Delnil (ANTIBACTERIALS)

Delnil (ANTIBACTERIALS) MR Capsules are indicated for the treatment of acne.

Delnil (ANTIBACTERIALS) is indicated as an adjunct to scaling and root planing procedures for reduction of pocket depth in patients with adult periodontitis. Delnil (ANTIBACTERIALS) may be used as part of a periodontal maintenance program which includes good oral hygiene and scaling and root planing.

Dosage:

Adults: One 100 mg capsule every 24 hours.

Children over 12 years: One 100 mg capsule every 24 hours.

Children under 12 years: Delnil (ANTIBACTERIALS) is not recommended.

Elderly: No special dosing requirements.

Administration:

To reduce the risk of oesophageal irritation and ulceration, the capsules should be swallowed whole with plenty of fluid, while sitting or standing. Unlike earlier tetracyclines, absorption of Delnil (ANTIBACTERIALS) MR is not significantly impaired by food or moderate amounts of milk.

Treatment of acne should be continued for a minimum of 6 weeks. If, after six months, there is no satisfactory response Delnil (ANTIBACTERIALS) MR should be discontinued and other therapies considered. If Delnil (ANTIBACTERIALS) MR is to be continued for longer than six months, patients should be monitored at least three monthly thereafter for signs and symptoms of hepatitis or SLE or unusual pigmentation (see Special Warnings and Precautions).

Delnil (ANTIBACTERIALS) is provided as a dry powder, packaged in a unit dose cartridge with a deformable tip (see Figure 1), which is inserted into a spring-loaded cartridge handle mechanism (see Figure 2) to administer the product.

The oral health care professional removes the disposable cartridge from its pouch and connects the cartridge to the handle mechanism (see Figures 3-4). Delnil (ANTIBACTERIALS) is a variable dose product, dependent on the size, shape, and number of pockets being treated. In US clinical trials, up to 122 unit dose cartridges were used in a single visit and up to 3 treatments, at 3-month intervals, were administered in pockets with pocket depth of 5 mm or greater.

Figure  1,2,3 and 4

The administration of Delnil (ANTIBACTERIALS) does not require local anesthesia. Professional subgingival administration is accomplished by inserting the unit-dose cartridge to the base of the periodontal pocket and then pressing the thumb ring in the handle mechanism to expel the powder while gradually withdrawing the tip from the base of the pocket. The handle mechanism should be sterilized between patients. Delnil (ANTIBACTERIALS) does not have to be removed, as it is bioresorbable, nor is an adhesive or dressing required.

Known hypersensitivity to tetracyclines, or to any of the components of Delnil (ANTIBACTERIALS) MR. Use in pregnancy, lactation, children under the age of 12 years, complete renal failure.

Delnil (ANTIBACTERIALS)® should not be used in any patient who has a known sensitivity to minocycline or tetracyclines.

Delnil (ANTIBACTERIALS) MR should be used with caution in patients with hepatic dysfunction and in conjunction with alcohol and other hepatotoxic drugs. It is recommended that alcohol consumption should remain within the Government's recommended limits.

Rare cases of auto-immune hepatotoxicity and isolated cases of systemic lupus erythematosus (SLE) and also exacerbation of pre-existing SLE have been reported. If patients develop signs or symptoms of SLE or hepatotoxicity, or suffer exacerbation of pre-existing SLE, minocycline should be discontinued.

Clinical studies have shown that there is no significant drug accumulation in patients with renal impairment when they are treated with Delnil (ANTIBACTERIALS) MR in the recommended doses. In cases of severe renal insufficiency, reduction of dosage and monitoring of renal function may be required. The anti-anabolic action of the tetracyclines may cause an increase in serum urea. In patients with significantly impaired renal function, higher serum levels of tetracyclines may lead to uraemia, hyperphosphataemia and acidosis. If renal impairment exists, even usual oral and parenteral doses may lead to excessive systemic accumulations of the drug and possible liver toxicity.

Caution is advised in patients with myasthenia gravis as tetracyclines can cause weak neuromuscular blockade.

