Solodyn

minocycline hydrochloride

Dosage Form: tablet, film coated, extended release
Solodyn®

(MINOCYCLINE HCl, USP)

EXTENDED RELEASE TABLETS

Rx Only

KEEP OUT OF REACH OF CHILDREN

To reduce the development of drug-resistant bacteria as well as to maintain the effectiveness of other antibacterial drugs, Solodyn® should be used only as indicated.

Solodyn® is indicated to treat only inflammatory lesions of non-nodular moderate to severe acne vulgaris.

This formulation of minocycline has not been evaluated in the treatment of infections.

Solodyn Description

Minocycline hydrochloride, a semi synthetic derivative of tetracycline, is [4S - (4α,4aα,5aα,12aα)] - 4,7 - Bis(dimethylamino) - 1,4,4a,5,5a,6,11,12a - octahydro - 3,10,12,12a - tetrahydroxy - 1,11 - dioxo - 2 - naphthacenecarboxamide mono hydrochloride. The structural formula is represented below:

C23H27N3O7•HCl             M. W. 493.95

Solodyn® Tablets for oral administration contain minocycline hydrochloride USP equivalent to 45 mg, 65 mg, 90 mg, 115 mg, or 135 mg of minocycline. In addition, 45 mg, 65 mg, 90 mg, 115 mg, and 135 mg tablets contain the following inactive ingredients: lactose monohydrate NF, hypromellose type 2910 USP, magnesium stearate NF, colloidal silicon dioxide NF, and carnauba wax NF. The 45 mg tablets also contain opadry II gray which contains: lactose monohydrate NF, hypromellose type 2910 USP, titanium dioxide USP, triacetin USP, and iron oxide black JPE. The 65 mg tablets also contain opadry II blue which contains: hypromellose type 2910 USP, lactose monohydrate NF, FD&C Blue #1, polyethylene glycol 3350 NF, FD&C Blue #2, titanium dioxide USP, triacetin USP, and D&C Yellow #10. The 90 mg tablets also contain opadry II yellow which contains: hypromellose type 2910 USP, lactose monohydrate NF, titanium dioxide USP, iron oxide yellow NF, polyethylene glycol 3350 NF, and triacetin USP. The 115 mg tablets also contain opadry II green which contains: hypromellose type 2910 USP, lactose monohydrate NF, D&C yellow #10, triacetin USP, FD&C Blue #1, titanium dioxide USP, and FD&C Blue #2. The 135 mg tablets also contain opadry II pink which contains: hypromellose type 2910 USP, lactose monohydrate NF, titanium dioxide USP, polyethylene glycol 3350 NF, iron oxide red NF, and triacetin USP.

Solodyn - Clinical Pharmacology

Pharmacokinetics

Solodyn® Tablets are not bioequivalent to minocycline products. Based on pharmacokinetic studies in healthy adults, Solodyn® Tablets produce a delayed Tmax at 3.5–4.0 hours as compared to a non-modified release reference minocycline product (Tmax at 2.25–3 hours). At steady-state (Day 6), the mean AUC(0–24) and Cmax were 33.32 µg×hr/mL and 2.63 µg/mL for Solodyn® Tablets and 46.35 µg×hr/mL and 2.92 µg/mL for Minocin® capsules, respectively. These parameters are based on dose adjusted to 135 mg per day for both products.

A single-dose, four-way crossover study demonstrated that all strengths of Solodyn® Tablets (45 mg, 90 mg, and 135 mg) exhibited dose-proportional pharmacokinetics.

When Solodyn® Tablets were administered concomitantly with a meal that included dairy products, the extent and timing of absorption of minocycline did not differ from that of administration under fasting conditions.

Microbiology

Minocycline is bacteriostatic exerting its antimicrobial effect by the inhibition of bacterial protein synthesis. Minocycline is lipid soluble and distributes in to the skin and sebum. Minocycline has been shown to have in vitro activity against Propionibacterium acnes, an organism associated with acne vulgaris, however, the clinical significance of this activity against P. acnes in patients with acne vulgaris is not known.

Clinical Studies

The safety and efficacy of Solodyn® in the treatment of inflammatory lesions of non-nodular moderate to severe acne vulgaris was assessed in two 12-week, multi-center, randomized, double-blind, placebo-controlled, studies in subjects ≥ 12 years. The mean age of subjects was 20 years and subjects were from the following racial groups: White (73%), Hispanic (13%), Black (11%), Asian/Pacific Islander (2%), and Other (2%).

