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Danaparoid Sodium 750 anti-Xa units/0.6 ml, solution for injection | Clinical particulars - Contraindications | Contraindications
• As with heparins, in patients receiving Danaparoid Sodium for treatment rather than for prophylaxis, locoregional anaesthesia in elective surgical procedures is contra-indicated.
• severe haemorrhagic diathesis, e.g. haemophilia and idiopathic thrombocytopenic purpura, unless the patient also has HIT and no alternative anti-thrombotic treatment is available
• haemorrhagic stroke in the acute phase
• uncontrollable active bleeding state
• severe renal- and/or hepatic insufficiency, unless the patient also has HIT and no alternative anti-thrombotic treatment is available
• severe uncontrolled hypertension
• active gastroduodenal ulcer, unless it is the reason for operation
• diabetic retinopathy
• acute bacterial endocarditis
• a positive in vitro aggregation test for the heparin-induced antibody in the presence of Danaparoid Sodium in patients with a history of thrombocytopenia induced by heparin or heparin-like anticoagulants
• hypersensitivity to sulphite.
• hypersensitivity to the active substance or to any of the excipients.
4.4 |
Danaparoid Sodium 750 anti-Xa units/0.6 ml, solution for injection | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Danaparoid Sodium should not be used if an in vitro test for the heparin-induced antibody in the presence of Danaparoid Sodium is positive in patients with thrombocytopenia induced by heparin or heparin-like anticoagulants, unless no suitable alternative antithrombotic treatment is available.
The incidence of serological cross-reactivity of Danaparoid Sodium with the heparin-induced antibody before the start of therapy is approximately 5%. The incidence of clinical cross-reactivity developing during Danaparoid Sodium therapy is approximately 3% and many of these patients had a negative pre-treatment serological cross-reactivity test. Although the risk of antibody-induced thrombocytopenia and thrombosis during Danaparoid Sodium therapy (i.e. clinical cross-reactivity) is very small, it is advisable to check the number of platelets daily during the first week of treatment, on alternate days during the second and third weeks, and weekly to monthly thereafter. If a pre-treatment cross-reactivity test with Danaparoid Sodium is positive but it is decided to use Danaparoid Sodium, then the number of platelets should be checked daily until Danaparoid Sodium treatment is stopped. If antibody-induced thrombocytopenia occurs, one should stop the use of Danaparoid Sodium and consider alternative treatment.
Danaparoid Sodium should not be administered to patients with severe hemorrhagic diathesis, e.g. hemophilia and idiopathic thrombocytopenic purpura, unless the patient also has HIT and no suitable alternative antithrombotic treatment is available.
Danaparoid Sodium should not be used in patients with severe renal and hepatic insufficiency unless the patient also has HIT and no alternative antithrombotic treatment is available.
Danaparoid Sodium should be used with caution in patients with moderately impaired renal, and/or liver function with impaired haemostasis, ulcerative lesions of the gastro-intestinal tract or other diseases which may lead to an increased danger of haemorrhage into a vital organ or site.
Danaparoid Sodium should not be administered to patients with active gastric or duodenal ulceration, unless it is the reason for operation.
• Since severe bleeding may occur post-operatively in HIT patients undergoing a cardiopulmonary bypass procedure, Danaparoid Sodium is not recommended during the procedure, unless no other antithrombotic treatment is available.
• Danaparoid Sodium contains sodium sulphite. In asthma patients hypersensitive to sulphite the latter can result in bronchospasm and/or anaphylactic shock.
• Danaparoid Sodium should not be given by the intramuscular route.
• The safety and efficacy of Danaparoid Sodium in patients with non-haemorrhagic stroke remains to be confirmed.
• No incidences of osteoporosis have been reported in patients treated with the recommended dose of Danaparoid Sodium. However, as for heparin, treatment with glycosaminoglycuronan may result in osteoporosis if the dosage is inappropriate.
• It should be noted that the anti-Xa units of Danaparoid Sodium have a different relationship to clinical efficacy than those of heparin and low molecular weight heparins.
• As with heparins, in patients undergoing peridural or spinal anaesthesia or spinal puncture, the prophylactic use of Danaparoid Sodium may theoretically be associated with epidural or spinal haematoma resulting in prolonged or permanent paralysis. The risk is increased by the prolonged use of a peridural or spinal catheter for analgesia, by the concomitant use of drugs affecting haemostasis such as nonsteroidal anti-inflammatory drugs (NSAIDs), and by traumatic or repeated puncture.
• In decision-making on the interval between the last administration of Danaparoid Sodium at prophylactic doses and the placement or removal of a peridural or spinal catheter, the product characteristics and the patient profile should be taken into account. Subsequent dose should not take place before at least four hours have elapsed. Re-administration should be delayed until the surgical procedure is completed.
• Should a physician decide to administer Danaparoid Sodium in the context of peridural or spinal anaesthesia, extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurologic impairment, such as back pain, sensory and motor deficits (numbness and weakness in lower limbs) and bowel or bladder dysfunction. Nurses should be trained to detect such signs and symptoms. Patients should be instructed to inform immediately a nurse or a clinician if they experience any of these.
• If signs or symptoms of epidural or spinal haematoma are suspected, urgent diagnosis and treatment including spinal cord decompression should be initiated.
4.5 |
Danaparoid Sodium 750 anti-Xa units/0.6 ml, solution for injection | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
In clinical studies no clinically significant interactions with other medications have been found. Danaparoid Sodium may be used together with oral anticoagulants, drugs which interfere with platelet function (such as aspirin and non-steroidal anti-inflammatory drugs) or potentially ulcerogenic drugs (such as corticosteroids), but caution remains necessary this is particularly important in patients undergoing peridural or spinal anaesthesia or spinal puncture (see section 4.4.). Monitoring of anticoagulant activity of oral anticoagulants by prothrombin time and thrombotest is unreliable within 5 hours after Danaparoid Sodium administration.
There is no data available on the effect of Danaparoid Sodium on thyroid function tests
Interaction studies have only been performed in adults.
4.6 Pregnancy and lactation
PregnancyDanaparoid Sodium has been used in over 60 pregnancies (starting during the first trimester in almost 50% of the pregnancies, the second trimester in approximately 20% of the pregnancies and the third trimester in 25% of the pregnancies. For a small number of patients the starting trimester is unknown). Overall, the use of Danaparoid Sodium was successful.
Animal studies have not demonstrated any teratogenic effect or placental transfer. In the few cases in which human umbilical cord blood was tested for the presence of anti-Xa activity, no activity was found.
Although Danaparoid Sodium has been used with success in a small number of pregnancies, the available information is still considered to be insufficient to assess whether deleterious effects may occur in pregnancy during the use of Danaparoid Sodium.
Caution should be exercised when prescribing to pregnant women. If alternative antithrombotic treatment is unacceptable for medical reasons (e.g. HIT patients) Danaparoid Sodium can be used.