Cross-resistance between tetracyclines may develop in micro-organisms and cross-sensitisation in patients. Delnil (ANTIBACTERIALS) MR should be discontinued if there are signs/symptoms of overgrowth of resistant organisms, e.g. enteritis, glossitis, stomatitis, vaginitis, pruritus ani or Staphylococcal enteritis.

Patients taking oral contraceptives should be warned that if diarrhoea or breakthrough bleeding occur there is a possibility of contraceptive failure.

Minocycline may cause hyperpigmentation at various body sites (see Administration and 4.8 Undesirable Effects). Hyperpigmentation may present regardless of dose or duration of therapy but develops more commonly during long term treatment. Patients should be advised to report any unusual pigmentation without delay and Delnil (ANTIBACTERIALS) should be discontinued.

If a photosensitivity reaction occurs, patients should be warned to avoid direct exposure to natural or artificial light and to discontinue therapy at the first signs of skin discomfort.

As with other tetracyclines, bulging fontanelleles in infants and benign intracranial hypertension in juveniles and adults have been reported. Presenting features were headache and visual disturbances including blurring of vision, scotoma and diplopia. Permanent vision loss has been reported. Treatment should cease if evidence of raised intracranial pressure develops.

Use in the elderly:

Dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Use in children:

The use of tetracyclines during tooth development in children under the age of 12 years may cause permanent discolouration. Enamel hypoplasia has also been reported.

Laboratory monitoring:

Periodic laboratory evaluations of organ system function, including haematopoietic, renal and hepatic should be conducted.

WARNINGS

THE USE OF DRUGS OF THE TETRACYCLINE CLASS DURING TOOTH DEVELOPMENT (LAST HALF OF PREGNANCY, INFANCY, AND CHILDHOOD TO THE AGE OF 8 YEARS) MAY CAUSE PERMANENTDISCOLORATION OF THE TEETH (YELLOW-GRAY BROWN). This adverse reaction is more common during long-term use of the drugs, but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. TETRACYCLINE DRUGS, THEREFORE, SHOULD NOT BE USED IN THIS AGE GROUP, OR IN PREGNANT OR NURSING WOMEN, UNLESS THE POTENTIAL BENEFITS ARE CONSIDERED TO OUTWEIGH THE POTENTIAL RISKS. Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity has also been noted in animals treated early in pregnancy. If any tetracyclines are used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs, and treatment should be discontinued at the first evidence of skin erythema.

PRECAUTIONS

Hypersensitivity Reactions And Hypersensitivity Syndrome

The following adverse events have been reported with minocycline products when taken orally. Hypersensitivity reactions and hypersensitivity syndrome that included, but were not limited to anaphylaxis, anaphylactoid reaction, angioneurotic edema, urticaria, rash, eosinophilia, and one or more of the following: hepatitis, pneumonitis, nephritis, myocarditis, and pericarditis may be present. Swelling of the face, pruritus, fever and lymphadenopathy have been reported with the use of Delnil (ANTIBACTERIALS). Some of these reactions were serious. Post-marketing cases of anaphylaxis and serious skin reactions such as Stevens-Johnson syndrome and erythema multiforme have been reported with oral minocycline.

Autoimmune Syndromes

Tetracyclines, including oral minocycline, have been associated with the development of autoimmune syndromes including a Lupus-like syndrome manifested by arthralgia, myalgia, rash, and swelling. Sporadic cases of serum sickness-like reaction have presented shortly after oral minocycline use, manifested by fever, rash, arthralgia, lymphadenopathy and malaise. In symptomatic patients, liver function tests, ANA, CBC, and other appropriate tests should be performed to evaluate the patients. No further treatment with Delnil (ANTIBACTERIALS) should be administered to the patient.

The use of Delnil (ANTIBACTERIALS) in an acutely abscessed periodontal pocket has not been studied and is not recommended.

While no overgrowth by opportunistic microorganisms, such as yeast, were noted during clinical studies, as with other antimicrobials, the use of Delnil (ANTIBACTERIALS) may result in overgrowth of non-susceptible microorganisms including fungi. The effects of treatment for greater than 6 months have not been studied.

