4 days must be evaluated and non-inflammatory causes, such as disease progression, infections, metabolic syndromes and concomitant medication, should be excluded.
Treatment should be permanently discontinued in patients experiencing any objective prolonged weakness attributable to dinutuximab beta administration. For patients with moderate (Grade 2) neuropathy (motor with or without sensory), treatment should be interrupted and may be resumed after neurologic symptoms resolve.
Central neurotoxicity
Central neurotoxicity has been reported following treatment with Qarziba. If central neurotoxicity occurs the infusion should be interrupted immediately and the patient treated symptomatically, other influencing factors such as active infection, metastatic spread of neuroblastoma to CNS, neurotoxic concomitant medications should be ruled out.
Treatment with dinutuximab beta should be permanently discontinued following the occurrence of severe neurotoxicity that includes grade 3 or 4 central neurotoxicity with substantial prolonged neurological deficit without any detectable reason, recurrent grade 1-3 neurotoxicity and/or permanent neurological deficit and all grades of posterior reversible encephalopathy syndrome and transverse myelitis.
Systemic infections
Patients are likely to be immunocompromised as a result of prior therapies. As they typically have a central venous catheter in situ, they are at risk of developing systemic infection. Patients should have no evidence of systemic infection and any identified infection should be under control before starting therapy.
Haematologic toxicities
Occurrence of haematologic toxicities has been reported with Qarziba, such as erythropenia, thrombocytopenia or neutropenia. Grade 4 haematologic toxicities, improving to at least Grade 2 or baseline values by start of next treatment course, do not require dose modification.
Laboratory abnormalities
Regulatory monitoring of liver function and electrolytes is recommended.
4.5 |
Qarziba (Dinutuximab beta) | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed. A risk for indirect reduction of CYP activity due to higher TNF-α and IL-6 levels and, therefore, interactions with concomitantly used medicinal products, cannot be excluded.
Corticosteroids
Due to their immunosuppressive activity, concomitant treatment with corticosteroids is not recommended within 2 weeks prior to the first treatment course until 1 week after the last treatment course with dinutuximab beta, except for life-threatening conditions.
Vaccinations
Vaccinations should be avoided during administration of dinutuximab beta until 10 weeks after the last treatment course, due to immune stimulation through dinutuximab beta and possible risk for rare neurological toxicities.
Intravenous immunoglobulin
Concomitant use of intravenous immunoglobulins is not recommended as they may interfere with dinutuximab beta-dependent cellular cytotoxicity.
4.6 |
Qarziba (Dinutuximab beta) | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
There are no data on pregnant women. No animal data are available on teratogenicity or embryotoxicity. Dinutuximab beta target (GD2) is expressed on neuronal tissues, especially during embryofetal development, and may cross the placenta; therefore, Qarziba may cause fetal harm when administered to pregnant women.
Qarziba should not be used during pregnancy.
Breast-feeding
There are no data on lactating women. It is unknown whether dinutuximab beta is excreted in human milk. Breast-feeding should be discontinued during treatment with Qarziba and for 6 months after the last dose.
Fertility
The effects of dinutuximab beta on fertility in humans are unknown. In animals, dedicated fertility studies have not been conducted, but no adverse effects on reproductive organs were observed in toxicity studies performed in Guinea pig and cynomolgous monkey.
Qarziba should not be used in women of childbearing potential not using contraception. It is recommended that women of childbearing potential use contraception for 6 months after discontinuation of treatment with dinutuximab beta.
4.7 |
Qarziba (Dinutuximab beta) | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Dinutuximab beta has major influence on the ability to drive and use machines. Patients should not use or drive machines during treatment with dinutuximab beta.
4.8 |
Qarziba (Dinutuximab beta) | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
The safety of dinutuximab beta has been evaluated in 628 patients with high-risk and relapsed/refractory neuroblastoma, who received it as a continuous infusion (212) or as repeated daily infusions (416). It was combined with 13-cis retinoic in most patients and with IL-2 in 307 patients.
The most common adverse reactions were pyrexia (88%) and pain (77%) that occurred despite analgesic treatment. Other frequent adverse reactions were hypersensitivity (74.1%), vomiting (57%), diarrhoea (51%), capillary leak syndrome (40%), Anaemia (72.3%), neutropenia (52%), thrombocytopenia (49.6%)and hypotension (42.2%).
Tabulated list of adverse reactions
Adverse reactions reported in clinical trials are listed by system organ class and by frequency and summarised in the table below. These adverse reactions are presented by MedDRA system organ class and frequency. Frequency categories are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The type of adverse reactions seen in the post-marketing setting is consistent with the reactions seen in clinical trials.
System organ class
Very common
Common
Uncommon
Infections and infestations
infection (including pneumonia, skin infection, herpes virus infection, myelitis, encephalomyelitis), device related infection
sepsis
Blood and lymphatic system disorders
Anaemia leukopenia, neutropenia, thrombocytopenia
lymphopenia
disseminated intravascular coagulation, eosinophilia
Immune system disorders
hypersensitivity , cytokine release syndrome
anaphylactic reaction
serum sickness
Metabolism and nutrition disorders
fluid retention
decreased appetite, hypoalbuminaemia, hyponatraemia, hypokalaemia, hypophosphataemia, hypomagnesaemia, hypocalcaemia, dehydration
Psychiatric disorders
agitation, anxiety
Nervous system disorders
headache
peripheral neuropathy, seizure, paraesthesia, dizziness, tremor
intracranial pressure increased, posterior reversible encephalopathy syndrome
Eye disorders
mydriasis, pupillotonia, eye oedema (eyelid, periorbital)
ophthalmoplegia, papilloedema, accommodation disorder, blurred vision, photophobia
Cardiac disorders
tachycardia
cardiac failure, left ventricular dysfunction, pericardial effusion
Vascular disorders
hypotension, capillary leak syndrome
hypertension
hypovolaemic shock, veno-occlusive disease
Respiratory, thoracic and mediastinal disorders
hypoxia, cough
bronchospasm , dyspnoea, respiratory failure, lung infiltration, pulmonary oedema, pleural effusion, tachypnoea, laryngospasm
Gastrointestinal disorders
vomiting , diarrhoea, constipation, stomatitis
nausea, lip oedema, ascites, abdominal distension, ileus, dry lips
enterocolitis
Hepatobiliary disorders
hepatocellular injury
Skin and subcutaneous tissue disorders
pruritus , rash, urticaria
dermatitis (including exfoliative) , erythema, dry skin, hyperhidrosis, petechiae, photosensitivity reaction
Musculoskeletal and connective tissue disorders
muscle spasms
Renal and urinary disorders
oliguria, urinary retention, hyperphosphaturia, haematuria, proteinuria
renal failure
General disorders and administration site conditions
pyrexia, chills, pain*, peripheral oedema, face oedema
injection site reaction
Investigations
increased weight , increased transaminases, increased gamma glutamyltransferase, increased blood bilirubin increased blood creatinine
decreased weight, decreased glomerular filtration rate, hypertriglyceridaemia, prolonged activated partial thromboplastin time, prolonged prothrombin time, prolonged thrombin time
*
includes abdominal pain, pain in extremity, oropharyngeal pain, and Back pain reported in >10% of patients. In addition, other common pain types reported were arthralgia, injection site pain, musculoskeletal pain, bone pain, chest pain, and neck pain.
Description of selected adverse reactions
Hypersensitivity
The most frequent hypersensitivity reactions included hypotension (42.2%), urticaria (15%) and bronchospasm (5.3% ). Cytokine release syndrome was also reported in 32% of the patients. Serious anaphylactic reactions occurred in 3.5% of the patients.
Pain
Pain typically occurs during the first infusion of dinutuximab beta and decreases over the treatment courses. Most commonly, patients reported abdominal pain, pain in the extremities, back pain, chest pain, or arthralgia.
Capillary leak syndrome (CLS)
Overall, 10% of CLS were severe (grade 3-4) and their frequency decreased over the treatment courses.
Eye problems
These included impaired visual accommodation that is correctable with eye glasses, as well as mydriasis (10.7%), periorbital oedema and eyelid oedema (7.1%), blurred vision (3%) or photophobia (3%), which were usually reversible after treatment discontinuation. Severe eye disorders were also reported including ophthalmoplegia (2%) and optic atrophy.
Peripheral neuropathy
Both motor and sensory peripheral neuropathies have been reported, overall in 9% of the patients. Most events were of grade 1-2 and resolved.
Central Neurotoxicity
Reports of central neurotoxicity and severe neurotoxicity have been received including posterior reversible encephalopathy syndrome (0.7%) and seizures (1.7%).
Safety profile with and without IL-2
The combination of Qarziba with IL-2 increases the risk of adverse drug reactions compared to Qarziba without IL-2, especially for pyrexia (92% vs. 79%), CLS (50% vs. 25%), pain related to dinutuximab beta (75% vs. 63%), hypotension (43% vs. 26%), and peripheral neuropathy (14% vs. 7%), respectively.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Qarziba (Dinutuximab beta) | Clinical particulars - Overdose | Overdose
No cases of dinutuximab beta overdose have been reported.
In the case of overdose, patients should be carefully observed for signs or symptoms of adverse reactions and supportive care administered, as appropriate.
5. Pharmacological properties
5.1 |
Qarziba (Dinutuximab beta) | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Distribution
Calculations of pharmacokinetic parameters for dinutuximab beta are based upon measurements using non-validated bioanalytical methods. This has to be taken into consideration when interpreting PK parameters (Cmax, exposure, half-life) listed below.
The pharmacokinetics of dinutuximab beta, based on 10-day continuous intravenous infusion of 10 mg/m2/day (equal to a total dose of 100 mg/m2/course) were evaluated in studies 1 and 2. Mean plasma Cmax levels (around 12 micrograms/mL) were reached on the last day of infusion. Mean plasma Cmax levels, observed during 8-hour infusions (20 mg/m2/day on five consecutive days), were determined in another study (n=15). The observed Cmax levels were slightly higher (16.5 micrograms/mL) and were reached on the fifth infusion.
Biotransformation
Dinutuximab beta is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by ubiquitous proteolytic enzmes. Classical biotransformation studies have not been performed.
Elimination
The half-life observed in studies 1 and 2 was in the range of 190 hours, i.e. 8 days.
Special population
A population pharmacokinetic modelling approach was used to investigate the influence of covariates. The population pharmacokinetic model included allometric scaling (reference weight of 18.1 kg) on clearance and volume of distribution with exponents of 0.75 and 1, respectively.