LactationIn five cases in which breast milk samples were tested for anti-Xa activity, all showed no or negligible amounts of anti-Xa activity (which would be hydrolyzed in the infant's stomach and rendered harmless). Although the data are limited, if alternative antithrombotic treatment is unacceptable for medical reasons (e.g. HIT patients) Danaparoid Sodium can be used during lactation.
4.7 |
Danaparoid Sodium 750 anti-Xa units/0.6 ml, solution for injection | Clinical particulars - Fertility, pregnancy and lactation | Effects on ability to drive and use machines
Danaparoid Sodium is not known to have any effect on the ability to drive and use machines.
4.8 |
Danaparoid Sodium 750 anti-Xa units/0.6 ml, solution for injection | Clinical particulars - Effects on ability to drive and use machines | Undesirable effects
Enhanced bleeding or haematoma may occur at the operation site.
Bruising and/or pain may occur at injection sites.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Common
(≥1/100 to 1/10 of patients)
Uncommon
(≥1/1,000 to 1/100 of patients)
Rare
(≥1/10,000 to <1/1,000 of patients)
Blood and the lymphatic system disorders
thrombocytopenia*, heparin-induced thrombocytopenia
auto-immune thrombocytopenia
Immune system disorders
hypersensitivity, drug hypersensitivity
Skin and subcutaneous tissue disorders
rash
purpura, rash maculopapular, rash erythematous, pruritus, urticaria
rash generalised, rash maculovesicular, injection or infusion site rash, rash macular
General disorders and administration site conditions
Injection site reaction
Injection (inj.) site:
- hemorrhage
- discomfort
- hypersensitivity
- irritation
- coldness
- pruritus
inj. or infusion site:
- erythema
- pain
- swelling
- warmth
infusion site:
- bruising
- reaction
Injury, poisoning and procedural complications
post procedural hemorrhage
post procedural hematoma, operative hemorrhage
incision site hemorrhage, anastomotic hemorrhage
Note: terms are coded with MedDRA dictionary version 8.1
Antibody induced thrombocytopenia, as can be caused by (low molecular weight) heparin, was observed in rare cases during the use of Danaparoid Sodium, but only in patients who were already sensitised to either heparin or low molecular weight heparin (see section 4.4).
All above terms in this section and synonym terms (with same or less severity) coded with the MedDRA dictionary are considered as 'listed'.
All hemorrhages are listed adverse events for Danaparoid Sodium. This also means that symptoms or signs which are clearly directly related to a hemorrhage (e.g. anaemia, decreased Hb, rbc, hematocrit, faintness, tiredness, tamponade) are listed adverse events.
Liver abnormalities such as changes in transaminase and alkaline phosphatase have been observed, but no clinical significance has been demonstrated.
Very rarely, cases of epidural and spinal haematomas were reported in association with prophylactic use of heparins in the context of peridural or spinal anaesthesia and of spinal puncture. These haematomas have caused various degrees of neurological impairment, including prolonged or permanent paralysis (see Section 4.4 ' |
Danaparoid Sodium 750 anti-Xa units/0.6 ml, solution for injection | Clinical particulars - Undesirable effects | Special warnings and precautions for use').
4.9 |
Danaparoid Sodium 750 anti-Xa units/0.6 ml, solution for injection | Clinical particulars - Overdose | Overdose
In the event of serious bleeding other than caused by a surgical error, Danaparoid Sodium should be stopped and transfusion of fresh frozen plasma or, if uncontrollable, plasmapheresis should be considered. Although protamine partially neutralises the anticoagulant activity of Danaparoid Sodium the relevance for the reversal of the bleeding is not clear and therefore cannot be recommended. The effects of Danaparoid Sodium on anti-Xa activity cannot be antagonized with any known agent at this time.
5. Pharmacological properties
5.1 |
Danaparoid Sodium 750 anti-Xa units/0.6 ml, solution for injection | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Pharmacokinetic studies have primarily been based on the kinetics of relevant anticoagulant activities of danaparoid sodium, because no specific chemical assay methods are available. In animal models the time courses of the thrombin generation inhibitory activity and antithrombotic activities of danaparoid sodium were strongly related.
The absolute bioavailability of danaparoid sodium after subcutaneous administration approaches 100%. In humans the time to reach peak plasma anti-Xa activity levels is approximately 4-5 hours.
The half-lives of elimination of anti-Xa and thrombin generation inhibiting activities of approximately 25 hours and 7 hours respectively, after both subcutaneous and intravenous administration are independent of the dose. Steady-state levels of plasma anti-Xa activity are usually reached within 4-5 days of dosing. Measured by thrombin generation inhibiting activity steady-state levels are reached earlier, i.e. within 1-2 days.
Danaparoid sodium is mainly eliminated by renal excretion and animal experiments indicate that the liver is not involved in its metabolism. In patients with severely impaired renal function the half-life of elimination of plasma anti-factor Xa activity may be prolonged.
5.3 |
Danaparoid Sodium 750 anti-Xa units/0.6 ml, solution for injection | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
The results of pre-clinical studies do not add to the information included in the other sections of the SmPC.
6. |
Danaparoid Sodium 750 anti-Xa units/0.6 ml, solution for injection | Pharmaceutical particulars - List of excipients | List of excipients
Sodium sulphite
Sodium chloride
Hydrochloric acid
Water
Ph. Eur.
Ph. Eur.
Ph. Eur.
Ph. Eur.
6.2 |
Danaparoid Sodium 750 anti-Xa units/0.6 ml, solution for injection | Pharmaceutical particulars - Incompatibilities | Incompatibilities
When administered as an intravenous bolus or infusion, Danaparoid Sodium should be given separately and not mixed with other drugs. However, Danaparoid Sodium is compatible with, and therefore can be added to, infusions of saline, dextrose or dextrose-saline.
6.3 |
Danaparoid Sodium 750 anti-Xa units/0.6 ml, solution for injection | Pharmaceutical particulars - Shelf life | Shelf life
3 years.
6.4 |
Danaparoid Sodium 750 anti-Xa units/0.6 ml, solution for injection | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Do not store above 30°C. Do not freeze. Keep the ampoules in the outer carton to protect from light.
6.5 |
Danaparoid Sodium 750 anti-Xa units/0.6 ml, solution for injection | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
1-ml glass ampoules containing 750 anti-factor Xa units (0.6ml) danaparoid sodium per ampoule (1250 anti-factor Xa units/ml) in packs of 10 or 20 ampoules.
6.6 |
Danaparoid Sodium 750 anti-Xa units/0.6 ml, solution for injection | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
See section 4.2
7. |
Danaparoid Sodium 750 anti-Xa units/0.6 ml, solution for injection | Marketing authorisation holder | Generics [UK] Ltd. t/a Mylan
Station Close
Potters Bar
Hertfordshire
EN6 1TL
United Kingdom
8. Marketing authorisation number(s)
PL 46302/0228
9. |
Danaparoid Sodium 750 anti-Xa units/0.6 ml, solution for injection | Date of first authorisation/renewal of the authorisation | 14 April 1993/09 October 1998
10. |
Danaparoid Sodium 750 anti-Xa units/0.6 ml, solution for injection | Date of revision of the text | 01/2021 |
Dandrazol 2% Shampoo | Name of the medicinal product | Dandrazol 2% Shampoo
2. |
Dandrazol 2% Shampoo | Qualitative and quantitative composition | Ketoconazole 20mg/g.