Delnil (ANTIBACTERIALS) should be used with caution in patients having a history of predisposition to oral candidiasis. The safety and effectiveness of Delnil (ANTIBACTERIALS) has not been established for the treatment of periodontitis in patients with coexistent oral candidiasis.

Delnil (ANTIBACTERIALS) has not been clinically tested in immunocompromised patients (such as those immunocompromised by diabetes, chemotherapy, radiation therapy, or infection with HIV).

If superinfection is suspected, appropriate measures should be taken.

Delnil (ANTIBACTERIALS) has not been clinically tested in pregnant women.

Delnil (ANTIBACTERIALS) has not been clinically tested for use in the regeneration of alveolar bone, either in preparation for or in conjunction with the placement of endosseous (dental) implants or in the treatment of failing implants.

Carcinogenicity, Mutagenicity, Impairment Of Fertility

Dietary administration of minocycline in long-term tumorigenicity studies in rats resulted in evidence of thyroid tumor production. Minocycline has also been found to produce thyroid hyperplasia in rats and dogs. In addition, there has been evidence of oncogenic activity in rats in studies with a related antibiotic, oxytetracycline (i.e., adrenal and pituitary tumors). Minocycline demonstrated no potential to cause genetic toxicity in a battery of assays which included a bacterial reverse mutation assay (Ames test), an in vitro mammalian cell gene mutation test (L5178Y/TK+/-mouse lymphoma assay), an in vitro mammalian chromosome aberration test, and an in vivo micronucleus assay conducted in ICR mice.

Fertility and general reproduction studies have provided evidence that minocycline impairs fertility in male rats.

Pregnancy

Teratogenic Effects: (See WARNINGS).

Labor And Delivery

The effects of tetracyclines on labor and delivery are unknown.

Nursing Mothers

Tetracyclines are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from the tetracyclines, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother (See WARNINGS).

Pediatric Use

Since adult periodontitis does not affect children, the safety and effectiveness of Delnil (ANTIBACTERIALS) in pediatric patients cannot be established.

If a photosensitivity reaction occurs, patients should be warned to avoid direct exposure to natural or artificial light and to discontinue therapy at the first signs of skin discomfort.

As with other tetracyclines, bulging fontanelleles in infants and benign intracranial hypertension in juveniles and adults have been reported. Presenting features were headache and visual disturbances including blurring of vision, scotoma and diplopia. Permanent vision loss has been reported. Treatment should cease if evidence of raised intracranial pressure develops.

Use in the elderly:

Dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Use in children:

The use of tetracyclines during tooth development in children under the age of 12 years may cause permanent discolouration. Enamel hypoplasia has also been reported.

Laboratory monitoring:

Periodic laboratory evaluations of organ system function, including haematopoietic, renal and hepatic should be conducted.

Tetracyclines depress plasma prothrombin activity and reduced doses of concomitant anticoagulants may be necessary.

Diuretics may aggravate nephrotoxicity by volume depletion.

Bacteriostatic drugs may interfere with the bactericidal action of penicillin. Avoid giving tetracycline-class drugs in conjunction with penicillin. Absorption of Delnil (ANTIBACTERIALS) MR is impaired by the concomitant administration of antacids, iron, calcium, magnesium, aluminium bismuth and zinc salts (interactions with specific salts, antacids, bismuth containing ulcer - healing drugs, quinapril which contains a magnesium carbonate excipient). It is recommended that any indigestion remedies, vitamins, or other supplements containing these salts are taken at least 3 hours before or after a dose of Delnil (ANTIBACTERIALS) MR. Unlike earlier tetracyclines, absorption of Delnil (ANTIBACTERIALS) MR is not significantly impaired by food or moderate amounts of milk.

There is an increased risk of ergotism when ergot alkaloids or their derivatives are given with tetracyclines.

The concomitant use of tetracyclines may reduce the efficacy of oral contraceptives.

Administration of isotretinoin or other systemic retinoids or retinol should be avoided shortly before, during and shortly after minocycline therapy. Each of these agents alone has been associated with pseudotumor cerebri (benign intracranial hypertension) (see 4.4 Special warnings and precautions).