The exposure (Cmax and AUC24h on day 1 and day 10 during a 10-day infusion) is predicted to be similar in subjects with ages less than or equal to 12 years and decreases slightly for older, heavier subjects. Effects of gender and age were not found to influence the pharmacokinetics of dinutuximab beta but data in children less than 2 years of age are very limited and insufficient to support dosing.
An effect of ADA formation on the volume of distribution was found (increase of 37% in volume). Therefore, ADA formation would be predicted to have a slight impact (less than 10% decrease) on exposure within 24 hours after administration, under non-steady state conditions. After reaching steady state, no difference in exposure is predicted, with and without ADA formation.
Markers for renal (eGFR) and hepatic (bilirubin) function did not show a relationship with exposure (Cmax and AUC24h on day 1 and day 10 during a 10-day infusion).
5.3 |
Qarziba (Dinutuximab beta) | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
General toxicology
Dinutuximab beta has been administered to male and female juvenile Guinea pigs, as well as male and female young cynomolgus monkeys, as repeat-dose regimens that exceeded the recommended clinical dose. Findings of note included changes (decrease) in thymus weight as well as bone marrow changes (atrophy affecting myeloid and erythroid precursor cell lines). The bone marrow changes were slight to severe and recovered after cessation of dosing. No effects on cardiovascular functions (ECG, blood pressure) were observed in monkeys.
Other
No non-clinical studies to evaluate the potential of dinutuximab beta to cause carcinogenicity, genotoxicity or developmental and reproductive toxicity have been conducted. In the repeat-dose toxicity studies in Guinea pigs and cynomolgus monkeys, no adverse effects of dinutuximab beta were observed on reproductive organs at exposure levels above clinical levels.
6. |
Qarziba (Dinutuximab beta) | Pharmaceutical particulars - List of excipients | List of excipients
Histidine
Sucrose
Polysorbate 20
Water for injections
Hydrochloric acid (for pH adjustment)
6.2 |
Qarziba (Dinutuximab beta) | Pharmaceutical particulars - Incompatibilities | Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 |
Qarziba (Dinutuximab beta) | Pharmaceutical particulars - Shelf life | Shelf life
Unopened vial
4 years
Diluted solution (solution for infusion)
Chemical and physical in-use stability has been demonstrated for up to 48 hours at 25 °C (50 mL syringe) and for up to 7 days at 37 °C (250 mL infusion bag), after cumulative storage in a refrigerator (2 °C – 8 °C) for 72 hours (see section 6.6).
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would not normally be longer than 24 hours at 2 to 8 °C, unless dilution has taken place in controlled and validated aseptic conditions.
6.4 |
Qarziba (Dinutuximab beta) | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Store in a refrigerator (2 °C – 8 °C).
Keep the vial in the outer carton in order to protect from light.
For storage conditions after dilution of the medicinal product, see section 6.3.
6.5 |
Qarziba (Dinutuximab beta) | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Clear Type I glass vial (6 mL) with a halobutyl rubber stopper and aluminium flip-off cap, containing a minimum extractable volume of 4.5 mL concentrate for solution for infusion.
Each carton contains 1 vial.
6.6 |
Qarziba (Dinutuximab beta) | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
The solution for infusion must be prepared under aseptic conditions. The solution must not be exposed to direct sunlight or heat.
The patient specific daily dose of Qarziba is calculated based on body surface area (see section 4.2).
Qarziba should be diluted aseptically to the patient specific concentration/dose with sodium chloride 9 mg/mL (0.9%) solution for infusion containing 1% human albumin (e.g. 5 mL of human albumin 20% per 100 mL sodium chloride solution).
For continuous infusions, the solution for infusion can be prepared freshly on a daily basis, or sufficient for up to 5 days of continuous infusion. The daily dose is 10 mg/m2. The amount of solution to be infused per day (within a treatment course of 10 consecutive days) should be 48 mL; with 240 mL for a 5-day dose. It is recommended to prepare 50 mL solution in a 50 mL syringe, or 250 mL in an infusion bag suitable for the employed infusion pump, i.e. an overfill of 2 mL (syringe) or 10 mL (infusion bag) to allow for dead volumes of the infusion systems.
For repeated daily 8-hour infusions, the daily dose is 20 mg/m2 and the calculated dose should be diluted in 100 mL sodium chloride 9 mg/mL (0.9%) containing 1% human albumin.
The solution for infusion should be administered via a peripheral or central intravenous line. Other intravenously co-administered agents should be delivered via a separate infusion line. The container should be inspected visually for particulates prior to administration. It is recommended that a 0.22 micrometre in-line filter is used during infusion.
For continuous infusions, any medical device suitable for infusion at a rate of 2 mL per hour can be used, e.g. syringe infusion pumps/infusors, electronic ambulatory infusion pumps. Note that elastomeric pumps are not considered suitable in combination with in-line filters.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. |
Qarziba (Dinutuximab beta) | Marketing authorisation holder | EUSA Pharma (UK) Limited
Breakspear Way,
HP2 4TZ Hemel Hempstead
United-Kingdom
8. Marketing authorisation number(s)
PLGB 44185/0005
9. |
Qarziba (Dinutuximab beta) | Date of first authorisation/renewal of the authorisation | Date of first authorisation: 01/01/2021
Date of latest renewal: 29/07/2021
10. |
Qarziba (Dinutuximab beta) | Date of revision of the text | 01/2023
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. |
Qlaira film-coated tablets | Name of the medicinal product | Qlaira, film-coated tablets
2. |
Qlaira film-coated tablets | Qualitative and quantitative composition | Each wallet (28 film-coated tablets) contains in the following order:2 dark yellow tablets each containing 3 mg estradiol valerate 5 medium red tablets each containing 2 mg estradiol valerate and 2 mg dienogest17 light yellow tablets each containing 2 mg estradiol valerate and 3 mg dienogest 2 dark red tablets each containing 1 mg estradiol valerate
2 white tablets do not contain active substances
Excipient with known effect: lactose (not more than 50 mg per tablet)
For the full list of excipients, see section 6.1.
3. |
Qlaira film-coated tablets | Pharmaceutical form | Film-coated tablet (tablet).
Dark yellow film-coated tablet, round with biconvex faces, one side is marked with the letters “DD” in a regular hexagon
Medium red film-coated tablet, round with biconvex faces, one side is marked with the letters “DJ” in a regular hexagon
Light yellow film-coated tablet, round with biconvex faces, one side is marked with the letters “DH” in a regular hexagon
Dark red film-coated tablet, round with biconvex faces, one side is marked with the letters “DN” in a regular hexagon
White film-coated tablet, round with biconvex faces, one side is marked with the letters “DT” in a regular hexagon
4. |
Qlaira film-coated tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Oral contraception.
Treatment of heavy menstrual bleeding in women without organic pathology who desire oral contraception.
The decision to prescribe Qlaira should take into consideration the individual woman's current risk factors, particularly those for venous thromboembolism (VTE), and how the risk of VTE with Qlaira compares with other combined hormonal contraceptives (CHCs) (see sections 4.3 and 4.4).
4.2 |
Qlaira film-coated tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Method of administration
Oral use
PosologyHow to take Qlaira
Tablets must be taken in the order directed on the package every day at about the same time with some liquid as needed. Tablet taking is continuous. One tablet is to be taken daily for 28 consecutive days. Each subsequent pack is started the day after the last tablet of the previous wallet. Withdrawal bleeding usually starts during the intake of the last tablets of a wallet and may not have finished before the next wallet is started. In some women, the bleeding starts after the first tablets of the new wallet are taken.
How to start Qlaira
• No preceding hormonal contraceptive use (in the past month)
Tablet-taking has to start on day 1 of the woman's natural cycle (i.e. the first day of her menstrual bleeding).
• Changing from a combined hormonal contraceptive (combined oral contraceptive /COC), vaginal ring, or transdermal patch
The woman should start with Qlaira on the day after the last active tablet (the last tablet containing the active substances) of her previous COC. In case a vaginal ring or transdermal patch has been used, the woman should start using Qlaira on the day of removal.
• Changing from a progestogen-only method (progestogen-only pill, injection, implant) or from a progestogen-releasing intrauterine system (IUS)
The woman may switch any day from the progestogen-only pill (from an implant or the IUS on the day of its removal, from an injectable when the next injection would be due), but should in all of these cases be advised to additionally use a barrier method for the first 9 days of tablet-taking.
• Following first-trimester abortion
The woman may start immediately. When doing so, she needs not take additional contraceptive measures.
• Following delivery or second-trimester abortion
For breastfeeding women see section 4.6.
Women should be advised to start at day 21 to 28 after delivery or second-trimester abortion. When starting later, the woman should be advised to additionally use a barrier method for the first 9 days of tablet-taking. However, if intercourse has already occurred, pregnancy should be excluded before the actual start of COC use or the woman has to wait for her first menstrual period.
Management of missed tablets
Missed (white) placebo tablets can be disregarded. However, they should be discarded to avoid unintentionally prolonging the interval between active-tablet taking.
The following advice only refers to missed active tablets:
If the woman is less than 12 hours late in taking any tablet, contraceptive protection is not reduced. The woman should take the tablet as soon as she remembers and should take further tablets at the usual time.
If she is more than 12 hours late in taking any tablet, contraceptive protection may be reduced. The woman should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time.
Depending on the day of the cycle on which the tablet has been missed (see chart below for details), back-up contraceptive measures (e.g. a barrier method such as a condom) have to be used according to the following principles:
DAY
Color Content of estradiol valerate (EV)/dienogest (DNG)
Principles to follow if missing one tablet for more than 12 hours:
1 – 2
Dark yellow tablets (3.0 mg EV)
- Take missed tablet immediately and the following tablet as usual (even if this means taking two tablets on the same day)
- Continue with tablet-taking in the normal way
- Use back-up contraception for the next 9 days
3 - 7
Medium red tablets (2.0 mg EV + 2.0 mg DNG)
8 – 17
Light yellow tablets (2.0 mg EV + 3.0 mg DNG)
18 – 24
Light yellow tablets (2.0 mg EV + 3.0 mg DNG)
- Discard current wallet, and start immediately with the first pill of a new wallet
- Continue with tablet-taking in the normal way
- Back-up contraception for the next 9 days
25 – 26
Dark red tablets (1.0 mg EV)
- Take missed tablet immediately and the following tablet as usual (even if this means taking two tablets on the same day)
- No back-up contraception necessary
27-28
White tablets (Placebos)
- Discard missed tablet and continue tablet-taking in the normal way
- No back-up contraception necessary
Not more than two tablets are to be taken on a given day.