Excipient with known effect:
Sodium laureth sulfate
For a full list of excipients see section 6.1
3. |
Dandrazol 2% Shampoo | Pharmaceutical form | Shampoo.
Clear, pink solution.
4. |
Dandrazol 2% Shampoo | Clinical particulars - Therapeutic indications | Therapeutic indications
Prevention and treatment of infections in which the yeast Malassezia (previously called Pityrosporum) is likely to be involved, such as dandruff, seborrhoeic dermatitis and tinea (pityriasis) versicolor.
4.2 |
Dandrazol 2% Shampoo | Clinical particulars - Posology and method of administration | Posology and method of administration
Adolescents and Adults:
Dandrazol 2% Shampoo is for use in adolescents and adults.
Shake the bottle well. Wash the hair or affected areas of the skin with Dandrazol shampoo. Leave in contact for 3-5 minutes before rinsing thoroughly.
* Seborrhoeic dermatitis and dandruff:
Treatment of: Use Dandrazol 2% shampoo twice weekly for 2-4 weeks.
Prophylaxis of: Use Dandrazol 2% shampoo once every 1-2 weeks.
* Tinea (Pityriasis) versicolor:
Treatment of: Use Dandrazol 2% Shampoo once daily for a maximum of 5 days.
Prophylaxis of: As patches of pityriasis versicolor become more apparent on exposure to the sun, Dandrazol 2% Shampoo may be used once daily for a maximum of 3 days in a single treatment course before exposure to sunshine.
Paediatric population:
The safe and effective use of Dandrazol 2% Shampoo in infants and children under the age of 12 years has not been established.
4.3 |
Dandrazol 2% Shampoo | Clinical particulars - Contraindications | Contraindications
Hypersensitivity to ketoconazole or any of the other ingredients of the preparation.
4.4 |
Dandrazol 2% Shampoo | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
To prevent a rebound effect after stopping prolonged treatment with topical corticosteroids, it is recommended to continue applying the topical corticosteroid together with Dandrazol 2% shampoo and to subsequently and gradually withdraw the steroid therapy over a period of 2-3 weeks.
Seborrhoeic dermatitis and dandruff are often associated with increased hair shedding, and this has also been reported, although rarely, with the use of ketoconazole containing shampoos (see Undesirable Effects).
Keep out of the eyes. If the shampoo should get into the eyes, they should be bathed with cold water.
This medicine contains 380 mg sodium laureth sulfate in 1 g. Sodium laureth sulfate may cause local skin reactions (such as stinging or burning sensation) or increase skin reactions caused by other products when applied on the same area.
4.5 |
Dandrazol 2% Shampoo | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
None known
4.6 |
Dandrazol 2% Shampoo | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Since no ketoconazole is detected in plasma following topical administration to the scalp, pregnancy and lactation are not a contra-indication for the use of Dandrazol 2% shampoo.
There are no adequate and well-controlled studies in pregnant or lactating women. Data on a limited number of exposed pregnancies indicate no adverse effects of topical ketoconazole on pregnancy or on the health of the foetus/newborn child. Animal studies have shown reproductive toxicity at doses that are not relevant to the topical administration of ketoconazole No effects on the breastfed newborn/infant are anticipated. See Pharmacokinetic properties, section 5.2.
Plasma concentrations of ketoconazole were not detectable after topical administration of ketoconazole 2% shampoo to the scalp of non-pregnant humans. Plasma levels were detected after topical administration of ketoconazole 2% shampoo on the whole body. There are no known risks associated with the use of ketoconazole 2% shampoo in pregnancy or lactation.
4.7 |
Dandrazol 2% Shampoo | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
None known
4.8 |
Dandrazol 2% Shampoo | Clinical particulars - Undesirable effects | Undesirable effects
The following table displays ADRs that have been reported with the use of Ketoconazole 2% Shampoo from either clinical trial or post marketing experiences.
The displayed frequency categories use the following convention:
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)
Not known (cannot be estimated form the available clinical trial data).
System Organ Class
Adverse Drug Reactions
Frequency Category
Uncommon
(≥1/1,000 to <1/100)
Rare
(≥1/10,000 and <1/1,000)
Not Known
Immune System disorders
Hypersensitivity
Nervous System Disorders
Dysgeusia
Infections and Infestations
Folliculitis
Eye Disorders
Increased lacrimation
Eye irritation
Skin and Subcutaneous Tissue Disorders
Alopecia
Dry skin
Hair texture abnormal
Rash
Skin burning sensation
Acne
Dermatitis contact
Skin disorder
Skin exfoliation
Angioedema
Urticaria
Hair colour changes
General Disorders and Administration Site Conditions
Application site erythema
Application site irritation
Application site pruritus
Application site reaction
Application site hypersensitivity
Application site pustules
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 at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Dandrazol 2% Shampoo | Clinical particulars - Overdose | Overdose
In the event of accidental ingestion, only supportive measures should be carried out. In order to avoid aspiration, neither emesis nor gastric lavage should be instigated.
5. Pharmacological properties
5.1 |
Dandrazol 2% Shampoo | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Ketoconazole does not appear to be appreciably absorbed systemically following topical application of a 2% shampoo to skin. Ketoconazole was not detected in plasma of patients receiving topical application of 2% shampoo 4-10 times weekly for 6 months, or in patients using 2% shampoo 2-3 times weekly for an average of 16 months. Following a single topical application, substantial amounts of the drug were detected in hair 12 hours after application; however only 5% of the applied ketoconazole was detected in hair keratin. Following repeated (twice weekly for 2 months) application, 20% of the applied dose was detected in hair keratin.
5.3 |
Dandrazol 2% Shampoo | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
In vitro studies using ketoconazole in a microbial system (i.e., Ames test) have not shown the drug to be mutagenic. In addition, there was no evidence of mutagenicity in any stage of germ cell development in a dominant lethal mutation test in mice who received single oral doses of ketoconazole as high as 80 mg/kg. There was no evidence of carcinogenicity in a long-term feeding study in mice and rats. Hepatotoxicity featured prominently in high dose toxicology studies in animals and occurs in about 1 in 10,000 patients.
6. |
Dandrazol 2% Shampoo | Pharmaceutical particulars - List of excipients | List of excipients
Sodium laureth sulfate
Disodium laureth sulfosuccinate
PEG-120 Methyl glucose dioleate
PEG-7-Glyceryl Cocoate
Imidurea
Lauryldimonium hydroxypropyl hydrolysed collagen
Cocamide DEA
Sodium hydroxide
Sodium chloride
Erythrosine C.I. 45430 (E127)
Hydrochloric acid concentrated
Purified water
6.2 |
Dandrazol 2% Shampoo | Pharmaceutical particulars - Incompatibilities | Incompatibilities
None known
6.3 |
Dandrazol 2% Shampoo | Pharmaceutical particulars - Shelf life | Shelf life
2 years
6.4 |
Dandrazol 2% Shampoo | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Do not store above 25 °C
6.5 |
Dandrazol 2% Shampoo | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
White opaque HDPE bottle with PP closure.