In two efficacy and safety trials, a total of 924 subjects with non-nodular moderate to severe acne vulgaris received Solodyn® or placebo for a total of 12 weeks, according to the following dose assignments.

Subject's Weight (lbs.)	Subject's Weight (kg)	Available Caplet Strength (mg)	Actual mg/kg Dose
99 – 131	45.00 – 59.54	45	1.00 – 0.76
132 – 199	60.00 – 90.45	90	1.50 – 1.00
200 – 300	90.91 – 136.36	135	1.48 – 0.99

The two primary efficacy endpoints were:

1)

Mean percent change in inflammatory lesion counts from Baseline to 12 weeks.

2)

Percentage of subjects with an Evaluator's Global Severity Assessment (EGSA) of clear or almost clear at 12 weeks.

Efficacy results are presented in Table 1.

Table 1 – Efficacy Results at Week 12

	Study 1		Study 2
	Solodyn® (1 mg/kg) N = 300	Placebo N = 151	Solodyn® (1 mg/kg) N = 315	Placebo N = 158
* Evaluator's Global Severity Assessment
Mean Percent Improvement in Inflammatory Lesions	43.1%	31.7%	45.8%	30.8%
No. (%) of Subjects Clear or Almost Clear on the EGSA*	52 (17.3%)	12 (7.9%)	50 (15.9%)	15 (9.5%)

Solodyn® did not demonstrate any effect on non-inflammatory lesions (benefit or worsening).

Indications and Usage for Solodyn

Solodyn® is indicated to treat only inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 12 years of age and older. Solodyn® did not demonstrate any effect on non-inflammatory lesions. Safety of Solodyn® has not been established beyond 12 weeks of use.

This formulation of minocycline has not been evaluated in the treatment of infections.

To reduce the development of drug-resistant bacteria as well as to maintain the effectiveness of other antibacterial drugs, Solodyn® should be used only as indicated.

Contraindications

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

Warnings

Teratogenic effects

1) MINOCYCLINE, LIKE OTHER TETRACYCLINE-CLASS ANTIBIOTICS, 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.

Solodyn® should not be used during pregnancy nor by individuals of either gender who are attempting to conceive a child (see PRECAUTIONS: Impairment of Fertility & Pregnancy).

2) 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.

3) 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 PRECAUTIONS: Pregnancy section).

Gastro-intestinal effects

1. Pseudomembranous colitis has been reported with nearly all antibacterial agents and may range from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of "antibiotic-associated colitis".

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

2. 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.

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 antibiotics 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.

Central nervous system effects

1. 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.

2. 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 and should be routinely checked for papilledema while on treatment.

Concomitant use of isotretinoin and minocycline should be avoided because isotretinoin, a systemic retinoid, is also known to cause pseudotumor cerebri.

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 UVA/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.

Precautions

General

Safety of Solodyn® beyond 12 weeks of use has not been established.

As with other antibiotic preparations, use of Solodyn® may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, the antibiotic should be discontinued and appropriate therapy instituted.

Bacterial resistance to the tetracyclines may develop in patients using Solodyn,® 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 Solodyn,® it should be used only as indicated.

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.

Serious Skin/Hypersensitivity Reaction

Post-marketing cases of anaphylaxis and serious skin reactions such as Stevens Johnson syndrome and erythema multiforme have been reported with minocycline use in treatment of acne.

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.

Information for Patients

(See Patient Package Insert that accompanies this Package Insert for additional information to give patients)

1. Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines, including minocycline. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/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. Treatment should be discontinued at the first evidence of skin erythema.


2. Patients who experience central nervous system symptoms (see WARNINGS) should be cautioned about driving vehicles or using hazardous machinery while on minocycline therapy. Patients should also be cautioned about seeking medical help for headaches or blurred vision.


3. Concurrent use of tetracycline may render oral contraceptives less effective (See Drug Interactions).


4. Autoimmune syndromes, including drug-induced lupus-like syndrome, autoimmune hepatitis, vasculitis and serum sickness have been observed with tetracycline-class antibiotics, including minocycline. Symptoms may be manifested by arthralgia, fever, rash and malaise. Patients who experience such symptoms should be cautioned to stop the drug immediately and seek medical help.