Interference with laboratory and other diagnostic tests:

False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.

Use in pregnancy:

Delnil (ANTIBACTERIALS) MR should not be used in pregnancy unless considered essential

Results of animal studies indicate that tetracyclines cross the placenta, are found in foetal tissues and can have toxic effects on the developing foetus (often related to retardation of skeletal development). Evidence of embryotoxicity has also been noted in animals treated early in pregnancy. Delnil (ANTIBACTERIALS) MR therefore, should not be used in pregnancy unless considered essential.

In humans, Delnil (ANTIBACTERIALS), like other tetracycline-class antibiotics, crosses the placenta and may cause foetal harm when administered to a pregnant woman. In addition, there have been post marketing reports of congenital abnormalities including limb reduction. If Delnil (ANTIBACTERIALS) is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to the foetus.

The use of drugs of the tetracycline class during tooth development (last half of pregnancy) may cause permanent discolouration of the teeth (yellow-grey-brown). This adverse reaction is more common during long term use of the drugs but has been observed following repeated short term courses. Enamel hypoplasia has also been reported.

Tetracyclines administered during the last trimester form a stable calcium complex throughout the human skeleton. A decrease in fibula growth rate has been observed in premature human infants given oral tetracyclines in doses up to 25mg/kg every 6 hours. Changes in fibula growth rate were shown to be reversible when the drug was discontinued.

Use in lactation:

Tetracyclines have been found in the milk of lactating women who are taking a drug in this class. Permanent tooth discolouration may occur in the developing infant and enamel hypoplasia has been reported.

Headache, light-headedness, dizziness, tinnitus and vertigo (more common in women) and, rarely, impaired hearing have occurred with Delnil (ANTIBACTERIALS) MR. Patients should be warned about the possible hazards of driving or operating machinery during treatment. These symptoms may disappear during therapy and usually disappear when the drug is discontinued.

Adverse reactions are listed in the Table in CIOMS frequency categories under MedDRA system/organ classes:

Common: > 1%

Uncommon: > 0.1% and < 1%

Rare: > 0.01% and < 0.1%

Very Rare: < 0.01%

Infections and Infestations

Very Rare: Oral and anogenital candidiasis, vulvovaginitis.

Blood and Lymphatic System Disorders

Rare: Eosinophilia, leucopenia, neutropenia, thrombocytopenia.

Very Rare: Haemolytic anaemia, pancytopenia.

There are also reports of: Agranulocytosis

Immune System Disorders

Rare: Anaphylaxis /anaphylactoid reaction (including shock), including fatalities.

There are also reports of: Hypersensitivity, pulmonary infiltrates, anaphylactoid purpura.

Endocrine Disorders

Very Rare: Abnormal thyroid function, brown-black discolouration ofthe thyroid.

Metabolism and Nutrition Disorders

Rare: Anorexia

Nervous System Disorders

Common: Dizziness (light-headedness).

Rare: Headache, hypesthesia, paraesthesia, intracranial hypertension, vertigo.

Very Rare: Bulging fontanelle.

There are also reports of: convulsions, sedation.

Ear and Labyrinth Disorders

Rare: Impaired hearing, tinnitus.

Cardiac Disorders

Rare: Myocarditis, pericarditis.

Respiratory, Thoracic and Mediastinal Disorders

Rare: Cough, dyspnoea.

Very Rare: Bronchospasm, exacerbation of asthma, pulmonary eosinophilia.

There are also reports of: Pneumonitis.

Gastrointestinal Disorders

Rare: Diarrhoea, nausea, stomatitis, discolouration of teeth including adult tooth discolouration), vomiting.

Very Rare: Dyspepsia, dysphagia, enamel hypoplasia, enterocolitis, oesophagitis, oesophageal ulceration, glossitis, pancreatitis, pseudomembranous colitis.

There are also reports of: Oral cavity discolouration (including tongue, lip and gum).

