Minocycline Hydrochloride: Package Insert and Label Information

MINOCYCLINE HYDROCHLORIDE — minocycline hydrochloride tablet, extended release
Lupin Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

1.1 Indication

Minocycline hydrochloride extended-release tablets USP are indicated to treat only inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 12 years of age and older.

1.2 Limitations of Use

Minocycline hydrochloride extended-release tablets USP did not demonstrate any effect on non-inflammatory acne lesions. Safety of minocycline hydrochloride extended-release tablets USP have not been established beyond 12 weeks of use. This formulation of minocycline has not been evaluated in the treatment of infections [see CLINICAL STUDIES (14)]

To reduce the development of drug-resistant bacteria as well as to maintain the effectiveness of other antibacterial drugs, minocycline hydrochloride extended-release tablets USP should be used only as indicated [see WARNINGS AND PRECAUTIONS (5.11)]

2 DOSAGE AND ADMINISTRATION

The recommended dosage of minocycline hydrochloride extended-release tablet USP are approximately 1 mg/kg once daily for 12 weeks. Higher doses have not shown to be of additional benefit in the treatment of inflammatory lesions of acne, and may be associated with more acute vestibular side effects.

The following table shows tablet strength and body weight to achieve approximately 1 mg/kg.

Table 1: Dosing Table for Minocycline Hydrochloride Extended-release Tablets USP

Patient’s Weight ( lbs .)	Patient’s Weight ( kg )	Tablet Strength ( mg )	Actual mg / kg Dose
99 — 109	45 — 49	45	1 — 0.92
110 — 131	50 — 59	55	1.10 — 0.93
132 — 157	60 — 71	65	1.08 — 0.92
158 — 186	72 — 84	80	1.11 — 0.95
187 — 212	85 — 96	90	1.06 — 0.94
213 — 243	97 — 110	105	1.08 — 0.95
244 — 276	111 — 125	115	1.04 — 0.92
277 — 300	126 — 136	135	1.07 — 0.99

Minocycline hydrochloride extended-release tablets USP may be taken with or without food [see CLINICAL PHARMACOLOGY (12.3) ]. Ingestion of food along with minocycline hydrochloride extended-release tablets USP may help reduce the risk of esophageal irritation and ulceration.

In patients with renal impairment, the total dosage should be decreased by either reducing the recommended individual doses and/or by extending the time intervals between doses [see WARNINGS AND PRECAUTIONS (5.4)] .

3 DOSAGE FORMS AND STRENGTHS

• 45 mg extended-release tablets: pink colored, round shaped, biconvex, film-coated tablets debossed with “F21” on one side and “LU” on the other side.
• 55 mg extended release tablets: green colored, round shaped, biconvex, film-coated tablets debossed with “F26” on one side and “LU” on the other side.
• 90 mg extended-release tablets: pale yellow colored, round shaped, biconvex, film-coated tablets debossed with “F22” on one side and “LU” on the other side.
• 135 mg extended-release tablets: brown colored, capsule shaped, biconvex, film-coated tablets debossed with “F23” on one side and “LU” on the other side.

4 CONTRAINDICATIONS

This drug is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines.

5 WARNINGS AND PRECAUTIONS

5.1 Teratogenic Effects

A. MINOCYCLINE, LIKE OTHER TETRACYCLINE-CLASS DRUGS, CAN CAUSE FETAL HARM WHEN ADMINISTERED TO A PREGNANT WOMAN. IF ANY TETRACYCLINE IS USED DURING PREGNANCY OR IF THE PATIENT BECOMES PREGNANT WHILE TAKING THESE DRUGS, THE PATIENT SHOULD BE APPRISED OF THE POTENTIAL HAZARD TO THE FETUS.

Minocycline hydrochloride extended-release tablets should not be used during pregnancy or by individuals of either gender who are attempting to conceive a child [see NONCLINICAL TOXICOLOGY (13.1)and USE IN SPECIFIC POPULATIONS (8.1)].

B. THE USE OF DRUGS OF THE TETRACYCLINE CLASS DURING TOOTH DEVELOPMENT (LAST HALF OF PREGNANCY, INFANCY, AND CHILDHOOD UP TO THE AGE OF 8 YEARS) MAY CAUSE PERMANENT DISCOLORATION OF THE TEETH (YELLOW-GRAY-BROWN).

This adverse reaction is more common during long-term use of the drug but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. TETRACYCLINE DRUGS, THEREFORE, SHOULD NOT BE USED DURING TOOTH DEVELOPMENT.

C. All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in premature human infants given oral tetracycline in doses of 25 mg/ kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued.

Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can cause retardation of skeletal development on the developing fetus. Evidence of embryotoxicity has been noted in animals treated early in pregnancy [see USE IN SPECIFIC POPULATIONS (8.1)].

5.2 Pseudomembranous Colitis

Clostridium difficile associated diarrhea (CDAD) has been reported with nearly all antibacterial agents, including minocycline, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.3 Hepatotoxicity

Post-marketing cases of serious liver injury, including irreversible drug-induced hepatitis and fulminant hepatic failure (sometimes fatal) have been reported with minocycline use in the treatment of acne.