Pack sizes 60, 80, 100, 120, 125, 150ml.
6.6 |
Dandrazol 2% Shampoo | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
No special instructions.
7. |
Dandrazol 2% Shampoo | Marketing authorisation holder | Transdermal Limited
Merlin House
Brunel Road
Theale
Reading RG7 4AB
United Kingdom
8. Marketing authorisation number(s)
PL 14308/0004
9. |
Dandrazol 2% Shampoo | Date of first authorisation/renewal of the authorisation | 30/01/2009
10. |
Dandrazol 2% Shampoo | Date of revision of the text | 07/10/2021 |
Dandrazol Anti-Dandruff Shampoo | Name of the medicinal product | Dandrazol Anti-Dandruff Shampoo
2. |
Dandrazol Anti-Dandruff Shampoo | Qualitative and quantitative composition | Ketoconazole 20mg/g.
Excipient with known effect:
Sodium laureth sulfate
For a full list of excipients see section 6.1
3. |
Dandrazol Anti-Dandruff Shampoo | Pharmaceutical form | Shampoo.
Clear, pink solution.
4. |
Dandrazol Anti-Dandruff Shampoo | Clinical particulars - Therapeutic indications | Therapeutic indications
Prevention and treatment of dandruff.
4.2 |
Dandrazol Anti-Dandruff Shampoo | Clinical particulars - Posology and method of administration | Posology and method of administration
Adults and Adolescents aged over 12:
Dandrazol Anti-Dandruff Shampoo is for use in adults and children over 12 years.
Shake the bottle well. Wash the hair or affected areas of the skin with the Shampoo. Leave in contact for 3-5 minutes before rinsing thoroughly.
Treatment of: Use Dandrazol Anti-Dandruff Shampoo twice weekly for 2-4 weeks.
Prophylaxis of: Use Dandrazol Anti-Dandruff Shampoo once every 1-2 weeks.
Do not use more than directed.
Paediatric population
The safe and effective use of Dandrazol Anti-Dandruff Shampoo in infants and children under the age of 12 years has not been established.
Method of administration
For topical administration.
4.3 |
Dandrazol Anti-Dandruff Shampoo | Clinical particulars - Contraindications | Contraindications
Known hypersensitivity to the active substance ketoconazole or to any of the excipients listed in section 6.1.
4.4 |
Dandrazol Anti-Dandruff Shampoo | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
To prevent a rebound effect after stopping prolonged treatment with topical corticosteroids, it is recommended to continue applying the topical corticosteroid together with Dandrazol Anti-Dandruff Shampoo and to subsequently and gradually withdraw the steroid therapy over a period of 2-3 weeks.
Dandruff is associated with increased hair shedding, and this has also been reported, although rarely, with the use of ketoconazole containing shampoos (see Undesirable Effects).
Keep out of the eyes. If the shampoo should get into the eyes, they should be bathed with cold water.
If the scalp has not cleared within 4 weeks, a doctor or pharmacist should be consulted.
This medicine contains 380 mg sodium laureth sulfate in 1 g. Sodium laureth sulfate may cause local skin reactions (such as stinging or burning sensation) or increase skin reactions caused by other products when applied on the same area.
4.5 |
Dandrazol Anti-Dandruff Shampoo | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
None known
4.6 |
Dandrazol Anti-Dandruff Shampoo | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Since no ketoconazole is detected in plasma following topical administration to the scalp, pregnancy and lactation are not a contra-indication for the use of Dandrazol Anti-Dandruff Shampoo.
There are no adequate and well-controlled studies in pregnant or lactating women. Data on a limited number of exposed pregnancies indicate no adverse effects of topical ketoconazole on pregnancy or on the health of the foetus/newborn child. Animal studies have shown reproductive toxicity at doses that are not relevant to the topical administration of ketoconazole No effects on the breastfed newborn/infant are anticipated. See Pharmacokinetic properties, section 5.2.
Plasma concentrations of ketoconazole were not detectable after topical administration of ketoconazole 2% shampoo to the scalp of non-pregnant humans. Plasma levels were detected after topical administration of ketoconazole 2% shampoo on the whole body. There are no known risks associated with the use of ketoconazole 2% shampoo in pregnancy or lactation.
4.7 |
Dandrazol Anti-Dandruff Shampoo | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
None known
4.8 |
Dandrazol Anti-Dandruff Shampoo | Clinical particulars - Undesirable effects | Undesirable effects
The following table displays ADRs that have been reported with the use of Ketoconazole 2% Shampoo from either clinical trial or post marketing experiences. The displayed frequency categories use the following convention:
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 clinical trial data).
Table 1: Adverse Drug Reactions
System Organ Class
Adverse Drug Reactions
Frequency Category
Uncommon
(≥1/1,000 to <1/100)
Rare
(≥1/10,000 and <1/1,000)
Not Known
Immune System disorders
Hypersensitivity
Nervous System Disorders
Dysgeusia
Infections and Infestations
Folliculitis
Eye Disorders
Increased lacrimation
Eye irritation
Skin and Subcutaneous Tissue Disorders
Alopecia
Dry skin
Hair texture abnormal
Rash
Skin burning sensation
Acne
Dermatitis contact
Skin disorder
Skin exfoliation
Angioedema
Urticaria
Hair colour changes
General Disorders and Administration Site Conditions
Application site erythema
Application site irritation
Application site pruritus
Application site reaction
Application site hypersensitivity
Application site pustules
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 at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 |
Dandrazol Anti-Dandruff Shampoo | Clinical particulars - Overdose | Overdose
In the event of accidental ingestion, only supportive measures should be carried out. In order to avoid aspiration, neither emesis nor gastric lavage should be instigated.
5. Pharmacological properties
5.1 |
Dandrazol Anti-Dandruff Shampoo | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Ketoconazole does not appear to be appreciably absorbed systemically following topical application of a 2% shampoo to skin. Ketoconazole was not detected in plasma of patients receiving topical application of 2% shampoo 4-10 times weekly for 6 months, or in patients using 2% shampoo 2-3 times weekly for an average of 16 months. Following a single topical application, substantial amounts of the drug were detected in hair 12 hours after application; however only 5% of the applied ketoconazole was detected in hair keratin. Following repeated (twice weekly for 2 months) application, 20% of the applied dose was detected in hair keratin.
5.3 |
Dandrazol Anti-Dandruff Shampoo | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
In vitro studies using ketoconazole in a microbial system (i.e., Ames test) have not shown the drug to be mutagenic. In addition, there was no evidence of mutagenicity in any stage of germ cell development in a dominant lethal mutation test in mice who received single oral doses of ketoconazole as high as 80 mg/kg. There was no evidence of carcinogenicity in a long-term feeding study in mice and rats. Hepatotoxicity featured prominently in high dose toxicology studies in animals and occurs in about 1 in 10,000 patients.