If a woman has forgotten to start a new wallet, or if she has missed one or more tablets during days 3 -9 of the wallet, she may already be pregnant (provided she has had intercourse in the 7 days before the oversight). The more tablets (of those with the two combined active ingredients on days 3 – 24) that are missed and the closer they are to the placebo tablet phase, the higher the risk of a pregnancy.
If the woman missed tablets and subsequently has no withdrawal bleed at the end of the wallet /beginning of new wallet, the possibility of a pregnancy should be considered.
Advice in case of gastro-intestinal disturbances
In case of severe gastro-intestinal disturbances (e.g., vomiting or diarrhoea), absorption may not be complete and additional contraceptive measures should be taken.
If vomiting occurs within 3-4 hours after active tablet-taking, the next tablet should be taken as soon as possible. This tablet should be taken within 12 hours of the usual time of tablet-taking, if possible. If more than 12 hours elapse, the advice concerning missed tablets, as given in section 4.2 “Management of missed tablets”, is applicable. If the woman does not want to change her normal tablet-taking schedule, she has to take the corresponding tablet(s) needed from another pack.
Additional information on special populations
Children and adolescents
No data available for use in adolescents below 18 years.
Geriatric patients
Qlaira is not indicated after menopause.
Patients with hepatic impairment
Qlaira is contraindicated in women with severe hepatic diseases. See also section 4.3.
Patients with renal impairment
Qlaira has not been specifically studied in renally impaired patients.
4.3 |
Qlaira film-coated tablets | Clinical particulars - Contraindications | Contraindications
Combined hormonal contraceptives (CHCs) should not be used in the following conditions. Should any of the conditions appear for the first time during CHC use, the product should be stopped immediately.
• Presence or risk of venous thromboembolism (VTE)
o Venous thromboembolism – current VTE (on anticoagulants) or history of (e.g. deep venous thrombosis [DVT] or pulmonary embolism [PE])
o Known hereditary or acquired predisposition for venous thromboembolism, such as APC-resistance (including Factor V Leiden), antithrombin-III-deficiency, protein C deficiency, protein S deficiency
o Major surgery with prolonged immobilisation (see section 4.4)
o A high risk of venous thromboembolism due to the presence of multiple risk factors (see section 4.4)
• Presence or risk of arterial thromboembolism (ATE)
o Arterial thromboembolism – current arterial thromboembolism, history of arterial thromboembolism (e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris)
o Cerebrovascular disease – current stroke, history of stroke or prodromal condition (e.g. transient ischaemic attack, TIA)
o Known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant).
o History of migraine with focal neurological symptoms.
o A high risk of arterial thromboembolism due to multiple risk factors (see section 4.4) or to the presence of one serious risk factor such as:
• diabetes mellitus with vascular symptoms
• severe hypertension
• severe dyslipoproteinaemia
• Presence or history of severe hepatic disease as long as liver function values have not returned to normal.
• Presence or history of liver tumours (benign or malignant).
• Known or suspected sex-steroid influenced malignancies (e.g. of the genital organs or the breasts).
• Undiagnosed vaginal bleeding.
• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
4.4 |
Qlaira film-coated tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Warnings
If any of the conditions or risk factors mentioned below is present, the suitability of Qlaira should be discussed with the woman.
In the event of aggravation, or first appearance of any of these conditions or risk factors, the woman should be advised to contact her doctor to determine whether the use of Qlaira should be discontinued.
In case of suspected or confirmed VTE or ATE, CHC use should be discontinued. In case anticoagulant therapy is started, adequate alternative contraception should be initiated because of the teratogenicity of anticoagulant therapy (coumarins).
The following warnings and precautions are mainly derived from clinical and epidemiological data of ethinyl estradiol containing COCs.
• Circulatory Disorders
Risk of venous thromboembolism (VTE)
The use of any combined hormonal contraceptive (CHC) increases the risk of venous thromboembolism (VTE) compared with no use. Products that contain levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. Limited data suggests that Qlaira may have a risk of VTE in the same range. The decision to use any other product (such as Qlaira) than one known to have the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with CHCs, how her current risk factors influence this risk, and that her VTE risk is highest in the first ever year of use. There is also some evidence that the risk is increased when a CHC is re-started after a break in use of 4 weeks or more.
In women who do not use a CHC and are not pregnant about 2 out of 10,000 will develop a VTE over the period of one year. However, in any individual woman the risk may be far higher, depending on her underlying risk factors (see below).
Epidemiological studies in women who use low dose (<50 µg ethinylestradiol) combined hormonal contraceptives have found that out of 10,000 women between about 6 and 12 will develop a VTE in one year
It is estimated that out of 10,000 women who use a levonorgestrel-containing CHC about 61 will develop a VTE in one year.
Limited epidemiological evidence suggests that the risk of VTE with the use of Qlaira may be in the same range as the risk with other CHCs, including CHCs containing levonorgestrel.
The number of VTEs per year with low dose CHCs is fewer than the number expected in women during pregnancy or in the postpartum period.
VTE may be fatal in 1-2% of the cases.
Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal or retinal veins and arteries.
Risk factors for VTE
The risk for venous thromboembolic complications in CHC users may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see table).
Qlaira is contraindicated if a woman has multiple risk factors that put her at high risk of venous thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors – in this case her total risk of VTE should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed (see section 4.3).
Table: Risk factors for VTE
Risk factor
Comment
Obesity (body mass index over 30 kg/m2)
Risk increases substantially as BMI rises.
Particularly important to consider if other risk factors also present.
Prolonged immobilisation, major surgery, any surgery to the legs or pelvis, neurosurgery, or major trauma
Note: temporary immobilisation including air travel >4 hours can also be a risk factor for VTE, particularly in women with other risk factors
In these situations it is advisable to discontinue use of the pill (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation. Another method of contraception should be used to avoid unintentional pregnancy.
Antithrombotic treatment should be considered if Qlaira has not been discontinued in advance.
Positive family history (venous thromboembolism ever in a sibling or parent especially at a relatively early age e.g. before 50).
If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use
Other medical conditions associated with VTE
Cancer, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell disease
Increasing age
Particularly above 35 years
There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in the onset or progression of venous thrombosis.
The increased risk of thromboembolism in pregnancy, and particularly the 6-week period of the puerperium, must be considered (for information on “Pregnancy and lactation” see section 4.6).
Symptoms of VTE (deep vein thrombosis and pulmonary embolism)
In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.
Symptoms of deep vein thrombosis (DVT) can include:
o unilateral swelling of the leg and/or foot or along a vein in the leg
o pain or tenderness in the leg which may be felt only when standing or walking
o increased warmth in the affected leg; red or discoloured skin on the leg.
Symptoms of pulmonary embolism (PE) can include:
o sudden onset of unexplained shortness of breath or rapid breathing
o sudden coughing which may be associated with haemoptysis
o sharp chest pain
o severe light headedness or dizziness
o rapid or irregular heartbeat.
Some of these symptoms (e.g. “shortness of breath”, “coughing”) are non-specific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections).
Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of an extremity.
If the occlusion occurs in the eye symptoms can range from painless blurring of vision which can progress to loss of vision. Sometimes loss of vision can occur almost immediately.
Risk of arterial thromboembolism (ATE)
Epidemiological studies have associated the use of CHCs with an increased risk for arterial thromboembolism (myocardial infarction) or for cerebrovascular accident (e.g. transient ischaemic attack, stroke). Arterial thromboembolic events may be fatal.
Risk factors for ATE
The risk of arterial thromboembolic complications or of a cerebrovascular accident in CHC users increases in women with risk factors (see table). Qlaira is contraindicated if a woman has one serious or multiple risk factors for ATE that puts her at high risk of arterial thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors - in this case her total risk should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed (see section 4.3).
Table: Risk factors for ATE
Risk factor
Comment
Increasing age
Particularly above 35 years
Smoking
Women should be advised not to smoke if they wish to use a CHC. Women over 35 who continue to smoke should be strongly advised to use a different method of contraception.
Hypertension
Obesity (body mass index over 30 kg/m2)
Risk increases substantially as BMI increases.
Particularly important in women with additional risk factors
Positive family history (arterial thromboembolism ever in a sibling or parent especially at relatively early age e.g. below 50).
If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use
Migraine
An increase in frequency or severity of migraine during CHC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation
Other medical conditions associated with adverse vascular events
Diabetes mellitus, hyperhomocysteinaemia, valvular heart disease and atrial fibrillation, dyslipoproteinaemia and systemic lupus erythematosus.
Symptoms of ATE
In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.
Symptoms of a cerebrovascular accident can include:
o sudden numbness or weakness of the face, arm or leg, especially on one side of the body
o sudden trouble walking, dizziness, loss of balance or coordination
o sudden confusion, trouble speaking or understanding
o sudden trouble seeing in one or both eyes
o sudden, severe or prolonged headache with no known cause
o loss of consciousness or fainting with or without seizure.
Temporary symptoms suggest the event is a transient ischaemic attack (TIA).
Symptoms of myocardial infarction (MI) can include:
o pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone
o discomfort radiating to the back, jaw, throat, arm, stomach
o feeling of being full, having indigestion or choking
o sweating, nausea, vomiting or dizziness
o extreme weakness, anxiety, or shortness of breath
o rapid or irregular heartbeats.
• Tumours
An increased risk of cervical cancer in long-term users of COCs (> 5 years) has been reported in some epidemiological studies, but there continues to be controversy about the extent to which this finding is attributable to the confounding effects of sexual behaviour and other factors such as human papilloma virus (HPV).
A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using COCs. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.
In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been reported in users of COCs. In isolated cases, these tumours have led to life-threatening intra-abdominal hemorrhages. A hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal hemorrhage occur in women taking COCs.
Hepatitis C
During clinical trials with the hepatitis C virus (HCV) combination regimen ombitasvir/paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medicinal products such as CHCs. Additionally, also in patients treated with glecaprevir/pibrentasvir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir and also the regimen glecaprevir/pibrentasvir. See section 4.5.
• Other conditions
Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.
Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. However, if a sustained clinically significant hypertension develops during the use of a COC then it is prudent for the physician to withdraw the COC and treat the hypertension. Where considered appropriate, COC use may be resumed if normotensive values can be achieved with antihypertensive therapy.