5. Patients should be counseled about discoloration of skin, scars, teeth or gums that can arise from minocycline therapy.


6. Take Solodyn® exactly as directed. Skipping doses or not completing the full course of therapy may decrease the effectiveness of the current treatment course and increase the likelihood that bacteria will develop resistance and will not be treatable by other antibacterial drugs in the future.


7. Solodyn® should not be used by pregnant women or women attempting to conceive a child (See Pregnancy, Carcinogenesis and Mutagenesis sections).


8. It is recommended that Solodyn® not be used by men who are attempting to father a child (See Impairment of Fertility section).

Laboratory Tests

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.

Drug Interactions

1. Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.

2. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline-class drugs in conjunction with penicillin.

3. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity.

4. Absorption of tetracyclines is impaired by antacids containing aluminum, calcium or magnesium and iron-containing preparations.

5. In a multi-center study to evaluate the effect of Solodyn® on low dose oral contraceptives, hormone levels over one menstrual cycle with and without Solodyn® 1 mg/kg once-daily were measured.

Based on the results of this trial, minocycline-related changes in estradiol, progestinic hormone, FSH and LH plasma levels, of breakthrough bleeding, or of contraceptive failure, can not be ruled out. To avoid contraceptive failure, female patients are advised to use a second form of contraceptive during treatment with minocycline.

Drug/Laboratory Test Interactions

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

Carcinogenesis, Mutagenesis & Impairment of Fertility

Carcinogenesis

Long-term animal studies have not been performed to evaluate the carcinogenic potential of minocycline. A structurally related compound, oxytetracycline, was found to produce adrenal and pituitary tumors in rats.

Mutagenesis

Minocycline was not mutagenic in vitro in a bacterial reverse mutation assay (Ames test) or CHO/HGPRT mammalian cell assay in the presence or absence of metabolic activation. Minocycline was not clastogenic in vitro using human peripheral blood lymphocytes or in vivo in a mouse micronucleus test.

Impairment of Fertility

Male and female reproductive performance in rats was unaffected by oral doses of minocycline of up to 300 mg/kg/day (which resulted in up to approximately 40 times the level of systemic exposure to minocycline observed in patients as a result of use of Solodyn®). However, oral administration of 100 or 300 mg/kg/day of minocycline to male rats (resulting in approximately 15 to 40 times the level of systemic exposure to minocycline observed in patients as a result of use of Solodyn®) adversely affected spermatogenesis. Effects observed at 300 mg/kg/day included a reduced number of sperm cells per gram of epididymis, an apparent reduction in the percentage of sperm that were motile, and (at 100 and 300 mg/kg/day) increased numbers of morphologically abnormal sperm cells. Morphological abnormailities observed in sperm samples included absent heads, misshapen heads, and abnormal flagella.

Limited human studies suggest that minocycline may have a deleterious effect on spermatogenesis.

Solodyn® should not be used by individuals of either gender who are attempting to conceive a child.

Pregnancy

Teratogenic Effects

Pregnancy category D

(See WARNINGS)

All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. There are no adequate and well-controlled studies on the use of minocycline in pregnant women. Minocycline, like other tetracycline-class antibiotics, crosses the placenta and may cause fetal harm when administered to a pregnant woman. Rare spontaneous reports of congenital anomalies including limb reduction have been reported with minocycline use in pregnancy in post-marketing experience. Only limited information is available regarding these reports; therefore, no conclusion on causal association can be established.

Minocycline induced skeletal malformations (bent limb bones) in fetuses when administered to pregnant rats and rabbits in doses of 30 mg/kg/day and 100 mg/kg/day, respectively, (resulting in approximately 3 times and 2 times, respectively, the systemic exposure to minocycline observed in patients as a result of use of Solodyn®). Reduced mean fetal body weight was observed in studies in which minocycline was administered to pregnant rats at a dose of 10 mg/kg/day (which resulted in approximately the same level of systemic exposure to minocycline as that observed in patients who use Solodyn®).

Solodyn® should not be used during pregnancy. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and stop treatment immediately.