6. |
Dandrazol Anti-Dandruff Shampoo | Pharmaceutical particulars - List of excipients | List of excipients
Sodium laureth sulfate
Disodium laureth sulfosuccinate
PEG-120 Methyl glucose dioleate
PEG-7-Glyceryl Cocoate
Imidurea
Lauryldimonium hydroxypropyl hydrolysed collagen
Cocamide DEA
Sodium hydroxide
Sodium chloride
Erythrosine C.I. 45430 (E127)
Hydrochloric acid concentrated
Purified water
6.2 |
Dandrazol Anti-Dandruff Shampoo | Pharmaceutical particulars - Incompatibilities | Incompatibilities
None known
6.3 |
Dandrazol Anti-Dandruff Shampoo | Pharmaceutical particulars - Shelf life | Shelf life
2 years
6.4 |
Dandrazol Anti-Dandruff Shampoo | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Do not store above 25 °C
6.5 |
Dandrazol Anti-Dandruff Shampoo | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
White opaque HDPE bottle with PP closure.
Pack sizes 60, 80, 100ml.
6.6 |
Dandrazol Anti-Dandruff Shampoo | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
No special instructions.
7. |
Dandrazol Anti-Dandruff Shampoo | Marketing authorisation holder | Transdermal Limited
Merlin House
Brunel Road
Theale
Reading RG7 4AB
United Kingdom
8. Marketing authorisation number(s)
PL 14308/0006
9. |
Dandrazol Anti-Dandruff Shampoo | Date of first authorisation/renewal of the authorisation | 30/01/2009
10. |
Dandrazol Anti-Dandruff Shampoo | Date of revision of the text | 13/10/2021 |
Dantrium 100 mg Capsules | Name of the medicinal product | Dantrium Capsules 100 mg
2. |
Dantrium 100 mg Capsules | Qualitative and quantitative composition | Each capsule contains 100 mg dantrolene sodium
Excipient with known effect: lactose monohydrate and wheat starch.
For a full list of excipients, see section 6.1.
3. |
Dantrium 100 mg Capsules | Pharmaceutical form | Hard capsule
Dantrium Capsules are presented in as orange/orange capsules.
4. |
Dantrium 100 mg Capsules | Clinical particulars - Therapeutic indications | Therapeutic indications
Dantrium Capsules are indicated for the treatment of chronic, severe spasticity of skeletal muscle in adults.
4.2 |
Dantrium 100 mg Capsules | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
Dosage for Use in Spasticity for Adults
For the individual patient the lowest dose compatible with optimal response is recommended. A recommended dosage increment scale is shown below:
1st week One 25 mg capsule daily
2nd week One 25 mg capsule twice daily
3rd week Two 25 mg capsules twice daily
4th week Two 25 mg capsules three times daily
5th week Three 25 mg capsules three times daily
6th week Three 25 mg capsules four times daily
7th week One 100 mg capsule four times daily.
Each dosage level should be maintained for seven days in order to determine the patient's response. Therapy with a dose four times daily may offer maximum benefit to some patients. Maximum daily dose should not exceed 400 mg. In view of the potential for hepatotoxicity with long term use, if no observable benefit is derived from the administration of Dantrium after a total of 6-8 weeks, therapy should be discontinued.
Elderly
A similar dosage titration schedule should be used with the elderly.
Paediatric population
Dantrium is not recommended for use in children.
Method of administration
For oral use.
4.3 |
Dantrium 100 mg Capsules | Clinical particulars - Contraindications | Contraindications
Dantrium is contraindicated where spasticity is utilised to sustain upright posture and balance in locomotion or whenever spasticity is utilised to obtain or maintain increased function.
Dantrium is contraindicated in patients with evidence of hepatic dysfunction.
Dantrium is not indicated for the treatment of acute skeletal muscle spasms. Dantrium should not be administered to children.
Dantrium is contraindicated in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Wheat allergy (other coeliac disease) (see section 4.4).
4.4 |
Dantrium 100 mg Capsules | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Fatal and non-fatal liver disorders of an idiosyncratic or hypersensitivity type may occur with Dantrium therapy.
Patients should be instructed to contact their physician should signs or symptoms of hepatotoxicity (e.g., discoloured faeces, generalised pruritus, jaundice, anorexia, nausea, vomiting) occur during therapy.
Factors that may increase the risk of developing hepatotoxicity include:
- Higher daily doses (doses exceeding 400 mg daily)
- Duration of therapy (most frequently reported between 2 and 12 months of treatment)
- Female gender
- Age greater than 30 years
- Prior history of liver disease/dysfunction
- Receiving other hepatotoxic therapies concomitantly.
Spontaneous reports also suggest a higher proportion of hepatic events with fatal outcome in elderly patients.
At the start of Dantrium therapy, it is desirable to do liver function studies (SGOT/AST, SGPT/ALT, alkaline phosphatase, total bilirubin) for a baseline or to establish whether there is pre-existing liver disease. If baseline liver abnormalities exist and are confirmed, there is a clear possibility that the potential for Dantrium hepatotoxicity could be enhanced, although such a possibility has not yet been established.
Liver functions studies (e.g. serum, SGOT/AST, SGPT/ALT) should be performed at appropriate intervals during Dantrium therapy. If such studies reveal abnormal values, therapy should generally be discontinued. Only where benefits of the drug have been of major importance to the patient, should re-introduction or continuation of therapy be considered.
Some patients have revealed a return to normal laboratory values in the face of continued therapy while others have not.
If symptoms compatible with hepatitis, accompanied by abnormalities in liver function tests or jaundice appear, Dantrium should be discontinued. If caused by Dantrium and detected early, the abnormalities in liver function have reverted to normal when the drug was discontinued.
Dantrium has been re-introduced in a few patients who have developed clinical signs, or elevated serum enzymes, of hepatocellular injury.
Re-introduction of Dantrium therapy should only be contemplated in patients who clearly need the drug, and only after complete reversal of the signs of hepatotoxicity and liver function tests. Patients being re-challenged with Dantrium should be hospital in-patients, and small, gradually increasing doses should be used. Laboratory test monitoring should be frequent, and the drug should be withdrawn immediately if there is any indication of recurrent liver abnormality. Some patients have reacted with unmistakable signs of liver abnormality upon administration of a challenge dose, whilst others have not.
The use of Dantrium with other potentially hepatotoxic drugs should be avoided.
There are isolated cases of possibly significant effects of Dantrium on the cardiovascular and respiratory systems. These cases also have other features suggesting a pre-disposition to cardiovascular disease, and impaired respiratory function, particularly obstructive pulmonary disease. Dantrium should be used with caution in such patients.
Caution should be exercised in the simultaneous administration of tranquillising agents and alcohol.