The following conditions have been reported to occur or deteriorate with both pregnancy and COC use, but the evidence of an association with COC use is inconclusive: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic uremic syndrome; Sydenham's chorea; herpes gestationis; otosclerosis-related hearing loss.
Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema
Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. Recurrence of cholestatic jaundice which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of COCs.
Although COCs may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics using low-dose COCs (containing <0.05 mg ethinylestradiol). However, diabetic women should be carefully observed while taking COCs, particularly in the early stage of COC use.
Worsening of endogenous depression, of epilepsy, of Crohn's disease and of ulcerative colitis has been reported during COC use.
Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (see section 4.8). Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment.
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking COCs.
Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since the level of circulating estrogens may be increased after administration of Qlaira.
This medicinal product contains not more than 50 mg lactose per tablet. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Medical examination/consultation
Prior to the initiation or reinstitution of Qlaira a complete medical history (including family history) should be taken and pregnancy must be ruled out. Blood pressure should be measured and a physical examination should be performed, guided by the contra-indications (see section 4.3) and warnings (see section 4.4). It is important to draw a woman's attention to the information on venous and arterial thrombosis, including the risk of Qlaira compared with other CHCs, the symptoms of VTE and ATE, the known risk factors and what to do in the event of a suspected thrombosis.
The woman should also be instructed to carefully read the user leaflet and to adhere to the advice given. The frequency and nature of examinations should be based on established practice guidelines and be adapted to the individual woman.
Women should be advised that hormonal contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.
Reduced efficacy
The efficacy of COCs may be reduced for example in the following events: missed active tablets (section 4.2), gastro-intestinal disturbances (section 4.2) during active tablet taking or concomitant medication (section 4.5).
Cycle control
With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. Therefore, the evaluation of any irregular bleeding is only meaningful after an adaptation interval of about 3 cycles.
Based on patient diaries from a comparative clinical trial, the percentage of women per cycle experiencing intracyclic bleeding was 10 – 18 % for women using Qlaira.
Users of Qlaira may experience amenorrhea although not being pregnant. Based on patient diaries, amenorrhea occurs in approximately 15% of cycles.
If Qlaira has been taken according to the directions described in Section 4.2, it is unlikely that the woman is pregnant. If Qlaira has not been taken according to these directions prior to the first missed withdrawal bleed or if the withdrawal bleeding is missed in two consecutive cycles, pregnancy must be ruled out before Qlaira use is continued.
If bleeding irregularities persist or occur after previously regular cycles, then non-hormonal causes should be considered and adequate diagnostic measures are indicated to exclude malignancy or pregnancy. These may include curettage.
1 Mid-point of range of 5-7 per 10,000 WY, based on a relative risk for CHCs containing levonorgestrel versus non-use of approximately 2.3 to 3.6
4.5 |
Qlaira film-coated tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.
Interaction studies have only been performed in adults.
The following interactions have been reported in the literature for COCs in general or were studied in clinical trials with Qlaira.
• Effects of other medicinal products on Qlaira
Interactions can occur with drugs that induce microsomal enzymes which can result in increased clearance of sex hormones and which may lead to breakthrough bleeding and/or contraceptive failure.
Management
Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction is generally seen within a few weeks. After the cessation of drug therapy enzyme induction may be sustained for about 4 weeks.
Short-term treatment
Women on treatment with enzyme-inducing drugs should temporarily use a barrier method or another method of contraception in addition to the COC. The barrier method must be used during the whole time of the concomitant drug therapy and for 28 days after its discontinuation. If the drug therapy runs beyond the end of the active tablets in the COC pack, the placebo tablets must be discarded and the next COC pack should be started right away.
Long-term treatment
In women on long-term treatment with hepatic enzyme-inducing active substances, another reliable, non-hormonal, method of contraception is recommended.
Substances increasing the clearance of COCs (diminished efficacy of COCs by enzyme-induction), e.g.:
Barbiturates, carbamazepine, phenytoin, primidone, rifampicin, and HIV medication ritonavir, nevirapine and efavirenz and possibly also felbamate, griseofulvin, oxcarbazepine, topiramate and products containing the herbal remedy St. John's Wort (hypericum perforatum).
In a clinical study the strong cytochrome P450 (CYP 3A4) inducer rifampicin led to significant decreases in steady state concentrations and systemic exposures of dienogest and estradiol. The AUC (0-24h) of dienogest and estradiol at steady state, were decreased by 83% and 44%, respectively.
Substances with variable effects on the clearance of COC:
When co-administered with COCs, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with HCV inhibitors can increase or decrease plasma concentrations of estrogen or progestins. The net effect of these changes may be clinically relevant in some cases.
Therefore, the prescribing information of concomitant HIV/HCV medications should be consulted to identify potential interactions and any related recommendations. In case of any doubt, an additional barrier contraceptive method should be used by women on protease inhibitor or non-nucleoside reverse transcriptase inhibitor therapy.
Substances decreasing the clearance of COCs (enzyme inhibitors):
Dienogest is a substrate of CYP3A4.
The clinical relevance of potential interactions with enzyme inhibitors remains unknown.
Concomitant administration of strong CYP3A4 inhibitors can increase plasma concentrations of the estrogen or the progestin or both.
Coadministration with the strong CYP3A4 enzyme inhibitor ketoconazole resulted in a 2.9-fold and 1.6-fold increase of AUC (0-24h) at steady state for dienogest and estradiol, respectively. Concomitant administration of the moderate inhibitor erythromycin increased the AUC (0-24h) of dienogest and estradiol at steady state by 1.6-fold and 1.3-fold, respectively.
• Effects of Qlaira on other medicinal products
Oral contraceptives may affect the metabolism of certain other active substances. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporin) or decrease (e.g. lamotrigine).
Pharmacokinetics of nifedipine were not affected by concomitant administration of 2 mg dienogest + 0.03 mg ethinyl estradiol thus confirming results of in vitro studies indicating that inhibition of CYP enzymes by Qlaira is unlikely at the therapeutic dose.
• Other interactions
During clinical trials with the HCV combination drug regimen ombitasvir/paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medicinal products such as CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir and also the regimen with glecaprevir/pibrentasvir (see section 4.4).
Laboratory tests
The use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins, e.g. corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.
4.6 |
Qlaira film-coated tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
Qlaira should not be used during pregnancy.
If pregnancy occurs during use of Qlaira, further intake must be stopped. However, extensive epidemiological studies with ethinylestradiol containing COCs have revealed neither an increased risk of birth defects in children born to women who used COCs prior to pregnancy, nor a teratogenic effect when COCs were taken inadvertently during pregnancy. Animal studies do not indicate a risk for reproductive toxicity (see section 5.3).The increased risk of VTE during the postpartum period should be considered when re-starting Qlaira (see section 4.2 and 4.4).
Breastfeeding
Lactation may be influenced by COCs as they may reduce the quantity and change the composition of breast milk. Therefore, the use of COCs should generally not be recommended until the nursing mother has completely weaned her child. Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the milk. These amounts may affect the child.
Fertility
Qlaira is indicated for the prevention of pregnancy. For information on return to fertility, see section 5.1.
4.7 |
Qlaira film-coated tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. No effects on ability to drive and use machines have been observed in users of COCs.
4.8 |
Qlaira film-coated tablets | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
The most commonly reported adverse reactions with Qlaira when used as an oral contraceptive or in the treatment of heavy menstrual bleeding in women without organic pathology who desire oral contraception are acne, breast discomfort, headache, intracyclic bleeding, nausea and weight increased.
Serious adverse reactions are arterial and venous thromboembolism, which are discussed in section 4.4.
Tabulated list of adverse reactions
The table below reports adverse reactions (ARs) by MedDRA system organ classes (MedDRA SOCs). The most appropriate MedDRA term (version 12.0) to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed, but should be taken into account as well. The frequencies are based on clinical trial data. The adverse reactions were recorded in 5 phase III clinical studies (N=2,266 women at risk for pregnancy, N=264 women suffering from dysfunctional uterine bleeding without organic pathology who desire oral contraception) and considered at least possibly causally related to Qlaira use. All ADRs listed in the category 'rare' occurred in 1 to 2 volunteers resulting in < 0.1%.
N= 2,530women (100.0%)
System Organ Class
Common (≥ 1/100 to <1/10)
Uncommon(≥ 1/1,000 to <1/100)
Rare (≥ 1/10,000 to < 1/1,000)
Infections and infestations
Fungal infection
Vulvovaginal mycotic infection1
Vaginal infection
Candidiasis
Oral herpes
Pelvic inflammatory disease
Presumed ocular histoplasmosis syndrome
Tinea versicolor
Urinary tract infection
Vaginitis bacterial
Metabolism and nutrition disorders
Increased appetite
Fluid retention
Hypertriglyceridaemia
Psychiatric disorders
Depression/depressed mood
Emotional disorder2
Insomnia
Libido decreased3
Mental disorder
Mood change4
Aggression
Anxiety
Dysphoria
Libido increased
Nervousness
Nightmare
Restlessness
Sleep disorder
Stress
Nervous system disorders
Headache5
Dizziness
Migraine6
Disturbance in attention
Paraesthesia
Vertigo
Eye disorders
Contact lens intolerance
Dry eye
Eye swelling
Cardiac disorders
Myocardial infarction
Palpitations
Vascular disorders
Hot flush
Hypertension
Bleeding varicose vein
Venous thromboembolism (VTE)Arterial thromboembolism (ATE)
Hypotension
Phlebitis superficialis
Vein pain
Gastrointestinal disorders
Abdominal pain7
Nausea
Diarrhoea
Vomiting
Constipation
Dry mouth
Dyspepsia
Gastrooesophageal reflux disease
Hepatobiliary disorders
Liver enzymes increased8
Focal nodular hyperplasia of the liver
Cholecystitis chronic
Skin and subcutaneous tissue disorders
Acne9
Alopecia
Hyperhidrosis
Pruritus10
Rash11
Allergic skin reaction12
Chloasma
Dermatitis
Hirsutism
Hypertrichosis
Neurodermatitis
Pigmentation disorder
Seborrhoea
Skin disorder13
Musculoskeletal and connective tissue disorders
Muscle spasms
Back pain
Pain in jaw
Sensation of heaviness
Renal and urinary disorders
Urinary tract pain
Reproductive system and breast disorders
Amenorrhea
Breast discomfort14
Dysmenorrhoea
Intracyclic bleeding (Metrorrhagia)15
Breast enlargement16
Breast mass
Cervical dysplasia
Dysfunctional uterine bleeding
Dyspareunia
Fibrocystic breast disease
Menorrhagia
Menstrual disorder
Ovarian cyst
Pelvic pain
Premenstrual syndrome
Uterine leiomyoma
Uterine spasm
Uterine/ vaginal bleeding incl. spotting17
Vaginal discharge
Vulvovaginal dryness
Abnormal withdrawal bleeding
Benign breast neoplasm
Breast cancer in situ
Breast cyst
Breast discharge
Cervical polyp
Cervix erythema
Coital bleeding
Galactorrhea
Genital discharge
Hypomenorrhoea
Menstruation delayed
Ovarian cyst ruptured
Vaginal odour
Vulvovaginal burning sensation
Vulvovaginal discomfort
Blood and lymphatic system disorders
Lymphadenopathy
Respiratory, thoracic and mediastinal disorders
Asthma
Dyspnoea
Epistaxis
General disorders and administration site conditions
Fatigue
Irritability
Oedema18
Chest pain
Malaise
Pyrexia
Investigations
Weight increased
Weight decreased
Blood pressure changes19
Smear cervix abnormal
1 including vulvovaginal candidiasis and fungus cervical specimen identified
2 including crying and affect lability
3 including loss of libido
4 including mood altered and mood swings
5 including tension headache and sinus headache
6 including migraine with aura and migraine without aura
7 including abdominal distension, abdominal pain upper and abdominal pain lower
8 including alanine aminotransferase increased, aspartate aminotransferase increased and gamma- glutamyltransferase increased
9 including acne pustular
10 including pruritus generalized and rash pruritic
11 including rash macular
12 including dermatitis allergic and urticaria
13 including skin tightness
14 including breast pain, breast tenderness, nipple disorder and nipple pain
15 including menstruation irregular
16 including breast swelling
17 including vaginal hemorrhage, genital hemorrhage and uterine hemorrhage
18 including oedema peripheral
19 including blood pressure increased and blood pressure decreased
Description of selected adverse reactions
An increased risk of arterial and venous thrombotic and thrombo-embolic events, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis and pulmonary embolism has been observed in women using CHCs, which are discussed in more detail in section 4.4.