Nursing Mothers

Tetracycline-class antibiotics are excreted in human milk. Because of the potential for serious adverse effects on bone and tooth development in nursing infants from the tetracycline-class antibiotics, 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

Solodyn® is indicated to treat only inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 12 years and older. Safety and effectiveness in pediatric patients below the age of 12 has not been established.

Use of tetracycline-class antibiotics below the age of 8 is not recommended due to the potential for tooth discoloration (see WARNINGS).

Geriatric Use

Clinical studies of Solodyn® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy.

Adverse Reactions

Because clinical trials are conducted under prescribed conditions, adverse reaction rates observed in the clinical trial may not reflect the rates observed in practice. However, adverse reaction information from clinical trials provides a basis for identifying the adverse events that appear to be related to drug use.

Adverse events reported in clinical trials for Solodyn® are described below in Table 2.

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

Adverse Event	Solodyn® (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)

Adverse reactions not observed in the clinical trials, but that have been reported with minocycline hydrochloride use in a variety of indications include:

Skin and hypersensitivity reactions: fixed drug eruptions, balanitis, erythema multiforme, Stevens-Johnson syndrome, anaphylactoid purpura, photosensitivity, pigmentation of skin and mucous membranes, hypersensitivity reactions, angioneurotic edema, anaphylaxis.

Autoimmune conditions: polyarthralgia, pericarditis, exacerbation of systemic lupus, pulmonary infiltrates with eosinophilia, transient lupus-like syndrome.

Central nervous system: pseudotumor cerebri, bulging fontanels in infants, decreased hearing.

Endocrine: thyroid discoloration, abnormal thyroid function.

Oncology: papillary thyroid cancer.

Oral: glossitis, dysphagia, tooth discoloration.

Gastrointestinal: enterocolitis, pancreatitis, hepatitis, liver failure.

Renal: reversible acute renal failure.

Hematology: hemolytic anemia, thrombocytopenia, eosinophilia.

Preliminary studies suggest that use of minocycline may have deleterious effects on human spermatogenesis (see Carcinogenesis, Mutagenesis, Impairment of Fertility section).

Overdosage

In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures. Minocycline is not removed in significant quantities by hemodialysis or peritoneal dialysis.

Solodyn Dosage and Administration

The recommended dosage of Solodyn® is approximately 1 mg/kg 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 3: Dosing Table for Solodyn®

Patient's Weight (lbs.)	Patient's Weight (kg)	Tablet Strength (mg)	Actual mg/kg Dose
99 – 120	45 – 54	45	1 – 0.83
121 – 170	55 – 77	65	1.18 – 0.84
171 – 225	78 – 102	90	1.15 – 0.88
226 – 276	103 – 125	115	1.12 – 0.92
277 – 300	126 – 136	135	1.07 – 0.99

Solodyn® Tablets may be taken with or without food (see CLINICAL PHARMACOLOGY). Ingestion of food along with Solodyn® may help reduce the risk of esophageal irritation and ulceration.

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

How is Solodyn Supplied

Solodyn® (MINOCYCLINE HCl, USP) Extended Release Tablets are supplied as aqueous film coated tablets containing minocycline hydrochloride equivalent to 45 mg, 65 mg, 90 mg, 115 mg, or 135 mg minocycline.

The 45 mg extended release tablets are gray, unscored, coated, and debossed with "DYN-045" on one side. Each tablet contains minocycline hydrochloride equivalent to 45 mg minocycline, supplied as follows:

NDC 99207-460-30	Bottle of 30
NDC 99207-460-10	Bottle of 100

The 65 mg extended release tablets are blue, unscored, coated, and debossed with "DYN-065" on one side. Each tablet contains minocycline hydrochloride equivalent to 65 mg minocycline, supplied as follows:

NDC 99207-463-30

Bottle of 30

The 90 mg extended release tablets are yellow, unscored, coated, and debossed with "DYN-090" on one side. Each tablet contains minocycline hydrochloride equivalent to 90 mg minocycline, supplied as follows:

NDC 99207-461-30	Bottle of 30
NDC 99207-461-10	Bottle of 100

The 115 mg extended release tablets are green, unscored, coated, and debossed with "DYN-115" on one side. Each tablet contains minocycline hydrochloride equivalent to 115 mg minocycline, supplied as follows:

NDC 99207-464-30

Bottle of 30

The 135 mg extended release tablets are pink (orange-brown), unscored, coated, and debossed with "DYN-135" on one side. Each tablet contains minocycline hydrochloride equivalent to 135 mg minocycline, supplied as follows:

NDC 99207-462-30	Bottle of 30
NDC 99207-462-10	Bottle of 100

Store at 25ºC (77ºF); excursions are permitted to 15º–30ºC (59º–86ºF) [See USP Controlled Room Temperature].