This medicine contains only very low levels of gluten (from wheat starch). It is regarded as 'gluten-free' and is very unlikely to cause problems in case of coeliac disease.
One capsule contains no more than 3.3 micrograms of gluten.
4.5 |
Dantrium 100 mg Capsules | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Hyperkalaemia and myocardial depression have been observed in malignant hyperthermia-susceptible patients receiving intravenous dantrolene sodium and concomitant calcium channel blockers.
The effects of non-depolarizing muscle relaxants may be potentiated in patients administered Dantrium.
4.6 |
Dantrium 100 mg Capsules | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
Although teratological studies in animals have proved satisfactory, Dantrolene sodium does cross the placenta and therefore the use of Dantrium is not advised during pregnancy.
Breast-feeding
Dantrolene sodium crosses the placenta, and has been detected in human milk. Therefore, the use of Dantrium is not advised in nursing mothers.
Fertility
There is no data on the effects of Dantrium on human fertility.
4.7 |
Dantrium 100 mg Capsules | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Patients should be advised not to drive a motor vehicle or undertake potentially dangerous work until Dantrium therapy has been stabilised, because some patients experience drowsiness and dizziness.
4.8 |
Dantrium 100 mg Capsules | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
The most frequently reported unwanted effects associated with the use of Dantrium have been drowsiness, dizziness, weakness, general malaise, fatigue and diarrhoea. These effects are generally transient, occur early in treatment, and can often be obviated by careful determination and regulation of the dosage. Diarrhoea may be severe, and may necessitate temporary withdrawal of Dantrium. If diarrhoea recurs upon re-introduction of Dantrium, then Dantrium therapy should probably be withdrawn permanently.
Dantrium has a potential for hepatotoxicity. Symptomatic hepatitis (fatal and non-fatal) has been reported at various dose levels although the incidence is greater in patients taking more than 400 mg/day. Liver dysfunction as evidenced by blood chemical abnormalities alone (liver enzyme elevation) has been observed in patients exposed to Dantrium for varying periods of time.
Overt hepatitis has occurred at varying intervals after initiation of therapy, but has most frequently been observed between the second and twelfth month of treatment. The risk of hepatic injury appears to be greater in females, in patients over 30 years old and in patients taking concomitant medication. There is some evidence that hepatic injury is more likely in patients using concomitant oral oestrogen.
Tabulated list of adverse reactions
System Organ Class
Frequency
Adverse Drug Reactions
Metabolism and nutrition disorders
Common
Anorexia
Psychiatric disorders
Common
Mental depression, mental confusion, insomnia, nervousness
Nervous system disorders
Common
Seizure, visual disturbances, speech disturbances, headache
Cardiac disorders
Common
Pericarditis
Uncommon
Exacerbation of pre-existing cardiac insufficiency,
Unknown
Bradycardia, tachycardia
Vascular disorders
Unknown
Labile blood pressure
Respiratory, thoracic and mediastinal disorders
Common
Pleural effusion with associated eosinophilia, respiratory depression
Unknown
Dyspnoea
Gastrointestinal disorders
Common
Nausea and/or vomiting, abdominal pain
Uncommon
Dysphagia, constipation (rarely progressing to signs of intestinal obstruction)
Unknown
Gastrointestinal bleeding
Hepatobiliary disorders
Common
Hepatotoxicity (see section 4.4), liver function test disturbances
Unknown
Jaundice, hepatitis
Skin and subcutaneous disorders
Common
Acne-like rash, skin rash
Uncommon
Sweating
Renal and urinary disorders
Uncommon
Incontinence, increased urinary frequency, urinary retention, haematuria, crystalluria
General disorders and administration site conditions
Common
Chills and /or fever
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 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 |
Dantrium 100 mg Capsules | Clinical particulars - Overdose | Overdose
There is no known constellation of symptoms with acute overdose. Symptoms that may occur include, but are not limited to, muscular weakness, alterations in the state of consciousness (e.g. lethargy, coma), vomiting, and diarrhoea. For acute over dosage, general supportive measures and gastric lavage should be employed as well as measures to reduce the absorption of Dantrium. The theoretical possibility of crystalluria in overdose has not been reported for Dantrium, but would be treated according to general principles, including administration of fluids. The value of dialysis in dantrolene sodium overdose is not known.
5. Pharmacological properties
5.1 |
Dantrium 100 mg Capsules | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Absorption
Dantrolene sodium is easily and almost completely absorbed from the gastrointestinal tract. After dosing on an empty stomach, plasma dantrolene sodium levels peak within three hours in most subjects.
Distribution
Dantrolene sodium is a highly lipophobic drug. In addition it lacks hydrophilicity. Dantrolene sodium binds to human serum albumin (HSA) with a molar ratio of 0.95 to 1.68 in-vitro. The association constant in-vitro is higher (2.3 to 5.4 x 10 -5 per mol). In-vitro dantrolene sodium can be displaced from HSA by warfarin, clofibrate and tolbutamide but these interactions have not been confirmed in humans (re. manufacturer's database). Single intravenous dose studies suggest that the primary volume of distribution is about 15 litres. Single oral doses achieve peak plasma concentration of about a quarter of that for a similarly sized intravenous dose.
Metabolism and Elimination
The biological half-life in plasma in most human subjects is between 5 and 9 hours, although half-lives as long as 12.1 ± 1.9 hours have been reported after a single intravenous dose. Inactivation is by hepatic metabolism in the first instance. There are two alternative pathways. Most of the drug is hydroxylated to 5-hydroxy-dantrolene. The minor pathway involves nitro-reduction to amino-dantrolene which is then acetylated (compound F-490). The 5-hydroxy metabolite is a muscle relaxant with nearly the same potency as the parent molecule, and may have a longer half-life than the parent compound. Compound F-490 is much less potent and is probably inactive at the concentrations achieved in clinical samples. Metabolites are subsequently excreted in the urine in the ratio of 79 5-hydroxy-dantrolene: 17 compound F-490: 4 unaltered dantrolene (salt or free acid). The proportion of drug excreted in the faeces depends upon dose size.
5.3 |
Dantrium 100 mg Capsules | Pharmacodynamic properties - Pharmacokinetic properties | Preclinical safety data
Carcinogenicity
Dantrolene sodium showed some evidence of tumourgenicity at high dose levels in Sprague-Dawley female rats. However, these effects were not seen in other studies in Fischer 344 rats or HaM/ICR mice. There is no clinical evidence of carcinogenicity in humans; however, this possibility cannot be absolutely excluded.
Sprague-Dawley female rats fed dantrolene sodium for 18 months at dosage levels of 15, 30 and 60 mg/kg/day showed an increased incidence of benign and malignant mammary tumours compared with concurrent controls. At the highest dose level, there was an increase in the incidence of benign hepatic lymphatic neoplasms. In a 30-month study at the same dose levels also in Sprague-Dawley rats, dantrolene sodium produced a decrease in the time of onset of mammary neoplasms. Female rats at the highest dose level showed an increased incidence of hepatic lymphangiomas and hepatic angiosarcomas.