5.4 Metabolic Effects

The anti-anabolic action of the tetracyclines may cause an increase in BUN. While this is not a problem in those with normal renal function, in patients with significantly impaired function, higher serum levels of tetracycline-class drugs may lead to azotemia, hyperphosphatemia, and acidosis. If renal impairment exists, even usual oral or parenteral doses may lead to excessive systemic accumulations of the drug and possible liver toxicity. Under such conditions, lower than usual total doses are indicated, and if therapy is prolonged, serum level determinations of the drug may be advisable.

5.5 Central Nervous System Effects

Central nervous system side effects including light-headedness, dizziness or vertigo have been reported with minocycline therapy. Patients who experience these symptoms should be cautioned about driving vehicles or using hazardous machinery while on minocycline therapy. These symptoms may disappear during therapy and usually rapidly disappear when the drug is discontinued.

5.6 Benign Intracranial Hypertension

Pseudotumor cerebri (benign intracranial hypertension) in adults and adolescents has been associated with the use of tetracyclines. Minocycline has been reported to cause or precipitate pseudotumor cerebri, the hallmark of which is papilledema. Clinical manifestations include headache and blurred vision. Bulging fontanels have been associated with the use of tetracyclines in infants. Although signs and symptoms of pseudotumor cerebri resolve after discontinuation of treatment, the possibility for permanent sequelae such as visual loss that may be permanent or severe exists. Patients should be questioned for visual disturbances prior to initiation of treatment with tetracyclines. If visual disturbance occurs during treatment, patients should be checked for papilledema. Concomitant use of isotretinoin and minocycline should be avoided because isotretinoin, a systemic retinoid, is also known to cause pseudotumor cerebri.

5.7 Autoimmune Syndromes

Tetracyclines have been associated with the development of autoimmune syndromes. The long-term use of minocycline in the treatment of acne has been associated with drug-induced lupus -like syndrome, autoimmune hepatitis and vasculitis. Sporadic cases of serum sickness have presented shortly after minocycline use. Symptoms may be manifested by fever, rash, arthralgia, and malaise. In symptomatic patients, liver function tests, ANA, CBC, and other appropriate tests should be performed to evaluate the patients. Use of all tetracycline-class drugs should be discontinued immediately.

5.8 Photosensitivity

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. This has been reported rarely with minocycline. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UV A/B treatment) while using minocycline. If patients need to be outdoors while using minocycline, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician.

5.9 Serious Skin/Hypersensitivity Reaction

Cases of anaphylaxis, serious skin reactions (e.g. Stevens Johnson syndrome), erythema multiforme, and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome have been reported postmarketing with minocycline use in patients with acne. DRESS syndrome consists of cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, and one or more of the following visceral complications such as: hepatitis, pneumonitis, nephritis, myocarditis, and pericarditis. Fever and lymphadenopathy may be present. In some cases, death has been reported. If this syndrome is recognized, the drug should be discontinued immediately.

5.10 Tissue Hyperpigmentation

Tetracycline-class antibiotics are known to cause hyperpigmentation. Tetracycline therapy may induce hyperpigmentation in many organs, including nails, bone, skin, eyes, thyroid, visceral tissue, oral cavity (teeth, mucosa, alveolar bone), sclerae and heart valves. Skin and oral pigmentation has been reported to occur independently of time or amount of drug administration, whereas other tissue pigmentation has been reported to occur upon prolonged administration. Skin pigmentation includes diffuse pigmentation as well as over sites of scars or injury.

5.11 Development of Drug-Resistant Bacteria

Bacterial resistance to the tetracyclines may develop in patients using minocycline hydrochloride extended-release tablets, therefore, the susceptibility of bacteria associated with infection should be considered in selecting antimicrobial therapy. Because of the potential for drug-resistant bacteria to develop during the use of minocycline hydrochloride extended-release tablets, it should be used only as indicated.

5.12 Superinfection

As with other antibiotic preparations, use of minocycline hydrochloride extended-release tablets may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, minocycline hydrochloride extended-release tablets should be discontinued and appropriate therapy instituted.

5.13 Laboratory Monitoring

Periodic laboratory evaluations of organ systems, including hematopoietic, renal and hepatic studies should be performed. Appropriate tests for autoimmune syndromes should be performed as indicated.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates observed in practice.

The following table summarizes selected adverse reactions reported in clinical trials at a rate of ≥1% for minocycline hydrochloride extended-release tablets.

Table 2: Selected Treatment-Emergent Adverse Reactions in at least 1% of Clinical Trial Subjects

Adverse Reactions	Minocycline hydrochloride extended – release tablets ( 1 mg / kg ) N = 674 (%)	Placebo N = 364 (%)
At least one treatment-emergent event	379 (56)	197 (54)
Headache	152 (23)	83 (23)
Fatigue	62 (9)	24 (7)
Dizziness	59 (9)	17 (5)
Pruritus	31 (5)	16 (4)
Malaise	26 (4)	9 (3)
Mood alteration	17 (3)	9 (3)
Somnolence	13 (2)	3 (1)
Urticaria	10 (2)	1 (0)
Tinnitus	10 (2)	5 (1)
Arthralgia	9 (1)	2 (0)
Vertigo	8 (1)	3 (1)
Dry mouth	7 (1)	5 (1)
Myalgia	7 (1)	4 (1)