Occurrence of amenorrhea and intracyclic bleeding based on patient diaries is summarized in section 4.4 Cycle control.
The following serious adverse events have been reported in women using COCs, which are discussed in section 4.4 Special warning and precautions for use:
Tumours
- The frequency of diagnosis of breast cancer is very slightly increased among COC users. As breast cancer is rare in women under 40 years of age the excess number is small in relation to the overall risk of breast cancer. Causation with COC use is unknown. For further information, see sections 4.3 and 4.4;
- Liver tumours;
Other conditions
- Erythema nodosum, Erythema multiforme;
- Breast discharge;
- Hypertension;
- Occurrence or deterioration of conditions for which association with COC use is not conclusive: Crohn's disease, ulcerative colitis, epilepsy, migraine, uterine myoma, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham's chorea, haemolytic uremic syndrome, cholestatic jaundice;
- In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema;
- Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal.
- Chloasma;
- Hypersensitivity (including symptoms such as rash, urticaria);
Interactions
Breakthrough bleeding and/or contraceptive failure may result from interactions of other drugs (enzyme inducers) with oral contraceptives (see section 4.5).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via;
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.
Malta
ADR Reporting
Website: www.medicinesauthority.gov.mt/adrportal
4.9 |
Qlaira film-coated tablets | Clinical particulars - Overdose | Overdose
There have been no reports of serious deleterious effects from overdose. Symptoms that may occur in case of taking an overdose of active tablets are: nausea, vomiting and, in young girls, slight vaginal bleeding. There are no antidotes and further treatment should be symptomatic.
5. Pharmacological properties
5.1 |
Qlaira film-coated tablets | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
• Dienogest
Absorption
Orally administered dienogest is rapidly and almost completely absorbed. Maximal serum concentrations of 90.5ng/ml are reached at about 1 hour after oral administration of the Qlaira tablet containing 2 mg estradiol valerate + 3 mg dienogest. Bioavailability is about 91 %. The pharmacokinetics of dienogest is dose-proportional within the dose range of 1 – 8 mg.
Concomitant food intake has no clinically relevant effect on the rate and extent of dienogest absorption.
Distribution
A relatively high fraction of 10% of circulating dienogest is present in the free form, with approx. 90% being bound non-specifically to albumin. Dienogest does not bind to the specific transport proteins SHBG and CBG. The volume of distribution at steady state (Vd,ss) of dienogest is 46 l after the intravenous administration of 85 µg 3H-dienogest.
BiotransformationDienogest is nearly completely metabolized by the known pathways of steroid metabolism (hydroxylation, conjugation), mainly by CYP3A4. The pharmacologically inactive metabolites are excreted rapidly resulting in dienogest as the major fraction in plasma accounting for approximately 50% of circulating dienogest derived compounds. The total clearance following the intravenous administration of 3H-dienogest was calculated as 5.1 l/h.
Elimination
The plasma half-life of dienogest is approximately 11 hours. Dienogest is extensively metabolized and only 1% of drug is excreted unchanged. The ratio of urinary to fecal excretion is about 3:1 after oral administration of 0.1 mg/kg. Following oral administration, 42% of the dose is eliminated within the first 24 h and 63% within 6 days by renal excretion. A combined 86% of the dose is excreted by urine and feces after 6 days.
Steady-State Conditions
Pharmacokinetics of dienogest are not influenced by SHBG levels. Steady state is reached after 3 days of the same dosage of 3 mg dienogest in combination with 2 mg estradiol valerate. Trough, maximum and average dienogest serum concentrations at steady state are 11.8 ng/ml, 82.9 ng/ml and 33.7 ng/ml, respectively. The mean accumulation ratio for AUC (0-24h) was determined to be 1.24.
• Estradiol valerate
Absorption
After oral administration estradiol valerate is completely absorbed. Cleavage to estradiol and valeric acid takes place during absorption by the intestinal mucosa or in the course of the first liver passage. This gives rise to estradiol and its metabolites estrone and estriol. Maximal serum estradiol concentrations of 70.6 pg/ml are reached between 1.5 and 12 hours after single ingestion of the tablet containing 3 mg estradiol valerate on Day 1.
Biotransformation
The valeric acid undergoes very fast metabolism. After oral administration approximately 3% of the dose is directly bioavailable as estradiol. Estradiol undergoes an extensive first-pass effect and a considerable part of the dose administered is already metabolized in the gastrointestinal mucosa. Together with the presystemic metabolism in the liver, about 95 % of the orally administered dose becomes metabolized before entering the systemic circulation. The main metabolites are estrone, estrone sulfate and estrone glucuronide.
Distribution
In serum 38 % of estradiol is bound to SHBG, 60 % to albumin and 2-3 % circulate in free form. Estradiol can slightly induce the serum concentrations of SHBG in a dose-dependent manner. On day 21 of the treatment cycle, SHBG was approximately 148% of the baseline, it decreased to about 141% of the baseline by day 28 (end of placebo phase). An apparent volume of distribution of approximately 1.2 l/kg was determined after iv. administration.
Elimination
The plasma half-life of circulating estradiol is about 90 min. After oral administration, however, the situation differs. Because of the large circulating pool of estrogen sulfates and glucuronides, as well as enterohepatic recirculation, the terminal half-life of estradiol after oral administration represents a composite parameter which is dependent on all of these processes and is in the range of about 13-20 h.
Estradiol and its metabolites are mainly excreted in urine, with about 10% being excreted in the stool.
Steady-state conditions
Pharmacokinetics of estradiol are influenced by SHBG levels. In young women, the measured estradiol plasma levels are a composite of the endogenous estradiol and the estradiol generated from Qlaira. During the treatment phase of 2 mg estradiol valerate + 3 mg dienogest, maximum and average estradiol serum concentrations at steady state are 66.0 pg/ml and 51.6 pg/ml, respectively. Throughout the 28 day cycle, stable minimum estradiol concentrations were maintained and ranged from 28.7 pg/ml to 64.7 pg/ml.
Special Populations
Pharmacokinetics of Qlaira was not investigated in patients with impaired renal or liver function.
5.3 |
Qlaira film-coated tablets | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Preclinical data reveal no special risks for humans based on conventional studies of repeated dose toxicity, genotoxicity, and toxicity to reproduction. A carcinogenicity study with dienogest in mice and a more limited study in rats showed no increase in tumours, however, it is well known that due to their hormonal action, sex steroids can promote the growth of certain hormone-dependent tissues and tumours.
6. |
Qlaira film-coated tablets | Pharmaceutical particulars - List of excipients | List of excipients
Active film-coated tablets
Placebo (inactive) film-coated tablet
Tablet core:
Lactose monohydrateMaize starch
Pregelatinized maize starchPovidone K25 (E1201)
Magnesium stearate (E572)
Lactose monohydrate Maize starchPovidone K25 (E1201)Magnesium stearate (E572)
Tablet coating:
Hypromellose type 2910 (E464)
Macrogol 6000Talc (E553b)Titanium dioxide (E171)Iron oxide red (E172)
and/or
Iron oxide yellow (E172)
Hypromellose type 2910 (E464)Talc (E553b)Titanium dioxide (E171)
6.2 |
Qlaira film-coated tablets | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable
6.3 |
Qlaira film-coated tablets | Pharmaceutical particulars - Shelf life | Shelf life
5 years
6.4 |
Qlaira film-coated tablets | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 |
Qlaira film-coated tablets | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Transparent PVC/Aluminium blister in a cardboard wallet
• Presentation
Pack sizes:
1 x 28 film-coated tablets
3 x 28 film-coated tablets
6 x 28 film-coated tablets
Each wallet (28 film-coated tablets) contains in the following order: 2 dark yellow tablets and 5 medium red tablets and 17 light yellow tablets and 2 dark red tablets and 2 white tablets
Not all pack sizes may be marketed.
6.6 |
Qlaira film-coated tablets | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
Any unused product or waste material should be disposed of in accordance with local requirements.