The only drug-related effect seen in a 30-month study in Fischer-344 rats was a dose-related reduction in the time of onset of mammary and testicular tumours. A 24-month study in HaM/ICR mice revealed no evidence of carcinogenic activity.
The significance of carcinogenicity data relative to use of dantrolene sodium in humans is unknown.
Mutagenicity
Dantrolene sodium has produced positive results in the Ames S. Typhimurium bacterial mutagenesis assay in the presence and absence of a liver activating system.
Reproductive toxicity
Dantrolene sodium administered to male and female rats at dose levels up to 45 mg/kg/day showed no adverse effects on fertility or general reproductive performance.
6. |
Dantrium 100 mg Capsules | Pharmaceutical particulars - List of excipients | List of excipients
Capsule content
Wheat starch
Talc
Magnesium stearate
Lactose monohydrate
Capsule shell
Gelatine
Titanium dioxide (E171)
Erythrosine (127)
Iron oxide
6.2 |
Dantrium 100 mg Capsules | Pharmaceutical particulars - Incompatibilities | Incompatibilities
Not applicable.
6.3 |
Dantrium 100 mg Capsules | Pharmaceutical particulars - Shelf life | Shelf life
3 years
6.4 |
Dantrium 100 mg Capsules | Pharmaceutical particulars - Special precautions for storage | Special precautions for storage
Store capsules in the blister and outer packaging away from light and moisture.
6.5 |
Dantrium 100 mg Capsules | Pharmaceutical particulars - Nature and contents of container | Nature and contents of container
Polyvinyl chloride/aluminium Blister Packs
6.6 |
Dantrium 100 mg Capsules | Pharmaceutical particulars - Special precautions for disposal and other handling | Special precautions for disposal and other handling
No special requirements.
A patient leaflet is provided for details of use and handling of the product.
7. |
Dantrium 100 mg Capsules | Marketing authorisation holder | Norgine Pharmaceuticals Limited
Norgine House
Widewater Place
Moorhall Road
Harefield
Uxbridge
UB9 6NS
UK
8. Marketing authorisation number(s)
PL 20011/0033
9. |
Dantrium 100 mg Capsules | Date of first authorisation/renewal of the authorisation | 25 October 1989
10. |
Dantrium 100 mg Capsules | Date of revision of the text | 04th January 2022 |
Dantrium 25mg Capsules | Name of the medicinal product | Dantrium Capsules 25 mg
2. |
Dantrium 25mg Capsules | Qualitative and quantitative composition | Each capsule contains 25 mg dantrolene sodium.
Excipient with known effect: lactose monohydrate and wheat starch.
For a full list of excipients, see section 6.1.
3. |
Dantrium 25mg Capsules | Pharmaceutical form | Hard capsule
Dantrium Capsules 25 mg are presented as light brown/orange capsules.
4. |
Dantrium 25mg Capsules | Clinical particulars - Therapeutic indications | Therapeutic indications
Dantrium Capsules are indicated for the treatment of chronic, severe spasticity of skeletal muscle in adults.
4.2 |
Dantrium 25mg Capsules | Clinical particulars - Posology and method of administration | Posology and method of administration
Posology
Dosage for Use in Spasticity for Adults
For the individual patient the lowest dose compatible with optimal response is recommended. A recommended dosage increment scale is shown below:
1st week
One 25 mg capsule daily
2nd week
One 25 mg capsule twice daily
3rd week
Two 25 mg capsules twice daily
4th week
Two 25 mg capsules three times daily
5th week
Three 25 mg capsules three times daily
6th week
Three 25 mg capsules four times daily
7th week
One 100 mg capsule four times daily.
Each dosage level should be maintained for seven days in order to determine the patient's response. Therapy with a dose four times daily may offer maximum benefit to some patients. Maximum daily dose should not exceed 400 mg. In view of the potential for hepatotoxicity with long term use, if no observable benefit is derived from the administration of Dantrium after a total of 6-8 weeks, therapy should be discontinued.
Elderly
A similar dosage titration schedule should be used with the elderly.
Paediatric population
Dantrium is not recommended for use in children.
Method of administration
For oral use.
4.3 |
Dantrium 25mg Capsules | Clinical particulars - Contraindications | Contraindications
Dantrium is contraindicated where spasticity is utilised to sustain upright posture and balance in locomotion or whenever spasticity is utilised to obtain or maintain increased function. Dantrium is contraindicated in patients with evidence of hepatic dysfunction. Dantrium is not indicated for the treatment of acute skeletal muscle spasms.
Dantrium is contraindicated in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Wheat allergy (other than coeliac disease), (see section 4.4).
4.4 |
Dantrium 25mg Capsules | Clinical particulars - Special warnings and precautions for use | Special warnings and precautions for use
Fatal and non-fatal liver disorders of an idiosyncratic or hypersensitivity type may occur with Dantrium therapy.
Patients should be instructed to contact their physician should signs or symptoms of hepatotoxicity (e.g., discoloured faeces, generalised pruritus, jaundice, anorexia, nausea, vomiting) occur during therapy.
Factors that may increase the risk of developing hepatotoxicity include:
- Higher daily doses (doses exceeding 400 mg daily)
- Duration of therapy (most frequently reported between 2 and 12 months of treatment)
- Female gender
- Age greater than 30 years
- Prior history of liver disease/dysfunction
- Receiving other hepatotoxic therapies concomitantly.
Spontaneous reports also suggest a higher proportion of hepatic events with fatal outcome in elderly patients.
At the start of Dantrium therapy, it is desirable to do liver function studies (SGOT/AST, SGPT/ALT, alkaline phosphatase, total bilirubin) for a baseline or to establish whether there is pre-existing liver disease. If baseline liver abnormalities exist and are confirmed, there is a clear possibility that the potential for Dantrium hepatotoxicity could be enhanced, although such a possibility has not yet been established.
Liver functions studies (e.g. serum, SGOT/AST, SGPT/ALT) should be performed at appropriate intervals during Dantrium therapy. If such studies reveal abnormal values, therapy should generally be discontinued. Only where benefits of the drug have been of major importance to the patient, should re-introduction or continuation of therapy be considered. Some patients have revealed a return to normal laboratory values in the face of continued therapy while others have not.
If symptoms compatible with hepatitis, accompanied by abnormalities in liver function tests or jaundice appear, Dantrium should be discontinued. If caused by Dantrium and detected early, the abnormalities in liver function have reverted to normal when the drug was discontinued.
Dantrium has been re-introduced in a few patients who have developed clinical signs, or elevated serum enzymes, of hepatocellular injury.
Re-introduction of Dantrium therapy should only be contemplated in patients who clearly need the drug, and only after complete reversal of the signs of hepatotoxicity and liver function tests. Patients being re-challenged with Dantrium should be hospital in-patients, and small, gradually increasing doses should be used. Laboratory test monitoring should be frequent, and the drug should be withdrawn immediately if there is any indication of recurrent liver abnormality. Some patients have reacted with unmistakable signs of liver abnormality upon administration of a challenge dose, whilst others have not.