Hepatobiliary Disorders

Rare: Increased liver enzymes, hepatitis, autoimmune hepatoxicity. ().

Very Rare: Hepatic cholestatis, hepatic failure (including fatalities), hyperbilirubinaemia, jaundice.

There are also reports of: Autoimmune hepatitis.

Skin and Subcutaneous Tissue Disorders

Rare: Alopecia, erythema multiforme, erythema nodosum, fixed drug eruption, hyperpigmentation of skin, photosensitivity, pruritis, rash, urticaria, vasculitis.

Very Rare: Angioedema, exfoliative dermatitis, hyperpigmentation of nails, Stevens-Johnson Syndrome, toxic epidermal necrolysis.

Musculoskeletal, Connective Tissue and Bone Disorders

Rare: Arthralgia, lupus-like syndrome, myalgia.

), joint stiffness, joint swelling.

Renal and Urinary Disorders

Rare: Increased serum urea, acute renal failure, interstitial nephritis.

Reproductive System and Breast Disorders

Very Rare: Balanitis.

General Disorders and Administration Site Conditions

Uncommon: Fever.

Very Rare: Discolouration of secretions.

The following syndromes have been reported. In some cases involving these syndromes, death has been reported. As with other serious adverse reactions, if any of these syndromes are recognised, the drug should be discontinued immediately:

- Hypersensitivity syndrome consisting of cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, and one or more of the following: hepatitis, pneumonitis, nephritis, myocarditis, pericarditis. Fever and lymphadenopathy may be present.

- Lupus-like syndrome consisting of positive antinuclear antibody, arthralgia, arthritis, joint stiffness or joint swelling, and one or more of the following: fever, myalgia, hepatitis, rash, vasculitis.

- Serum sickness-like syndrome consisting fever, urticaria or rash, and arthralgia, arthritis,joint stiffness or joint swelling. Eosinophilia may be present.

Hyperpigmentation of various body sites including the skin, nails, teeth, oral mucosa, bones, thyroid, eyes (including sclera and conjunctiva), breast mille, lacrimal secretions and perspiration has been reported. This blue/black/grey or muddy-brown discolouration may be localised or diffuse. The most frequently reported site is in the skin. Pigmentation is often reversible on discontinuation of the drug, although it may take several months or may persist in some cases. The generalised muddy-brown skin pigmentation may persist, particularly in areas exposed to the sun.

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.

The most frequently reported non-dental treatment-emergent adverse events in the 3 multicenter US trials were headache, infection, flu syndrome, and pain.

Table 5: Adverse Events (AEs) Reported in ≥ 3% of the Combined Clinical Trial Population of 3 Multicenter US Trials by Treatment Group

The change in clinical attachment levels was similar across all study arms, suggesting that neither the vehicle nor Delnil (ANTIBACTERIALS) compromise clinical attachment.

To report SUSPECTED ADVERSE REACTIONS, contact Valeant Pharmaceuticals North America LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Dizziness, nausea and vomiting are the adverse effects most commonly seen with overdose.

There is no specific antidote. In cases of overdose, discontinue medication, treat symptomatically with appropriate supportive measures. Delnil (ANTIBACTERIALS) is not removed in significant quantities by haemodialysis or peritoneal dialysis.

No information provided.

Delnil (ANTIBACTERIALS) MR Capsules have been formulated as a "double pulse" delivery system in which a portion of the minocycline dose is delivered in the stomach, and a second portion of the dose is available for absorption in the duodenum and upper GI tract.

In a pharmacokinetic study, 18 subjects (10 men and 8 women) with moderate to advanced chronic periodontitis were treated with a mean dose of 46.2 mg (25 to 112 unit doses) of Delnil (ANTIBACTERIALS). After fasting for at least 10 hours, subjects received subgingival application of Delnil (ANTIBACTERIALS) (1 mg per treatment site) following scaling and root planing at a minimum of 30 sites on at least 8 teeth. Investigational drug was administered to all eligible sites ≥ 5 mm in probing depth. Mean dose normalized saliva AUC and Cmax were found to be approximately 125 and 1000 times higher than those of serum parameters, respectively.