7. |
Qlaira film-coated tablets | Marketing authorisation holder | Bayer plc,
400 South Oak Way
Reading, RG2 6AD
8. Marketing authorisation number(s)
PL00010/0576
9. |
Qlaira film-coated tablets | Date of first authorisation/renewal of the authorisation | First Authorisation: 08.12.2008
Renewal of Authorisation: 03.11.2013
10. |
Qtern 5 mg/10 mg film-coated tablets | Name of the medicinal product | Qtern 5 mg/10 mg film-coated tablets
2. |
Qtern 5 mg/10 mg film-coated tablets | Qualitative and quantitative composition | Each tablet contains saxagliptin hydrochloride equivalent to 5 mg saxagliptin and dapagliflozin propanediol monohydrate equivalent to 10 mg dapagliflozin.
Excipient with known effect
Each tablet contains 40 mg of lactose.
For the full list of excipients, see section 6.1.
3. |
Qtern 5 mg/10 mg film-coated tablets | Pharmaceutical form | Film-coated tablet (tablet).
Light brown to brown, biconvex, 0.8 cm round, film-coated tablet, with “5/10” printed on one side, and “1122” printed on the other side, in blue ink.
4. |
Qtern 5 mg/10 mg film-coated tablets | Clinical particulars - Therapeutic indications | Therapeutic indications
Qtern, fixed dose combination of saxagliptin and dapagliflozin, is indicated in adults aged 18 years and older with type 2 diabetes mellitus:
• to improve glycaemic control when metformin and/or sulphonylurea (SU) and one of the monocomponents of Qtern do not provide adequate glycaemic control,
• when already being treated with the free combination of dapagliflozin and saxagliptin.
(See sections 4.2, 4.4, 4.5 and 5.1 for available data on combinations studied).
4.2 |
Qtern 5 mg/10 mg film-coated tablets | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
The recommended dose is one 5 mg saxagliptin/10 mg dapagliflozin tablet once daily (see sections 4.5 and 4.8).
Missed dose
If a dose is missed and it is ≥ 12 hours until the next dose, the dose should be taken. If a dose is missed and it is < 12 hours until the next dose, the missed dose should be skipped and the next dose taken at the usual time.
Special populations
Renal impairment
Qtern should not be initiated in patients with a glomerular filtration rate (GFR) < 60 mL/min and should be discontinued at GFR persistently below 45 mL/min. It should also not be used in patients with end-stage renal disease (ESRD) (see sections 4.4, 4.8, 5.1 and 5.2).
No dose adjustment is recommended based on renal function.
Hepatic impairment
This medicinal product can be used in patients with mild or moderate hepatic impairment. Patients with moderate hepatic impairment should be evaluated prior to initiation and during treatment.
It is not recommended for use in patients with severe hepatic impairment (see section 4.4).
Elderly (≥ 65 years)
No dose adjustment is recommended based on age. Renal function and risk of volume depletion should be taken into account (see sections 4.4 and 5.2).
Paediatric population
The safety and efficacy of this medicinal product in children and adolescents aged 0 to < 18 years have not yet been established. No data are available.
Method of administration
Qtern is taken orally once daily. It may be taken at any time of day with or without food. Tablet is to be swallowed whole.
4.3 |
Qtern 5 mg/10 mg film-coated tablets | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or history of a serious hypersensitivity reaction, including anaphylactic reaction, anaphylactic shock, and angioedema, to any dipeptidyl peptidase-4 (DPP-4) inhibitor or to any sodium-glucose co-transporter 2 (SGLT2) inhibitor (see sections 4.4, 4.8 and 6.1).
4.4 |
Qtern 5 mg/10 mg film-coated tablets | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Acute pancreatitis
Use of DPP-4 inhibitors has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptoms of acute pancreatitis; persistent, severe abdominal pain. If pancreatitis is suspected, this medicinal product should be discontinued; if acute pancreatitis is confirmed, it should not be restarted. Caution should be exercised in patients with a history of pancreatitis.
In post-marketing experience of saxagliptin, there have been spontaneously reported adverse reactions of acute pancreatitis (see section 4.8).
Renal impairment
The glycaemic efficacy of dapagliflozin is dependent on renal function, and efficacy is reduced in patients who have moderate renal impairment and likely absent in patients with severe renal impairment (see section 4.2). In subjects with moderate renal impairment (GFR < 60 mL/min), a higher proportion of subjects treated with dapagliflozin had adverse reactions of increase in creatinine, phosphorus, parathyroid hormone (PTH) and hypotension, compared with placebo. This medicinal product should not be initiated in patients with a GFR < 60 mL/min and should be discontinued at GFR persistently below 45 mL/min. The saxagliptin/dapagliflozin fixed dose combination has not been studied in severe renal impairment (GFR < 30 mL/min) or end-stage renal disease (ESRD).
Monitoring of renal function is recommended as follows:
• Prior to initiation of this medicinal product and at least yearly, thereafter (see sections 4.2, 4.8, 5.1 and 5.2).
• Prior to initiation of concomitant medicinal products that may reduce renal function and periodically thereafter.
• For renal function approaching moderate renal impairment, at least 2 to 4 times per year. If renal function persistently falls below GFR < 45 mL/min, treatment with this medicinal product should be discontinued.
Use in patients at risk for volume depletion and/or hypotension
Due to dapagliflozin's mechanism of action, this medicinal product increases diuresis which may lead to the modest decrease in blood pressure observed in clinical studies (see section 5.1). It may be more pronounced in patients with very high blood glucose concentrations.
Caution should be exercised in patients for whom a dapagliflozin-induced drop in blood pressure could pose a risk, such as patients on anti-hypertensive therapy with a history of hypotension or elderly patients.
In case of intercurrent conditions that may lead to volume depletion (e.g. gastrointestinal illness), careful monitoring of volume status (e.g. physical examination, blood pressure measurements, laboratory tests including haematocrit and electrolytes) is recommended. Temporary interruption of treatment with this medicinal product is recommended for patients who develop volume depletion until the depletion is corrected (see section 4.8).
Use in patients with hepatic impairment
There is limited experience in clinical trials in patients with hepatic impairment. Dapagliflozin and saxagliptin exposure is increased in patients with severe hepatic impairment (see sections 4.2 and 5.2).
The saxagliptin/dapagliflozin fixed dose combination can be used in patients with mild or moderate hepatic impairment. Patients with moderate hepatic impairment should be evaluated prior to initiation and during treatment. This medicinal product is not recommended for use in patients with severe hepatic impairment (see section 4.2).
Diabetic ketoacidosis
Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have been reported in patients treated with SGLT2 inhibitors, including dapagliflozin. In a number of cases, the presentation of the condition was atypical with only moderately increased blood glucose values, below 14 mmol/litres (250 mg/dL). It is not known if DKA is more likely to occur with higher doses of dapagliflozin.
The risk of diabetic ketoacidosis must be considered in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness. Patients should be assessed for ketoacidosis immediately if these symptoms occur, regardless of blood glucose level.
In patients where DKA is suspected or diagnosed, treatment with this medicinal product should be discontinued immediately.
Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses. Monitoring of ketones is recommended in these patients. Measurement of blood ketone levels is preferred to urine. Treatment with dapagliflozin may be restarted when the ketone values are normal and the patient's condition has stabilised.
Before initiating treatment with this medicinal product, factors in the patient history that may predispose to ketoacidosis should be considered.
Patients who may be at higher risk of DKA include patients with a low beta-cell function reserve (e.g. type 2 diabetes patients with low C-peptide or latent autoimmune diabetes in adults (LADA) or patients with a history of pancreatitis), patients with conditions that lead to restricted food intake or severe dehydration, patients for whom insulin doses are reduced and patients with increased insulin requirements due to acute medical illness, surgery or alcohol abuse. SGLT2 inhibitors should be used with caution in these patients.
Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved.
The safety and efficacy of the saxagliptin/dapagliflozin fixed dose combination in patients with type 1 diabetes have not been established and it should not be used for treatment of patients with type 1 diabetes. In type 1 diabetes mellitus studies with dapagliflozin, DKA was reported with common frequency.
Necrotising fasciitis of the perineum (Fournier's gangrene)
Post-marketing cases of necrotising fasciitis of the perineum (also known as Fournier's gangrene) have been reported in female and male patients taking SGLT2 inhibitors (see section 4.8). This is a rare but serious and potentially life-threatening event that requires urgent surgical intervention and antibiotic treatment.
Patients should be advised to seek medical attention if they experience a combination of symptoms of pain, tenderness, erythema, or swelling in the genital or perineal area, with fever or malaise. Be aware that either uro-genital infection or perineal abscess may precede necrotising fasciitis. If Fournier's gangrene is suspected, Qtern should be discontinued and prompt treatment (including antibiotics and surgical debridement) should be instituted.
Hypersensitivity reactions
This medicinal product must not be used in patients who have had any serious hypersensitivity reaction to a DPP-4 inhibitor or a SGLT2 inhibitor (see section 4.3).
During post-marketing experience with saxagliptin, including spontaneous reports and clinical trials, the following adverse reactions have been reported with the use of saxagliptin: serious hypersensitivity reactions, including anaphylactic reaction, anaphylactic shock, and angioedema.
This medicinal product should be discontinued if a serious hypersensitivity reaction is suspected. The event should be assessed and alternative treatment for diabetes should be instituted (see section 4.8).
Urinary tract infections
Urinary glucose excretion may be associated with an increased risk of urinary tract infection; therefore, temporary interruption of this medicinal product should be considered when treating pyelonephritis or urosepsis
Elderly (≥ 65 years)
Elderly patients may be at a greater risk for volume depletion and are more likely to be treated with diuretics.
Elderly patients are more likely to have impaired renal function, and/or to be treated with anti-hypertensive medicinal products that may cause changes in renal function such as angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II type 1 receptor blockers (ARB). The same recommendations for monitoring of renal function apply to elderly patients as to all patients (see sections 4.2, 4.4, 4.8, and 5.1).
Therapeutic experience with this medicinal product in patients 65 years and older is limited, and very limited in patients 75 years and older.
Skin disorders
Ulcerative and necrotic skin lesions have been reported in extremities of monkeys in non clinical toxicology studies with saxagliptin (see section 5.3). Skin lesions were not observed at an increased incidence in saxagliptin clinical trials. Post-marketing reports of rash have been described in the DPP-4 inhibitor class. Rash is also noted as an adverse reaction for this medicinal product (see section 4.8).
Therefore, in keeping with routine care of the diabetic patient, monitoring for skin disorders, such as blistering, ulceration or rash, is recommended.