The use of Dantrium with other potentially hepatotoxic drugs should be avoided.
There are isolated cases of possibly significant effects of Dantrium on the cardiovascular and respiratory systems. These cases also have other features suggesting a pre-disposition to cardiovascular disease, and impaired respiratory function, particularly obstructive pulmonary disease. Dantrium should be used with caution in such patients.
Caution should be exercised in the simultaneous administration of tranquillising agents and alcohol.
This medicine contains lactose.
This medicine contains only very low levels of gluten (from wheat starch). It is regarded as 'gluten-free' and is very unlikely to cause problems in case of coeliac disease.
One capsule contains no more than 3.8 micrograms of gluten.
4.5 |
Dantrium 25mg Capsules | Clinical particulars - Interaction with other medicinal products and other forms of interaction | Interaction with other medicinal products and other forms of interaction
Hyperkalaemia and myocardial depression have been observed in malignant hyperthermia-susceptible patients receiving intravenous dantrolene sodium and concomitant calcium channel blockers.
The effects of non-depolarizing muscle relaxants may be potentiated in patients administered Dantrium.
4.6 |
Dantrium 25mg Capsules | Clinical particulars - Fertility, pregnancy and lactation | Fertility, pregnancy and lactation
Pregnancy
Although teratological studies in animals have proved satisfactory, Dantrolene sodium does cross the placenta and therefore the use of Dantrium is not advised during pregnancy.
Breast-feeding
Dantrolene sodium has been detected in human milk. Therefore, the use of Dantrium is not advised in nursing mothers.
Fertility
There is no data on the effects of Dantrium on human fertility.
4.7 |
Dantrium 25mg Capsules | Clinical particulars - Effects on ability to drive and use machines | Effects on ability to drive and use machines
Patients should be advised not to drive a motor vehicle or undertake potentially dangerous work until Dantrium therapy has been stabilised, because some patients experience drowsiness and dizziness.
4.8 |
Dantrium 25mg Capsules | Clinical particulars - Undesirable effects | Undesirable effects
Summary of the safety profile
The most frequently reported unwanted effects associated with the use of Dantrium have been drowsiness, dizziness, weakness, general malaise, fatigue and diarrhoea. These effects are generally transient, occur early in treatment, and can often be obviated by careful determination and regulation of the dosage. Diarrhoea may be severe, and may necessitate temporary withdrawal of Dantrium. If diarrhoea recurs upon re-introduction of Dantrium, then Dantrium therapy should probably be withdrawn permanently.
Dantrium has a potential for hepatotoxicity. Symptomatic hepatitis (fatal and non-fatal) has been reported at various dose levels although the incidence is greater in patients taking more than 400 mg/day. Liver dysfunction as evidenced by blood chemical abnormalities alone (liver enzyme elevation) has been observed in patients exposed to Dantrium for varying periods of time.
Overt hepatitis has occurred at varying intervals after initiation of therapy, but has most frequently been observed between the second and twelfth month of treatment. The risk of hepatic injury appears to be greater in females, in patients over 30 years old and in patients taking concomitant medication. There is some evidence that hepatic injury is more likely in patients using concomitant oral oestrogen.
Tabulated list of adverse reactions
System Organ Class
Frequency
Adverse Drug Reactions
Metabolism and nutrition disorders
Common
Anorexia
Psychiatric disorders
Common
Mental depression, mental confusion, insomnia, nervousness
Nervous system disorders
Common
Seizure, visual disturbances, speech disturbances, headache
Cardiac disorders
Common
Pericarditis
Uncommon
Exacerbation of pre-existing cardiac insufficiency
Unknown
Bradycardia, tachycardia
Vascular disorders
Unknown
Labile blood pressure
Respiratory, thoracic and mediastinal disorders
Common
Pleural effusion with associated eosinophilia, respiratory depression
Unknown
Dyspnoea
Gastrointestinal disorders
Common
Nausea and/or vomiting, abdominal pain
Uncommon
Dysphagia, constipation (rarely progressing to signs of intestinal obstruction)
Unknown
Gastrointestinal bleeding
Hepatobiliary disorders
Common
Hepatotoxicity (see section 4.4), liver function test disturbances
Unknown
Jaundice, hepatitis
Skin and subcutaneous disorders
Common
Acne-like rash, skin rash
Uncommon
Sweating
Renal and urinary disorders
Uncommon
Incontinence, increased urinary frequency, urinary retention, haematuria, crystalluria
General disorders and administration site conditions
Common
Chills and /or fever
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 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 |
Dantrium 25mg Capsules | Clinical particulars - Overdose | Overdose
There is no known constellation of symptoms with acute overdose. Symptoms that may occur include, but are not limited to, muscular weakness, alterations in the state of consciousness (e.g. lethargy, coma), vomiting, and diarrhoea. For acute overdosage, general supportive measures and gastric lavage should be employed as well as measures to reduce the absorption of Dantrium. The theoretical possibility of crystalluria in overdose has not been reported for Dantrium, but would be treated according to general principles, including administration of fluids. The value of dialysis in dantrolene sodium overdose is not known.
5. Pharmacological properties
5.1 |
Dantrium 25mg Capsules | Pharmacodynamic properties - Pharmacodynamic properties | Pharmacokinetic properties
Absorption
Dantrolene sodium is easily and almost completely absorbed from the gastrointestinal tract. After dosing on an empty stomach, plasma dantrolene sodium levels peak within three hours in most subjects.
Distribution
Dantrolene sodium is a highly lipophobic drug. In addition it lacks hydrophilicity. Dantrolene sodium binds to human serum albumin (HSA) with a molar ratio of 0.95 to 1.68 in-vitro. The association constant in-vitro is higher (2.3 to 5.4 x 10 -5 per mol). In-vitro dantrolene sodium can be displaced from HSA by warfarin, clofibrate and tolbutamide but these interactions have not been confirmed in humans (re. manufacturer's database). Single intravenous dose studies suggest that the primary volume of distribution is about 15 litres. Single oral doses achieve peak plasma concentration of about a quarter of that for a similarly sized intravenous dose.
Metabolism and Elimination
The biological half-life in plasma in most human subjects is between 5 and 9 hours, although half-lives as long as 12.1 ± 1.9 hours have been reported after a single intravenous dose. Inactivation is by hepatic metabolism in the first instance. There are two alternative pathways. Most of the drug is hydroxylated to 5-hydroxy-dantrolene. The minor pathway involves nitro-reduction to amino-dantrolene which is then acetylated (compound F-490). The 5-hydroxy metabolite is a muscle relaxant with nearly the same potency as the parent molecule, and may have a longer half-life than the parent compound. Compound F-490 is much less potent and is probably inactive at the concentrations achieved in clinical samples. Metabolites are subsequently excreted in the urine in the ratio of 79 5-hydroxy-dantrolene: 17 compound F-490: 4 unaltered dantrolene (salt or free acid). The proportion of drug excreted in the faeces depends upon dose size.
5.3 |
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