Bullous pemphigoid
Post-marketing cases of bullous pemphigoid requiring hospitalisation have been reported with DPP-4 inhibitor use, including saxagliptin. In reported cases, patients typically responded to topical or systemic immunosuppressive treatment and discontinuation of the DPP4 inhibitor. If a patient develops blisters or erosions while receiving saxagliptin and bullous pemphigoid is suspected, this medicinal product should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment (see section 4.8).
Cardiac failure
There is no experience in clinical trials with dapagliflozin in NYHA class IV. Experience in NYHA class III-IV is limited with saxagliptin.
In the SAVOR trial, a small increase in the rate for hospitalisation for heart failure was observed in the saxagliptin-treated patients compared to placebo, although a causal relationship has not been established (see section 5.1). Additional analysis did not indicate a differential effect among NYHA classes.
Caution is warranted if the saxagliptin/dapagliflozin fixed dose combination is used in patients who have known risk factors for hospitalisation for heart failure, such as a history of heart failure or moderate to severe renal impairment. Patients should be advised of the characteristic symptoms of heart failure, and to immediately report such symptoms.
Arthralgia
Joint pain, which may be severe, has been reported in post-marketing reports for DPP-4 inhibitors (see section 4.8). Patients experienced relief of symptoms after discontinuation of the medicinal product and some experienced recurrence of symptoms with reintroduction of the same or another DPP-4 inhibitor. Onset of symptoms following initiation of therapy may be rapid or may occur after longer periods of treatment. If a patient presents with severe joint pain, continuation of therapy should be individually assessed.
Immunocompromised patients
Immunocompromised patients, such as patients who have undergone organ transplantation or patients diagnosed with human immunodeficiency syndrome have not been studied in the saxagliptin clinical programme. The efficacy and safety profile of the saxagliptin/dapagliflozin fixed dose combination in these patients has not been established.
Lower limb amputations
An increase in cases of lower limb amputation (primarily of the toe) has been observed in ongoing long-term, clinical studies with another SGLT2 inhibitor. It is unknown whether this constitutes a class effect. Like for all diabetic patients it is important to counsel patients on routine preventative foot care.
Use with medicinal products known to cause hypoglycaemia
Both saxagliptin and dapagliflozin can individually increase the risk of hypoglycaemia when combined with an insulin secretagogue. If this medicinal product is used in combination with insulin secretagogue (sulphonylurea), a reduction in the dose of sulphonylurea may be required to minimise the risk of hypoglycaemia (see section 4.8).
Urine laboratory assessments
Due to the mechanism of action of dapagliflozin, patients taking this medicinal product will test positive for glucose in their urine.
Use with potent CYP3A4 inducers
Using CYP3A4 inducers like carbamazepine, dexamethasone, phenobarbital, phenytoin, and rifampicin may reduce the glycaemic lowering effect of this medicinal product. Glycaemic control should be assessed when it is used concomitantly with a potent CYP3A4/5 inducer (see section 4.5).
Lactose
The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.
4.5 |
Qtern 5 mg/10 mg film-coated tablets | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Pharmacodynamic interactions
Diuretics
Dapagliflozin may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of dehydration and hypotension (see section 4.4).
Use with medicinal products known to cause hypoglycaemia
If this medicinal product is used in combination with insulin secretagogue (sulphonylurea), a reduction in the dose of sulphonylurea may be required to minimise the risk of hypoglycaemia (see section 4.4).
Pharmacokinetic interactions
Saxagliptin: The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5).
Dapagliflozin: The metabolism of dapagliflozin is primarily via glucuronide conjugation mediated by UDP glucuronosyltransferase 1A9 (UGT1A9).
Interactions with other oral anti-diabetic or cardiovascular medicinal products
Saxagliptin: Saxagliptin did not meaningfully alter the pharmacokinetics of dapagliflozin, metformin, glibenclamide, pioglitazone, digoxin, diltiazem or simvastatin. These medicinal products did not alter the pharmacokinetics of saxagliptin or its major active metabolite.
Dapagliflozin: Dapagliflozin did not meaningfully alter the pharmacokinetics of saxagliptin, metformin, pioglitazone, sitagliptin, glimepiride, voglibose, hydrochlorothiazide, bumetanide, valsartan, or simvastatin. These medicinal products did not alter the pharmacokinetics of dapagliflozin.
Effect of other medicinal products on saxagliptin or dapagliflozin
Saxagliptin: Concomitant administration of saxagliptin with the moderate inhibitor of CYP3A4/5 diltiazem, increased the Cmax and AUC of saxagliptin by 63% and 2.1-fold, respectively, and the corresponding values for the active metabolite were decreased by 44% and 34%, respectively. These pharmacokinetic effects are not clinically meaningful and do not require dose adjustment.
Concomitant administration of saxagliptin with the potent inhibitor of CYP3A4/5 ketoconazole, increased the Cmax and AUC of saxagliptin by 62% and 2.5-fold, respectively, and the corresponding values for the active metabolite were decreased by 95% and 88%, respectively. These pharmacokinetic effects are not clinically meaningful and do not require dose adjustment.
Concomitant administration of saxagliptin with the potent CYP3A4/5 inducer rifampicin reduced Cmax and AUC of saxagliptin by 53% and 76%, respectively. The exposure of the active metabolite and the plasma DPP-4 activity inhibition over a dose interval were not influenced by rifampicin (see section 4.4).
The coadministration of saxagliptin and CYP3A4/5 inducers, other than rifampicin (such as carbamazepine, dexamethasone, phenobarbital and phenytoin) has not been studied and may result in decreased plasma concentration of saxagliptin and increased concentration of its major metabolite.
Glycaemic control should be carefully assessed when saxagliptin is used concomitantly with a potent CYP3A4/5 inducer.
In studies conducted in healthy subjects, neither the pharmacokinetics of saxagliptin nor its major metabolite were meaningfully altered by metformin, glibenclamide, pioglitazone, digoxin, simvastatin, omeprazole, antacids or famotidine.
Dapagliflozin: Following coadministration of dapagliflozin with rifampicin (an inducer of various active transporters and drug-metabolising enzymes) a 22% decrease in dapagliflozin systemic exposure (AUC) was observed, but with no clinically meaningful effect on 24-hour urinary glucose excretion. No dose adjustment is recommended. A clinically relevant effect with other inducers (e.g. carbamazepine, phenytoin, phenobarbital) is not expected.
Following coadministration of dapagliflozin with mefenamic acid (an inhibitor of UGT1A9), a 55% increase in dapagliflozin systemic exposure was seen, but with no clinically meaningful effect on 24-hour urinary glucose excretion.
Effect of saxagliptin or dapagliflozin on other medicinal products
Saxagliptin: Saxagliptin did not meaningfully alter the pharmacokinetics of metformin, glibenclamide (a CYP2C9 substrate), pioglitazone [a CYP2C8 (major) and CYP3A4 (minor) substrate], digoxin (a P-gp substrate), simvastatin (a CYP3A4 substrate), the active components of a combined oral contraceptive (ethinylestradiol and norgestimate), diltiazem or ketoconazole.
Dapagliflozin: In interaction studies conducted in healthy subjects, using mainly a single-dose design, dapagliflozin did not alter the pharmacokinetics of metformin, pioglitazone [a CYP2C8 (major) and CYP3A4 (minor) substrate], sitagliptin, glimepiride (a CYP2C9 substrate), hydrochlorothiazide, bumetanide, valsartan, digoxin (a P-gp substrate) or warfarin (S-warfarin, a CYP2C9 substrate), or the anticoagulatory effects of warfarin as measured by INR. Combination of a single dose of dapagliflozin 20 mg and simvastatin (a CYP3A4 substrate) resulted in a 19% increase in AUC of simvastatin and 31% increase in AUC of simvastatin acid. The increase in simvastatin and simvastatin acid exposures are not considered clinically relevant.
Interference with 1,5-anhydroglucitol (1,5-AG) assay
Monitoring glycaemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycaemic control in patients taking SGLT2 inhibitors. Use of alternative methods to monitor glycaemic control is advised.
4.6 |
Qtern 5 mg/10 mg film-coated tablets | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
There are no data from the use of saxagliptin and dapagliflozin in pregnant women. Studies in animals with saxagliptin have shown reproductive toxicity at high doses (see section 5.3). Studies with dapagliflozin in rats have shown toxicity to the developing kidney in the time period corresponding to the second and third trimesters of human pregnancy (see section 5.3). Therefore, Qtern should not be used during pregnancy. If pregnancy is detected, treatment with Qtern should be discontinued.
Breast-feeding
It is unknown whether saxagliptin and dapagliflozin and/or its metabolites are excreted in human milk.
Animal studies have shown excretion of saxagliptin and/or metabolite in milk. Available pharmacodynamic/toxicological data in animals have shown excretion of dapagliflozin/metabolites in milk, as well as pharmacologically-mediated effects in breast-feeding offspring (see section 5.3). A risk to the newborns/infants cannot be excluded. Qtern should not be used while breast-feeding.
Fertility
The effect of saxagliptin and dapagliflozin on fertility in humans has not been studied. In male and female rats, dapagliflozin showed no effects on fertility at any dose tested. Effects on fertility were observed using saxagliptin in male and female rats at high doses producing overt signs of toxicity (see section 5.3).
4.7 |
Qtern 5 mg/10 mg film-coated tablets | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Qtern has no or negligible influence on the ability to drive and use machines. When driving or using machines, it should be taken into account that dizziness has been reported in studies with combined use of saxagliptin and dapagliflozin. In addition, patients should be alerted to the risk of hypoglycaemia if used in combination with other antidiabetic medicinal products known to cause hypoglycaemia (e.g. sulphonylureas).
4.8 |
Qtern 5 mg/10 mg film-coated tablets | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile of saxagliptin plus dapagliflozin
The combination of saxagliptin 5 mg and dapagliflozin 10 mg in 1 169 adults with type 2 diabetes mellitus (T2DM) and inadequate glycaemic control on metformin has been evaluated in three phase 3, randomised, double-blind, active/placebo-control, parallel group, multi-centre clinical trials for up to 52 weeks (see section 5.1). The pooled safety analysis comprised 3 treatment groups: saxagliptin plus dapagliflozin plus metformin (492 subjects), saxagliptin plus metformin (336 subjects), and dapagliflozin plus metformin (341 subjects). The safety profile of the combined use of saxagliptin plus dapagliflozin plus metformin was comparable to the adverse reactions identified for the respective mono-components.
The most frequently reported adverse reactions associated with Qtern are upper respiratory tract infections (very common), hypoglycaemia when used with SU (very common), and urinary tract infections (common). Diabetic ketoacidosis may occur rarely (see section 4.4).
Tabulated list of adverse reactions
The adverse reactions are presented in table 1. The safety profile is based on the summarised data from the saxagliptin/dapagliflozin combination clinical trials pooled safety data, and also clinical trials, post-authorisation safety studies and post-marketing experience with the mono-components. The adverse reactions are listed by system organ class (SOC) and frequency. Frequency categories were defined according to very common (≥ 1/10), common (≥ 1/ 100 to < 1/ 10), uncommon (≥ 1/1 000 to < 1/100), rare (1/10 000 to < 1/1 000), very rare (< 1/10 000), and not known (cannot be estimated from the available data).
Table 1. Compilation of reported adverse reactions
System organ class
Very common
CommonA
UncommonB
Rare
Very Rare
Not Known
Infections and infestations
Upper respiratory tract infection1
Urinary tract infection2, vulvovaginitis, balanitis and related genital infection3, gastroenteritisD
Fungal infection
Necrotising fasciitis of the perineum (Fournier's gangrene)C,F,7
Immune system disorders
Hypersensitivity reactionsC
Anaphylactic reactions including anaphylactic shockC
Metabolism and nutrition disorders
HypoglycaemiaD
(when used with SU)
Dyslipidaemia4
Volume depletionF, thirst
Diabetic KetoacidosisF,G,7
Nervous system disorders
Headache, dizziness
Gastro-intestinal disorders
Abdominal painC, diarrhoea, dyspepsiaD, gastritisD, nauseaC, vomitingD
Constipation, dry mouth, pancreatitisC
Skin and subcutaneous tissue disorders
Rash5
DermatitisC, pruritusC, urticariaC
AngioedemaC
Bullous pemphigoid C,7
Musculo-skeletal and connective tissue disorders
Arthralgia, back pain, myalgiaD
Renal and urinary disorders
Dysuria, polyuriaD,6
Nocturia
Reproductive system and breast disorders
Erectile dysfunction, pruritus genital, vulvovaginal pruritus
General disorders and administration site conditions
FatigueD, oedema peripheralD
Investigations
Creatinine renal clearance decreased during initial treatmentF, haematocrit increasedE
Blood creatinine increased during initial treatmentF, blood urea increased, weight decreased
A Adverse reactions reported in ≥ 2 % of subjects treated with the combined use of saxagliptin + dapagliflozin in the pooled safety analysis, or if reported in < 2% in the pooled safety analysis, they were based on the individual mono-components data.
B Frequencies of all uncommon adverse reactions were based on the individual mono-components data.
C Adverse reaction originates from saxagliptin or dapagliflozin post-marketing surveillance data.
D Adverse reactions were reported in ≥ 2 % of subjects with either mono-component and ≥ 1 % more than placebo, but not in the pooled analysis.
E Haematocrit values > 55 % were reported in 1.3 % of the subjects treated with dapagliflozin 10 mg versus 0.4 % of placebo subjects.
F Frequency is based on events in the dapagliflozin clinical programme.
G Reported in the dapagliflozin cardiovascular outcomes study in patients with type 2 diabetes (DECLARE). Frequency is based on annual rate.
1 Upper respiratory tract infection includes the following preferred terms: nasopharyngitis, influenza, upper respiratory tract infection, pharyngitis, rhinitis, sinusitis, pharyngitis bacterial, tonsillitis, acute tonsillitis, laryngitis, viral pharyngitis, and viral upper respiratory tract infection.
2 Urinary tract infection includes the following preferred terms: urinary tract infection, Escherichia urinary tract infection, pyelonephritis, and prostatitis.
3 Vulvovaginitis, balanitis and related genital infection include the following preferred terms: vulvovaginal mycotic infection, balanoposthitis, genital infection fungal, vaginal infection, and vulvovaginitis.
4 Dyslipidaemia includes the following preferred terms: dyslipidaemia, hyperlipidaemia, hypercholesterolaemia, and hypertriglyceridaemia.
5 Rash was reported during the post-marketing use of saxagliptin and dapagliflozin. Preferred terms reported in dapagliflozin clinical trials included in order of frequency: rash, rash generalised, rash pruritic, rash macular, rash maculo-papular, rash pustular, rash vesicular, and rash erythematous.
6 Polyuria includes the following preferred terms: polyuria, and pollakiuria.
7 See section 4.4
SU = sulphonylurea
Description of selected adverse reactions
Vulvovaginitis, balanitis and related genital infections
Saxagliptin/dapagliflozin combination: The reported adverse events of vulvovaginitis, balanitis and related genital infections from pooled safety analysis were reflective of the safety profile of dapagliflozin. Adverse events of genital infection were reported in 3.0 % in the saxagliptin plus dapagliflozin plus metformin group, 0.9 % of saxagliptin plus metformin group and 5.9 % of subjects in the dapagliflozin plus metformin group. The majority of the genital infection adverse events were reported in females (84 % of subjects with a genital infection), were mild or moderate in intensity, of single occurrence, and most patients continued on therapy.
Hypoglycaemia
In the pooled safety analysis, the overall incidence of hypoglycaemia (all reported events including those with central laboratory FPG ≤ 3.9 mmol/L) was 2.0% in subjects treated with saxagliptin 5 mg plus dapagliflozin 10 mg plus metformin (combination therapy), 0.6% in the saxagliptin plus metformin group, and 2.3% in the dapagliflozin plus metformin group.
In a 24-week study comparing the combination of saxagliptin and dapagliflozin plus metformin with or without SU, with insulin plus metformin with or without SU, the overall incidence rates for hypoglycaemia in patients without a background treatment of SU, were 12.7% for the combination compared to 33.1% for insulin. The overall incidence rates of hypoglycaemia in two 52-week studies comparing the combination therapy to glimepiride (SU) were: for the 1st study, 4.2% for the combination therapy versus 27.9% for glimepiride plus metformin versus 2.9% for dapagliflozin plus metformin; for the 2nd study, 18.5% for the combination therapy versus 43.1% for glimepiride plus metformin.
Volume depletion
Saxagliptin/dapagliflozin combination: Events suggestive of volume depletion (hypotension, dehydration, and hypovolaemia) were reported in two subjects (0.4%) in the saxagliptin plus dapagliflozin plus metformin group (serious adverse event [SAE] of syncope and an AE of urine output decreased), and 3 subjects (0.9%) in the dapagliflozin plus metformin group (2 AEs of syncope and 1 of hypotension).
Events related to decreased renal function
Saxagliptin/dapagliflozin combination: In the pooled safety analysis, the incidence of adverse events related to decreased renal function was 2.0% subjects in the saxagliptin plus dapagliflozin plus metformin group, 1.8% subjects in the saxagliptin plus metformin group, and 0.6% subjects in the dapagliflozin plus metformin group. Subjects with adverse events of renal impairment had lower mean eGFR values at baseline of 61.8 mL/min/1.73m2 compared to 93.6 mL/min/1.73m2 in the overall population. The majority of events were considered non-serious, mild or moderate in intensity, and resolved. The change in mean eGFR from baseline at week 24 was -1.17 mL/min/1.73m2 in the saxagliptin plus dapagliflozin plus metformin group, -0.46 mL/min/1.73 m2 in saxagliptin plus metformin, and 0.81 mL/min/1.73m2 in dapagliflozin plus metformin.
Dapagliflozin: Adverse reactions related to increased creatinine have been reported for dapagliflozin as a mono-component. The increases in creatinine were generally transient during continuous treatment or reversible after discontinuation of treatment.
Necrotising fasciitis of the perineum (Fournier's gangrene)
Cases of Fournier's gangrene have been reported post-marketing in patients taking SGLT2 inhibitors, including dapagliflozin (see section 4.4).
In the dapagliflozin cardiovascular outcomes study (DECLARE) with 17 160 type 2 diabetes mellitus patients and a median exposure time of 48 months, a total of 6 cases of Fournier's gangrene were reported, one in the dapagliflozin-treated group and 5 in the placebo group.
Diabetic ketoacidosis
In the dapagliflozin cardiovascular outcomes study (DECLARE), with a median exposure time of 48 months, events of DKA were reported in 27 patients in the dapagliflozin 10 mg group and 12 patients in the placebo group. The events occurred evenly distributed over the study period. Of the 27 patients with DKA events in the dapagliflozin group, 22 had concomitant insulin treatment at the time of the event. Precipitating factors for DKA were as expected in a type 2 diabetes mellitus population (see section 4.4).
Urinary tract infections
Saxagliptin/dapagliflozin combination: In the pooled safety analysis, urinary tract infections (UTIs) were balanced across the 3 treatment groups: 5.7% in the saxagliptin plus dapagliflozin plus metformin group, 7.4% in the saxagliptin plus metformin group and 5.6% in the dapagliflozin plus metformin group. One patient in the saxagliptin plus dapagliflozin plus metformin group experienced an SAE of pyelonephritis and discontinued treatment. The majority of the urinary tract infection adverse events were reported in females (81% of subjects with UTI), were mild or moderate in intensity, of single occurrence, and most patients continued on therapy.
Laboratory findings
Decrease in lymphocyte counts
Saxagliptin: In a pool of 5 placebo-controlled studies, a small decrease in absolute lymphocyte count was observed, approximately 100 cells/microl relative to placebo. Mean absolute lymphocyte counts remained stable with daily dosing up to 102 weeks in duration. This decrease in mean absolute lymphocyte count was not associated with clinically relevant adverse reactions.
Lipids
Saxagliptin/dapagliflozin combination: Data from the saxagliptin plus dapagliflozin plus metformin treatment arms of 3 phase 3 trials, demonstrated trends of mean percent increases from baseline (rounded to the nearest tenth) in total cholesterol (Total C), (ranging from 0.4% to 3.8%), LDL-C (ranging from 2.1% to 6.9%) and HDL-C (ranging 2.3% to 5.2%) along with mean percent decreases from baseline in triglycerides (ranging from -3.0% to -10.8%).
Special populations
Elderly
Saxagliptin/dapagliflozin combination: Of the 1 169 subjects treated in the pooled safety data from the 3 clinical trials, 1 007 subjects (86.1%) were aged < 65 years, 162 subjects (13.9%) were aged ≥ 65 years, and 9 subjects (0.8%) were aged ≥ 75 years. Generally, the most common adverse events reported in ≥ 65 years old were similar to < 65 years old. Therapeutic experience in patients 65 years and older is limited, and very limited in patients 75 years and older.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme: Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.