Protect from light, moisture, and excessive heat.

Dispense in tight, light-resistant container with child-resistant closure.

U.S. Patent 5,908,8381 and Patents Pending

Manufactured for:

Medicis, The Dermatology Company

Scottsdale, AZ 85256

Manufactured by:

Wellspring Pharmaceutical Canada Corp.

Oakville, Ontario L6H 1M5

Canada

N4605A

17100004

1

90 mg is also covered by U.S. Patents 7,541,347 and 7,544,373

Patient Information

Solodyn® (SO-lo-dīn) Extended Release Tablets

(minocycline HCl, USP)

Rx only

Read all patient information that comes with Solodyn® before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of speaking with your doctor about your condition or treatment.

What is Solodyn®?

Solodyn® is a tetracycline-class antibiotic medicine that contains minocycline. Solodyn® is only for the treatment of pimples and red bumps (non-nodular inflammatory lesions) that happen with moderate to severe acne in patients 12 years and older.

Solodyn® has not been studied for use longer than 12 weeks.

Solodyn® has not been studied for the treatment of infections.

Who should not take Solodyn®?

Do not take Solodyn® if you are allergic to minocycline or any other tetracycline antibiotics. Ask your doctor or pharmacist for a list of these medicines if you are not sure. See the end of this leaflet for a complete list of ingredients in Solodyn.®

Solodyn® should not be used by pregnant women, women attempting to conceive a child, or children up to 8 years old because:

1. Solodyn® may harm an unborn baby


2. Solodyn® may permanently turn a baby or child's teeth yellow-grey-brown during tooth development. Solodyn® should not be used during tooth development. Tooth development happens in the last half of pregnancy and birth to age 8 years.

It is recommended that Solodyn® not be used by men who are attempting to father a child.

What should I tell my doctor before taking Solodyn®?

Tell your doctor about all of your medical conditions including if you:

• have kidney problems. Your doctor may prescribe a lower dose of medicine for you.


• have any vision problems such as blurred vision.


• are pregnant or attempting to conceive a child. Solodyn® may harm your unborn baby. Stop taking Solodyn® and call your doctor if you become pregnant while taking it.


• are breastfeeding. Solodyn® passes into your milk and may harm your baby. You should decide whether to use Solodyn® or breastfeed, but not both.

Tell your doctor about all the other medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Solodyn® and other medicines may interact. Especially tell your doctor if you take:

• birth control pills. Solodyn® may make your birth control pills less effective. You should use a second form of birth control while taking Solodyn.®


• a blood thinner medicine. The dose of your blood thinner may be lowered.


• a penicillin antibiotic medicine. Solodyn® and penicillins should not be used together.


• antacids that contain aluminum, calcium, or magnesium or iron-containing products. These can affect how much Solodyn® passes into your body.


• Isotretinoin products.

Know the medicines you take. Keep a list of them to show your doctor and pharmacist.

How should I take Solodyn®?

• Solodyn® comes in 5 strengths. Your doctor will prescribe the strength that is best for your body weight. The usual dose of Solodyn® is 1 tablet each day for 12 weeks.


• Take Solodyn® at the same time each day, with or without food. Taking Solodyn® with food may lower your chances of getting irritation or ulcers in your esophagus. Your esophagus is the tube that connects your mouth to your stomach.


• Swallow Solodyn® Tablets whole. Do not chew, crush, or split the tablets.


• If you forget to take Solodyn,® take it as soon as you remember. Do not take more than one tablet of Solodyn® in one day.


• If you take too much Solodyn® at a time, call your doctor.


• If you do not notice an improvement in your acne after 12 weeks of treatment with Solodyn,® call your doctor.

What are the possible side effects of Solodyn®?

Solodyn® may cause serious side effects.

Stop Solodyn® and call your doctor if you have:

• watery diarrhea


• bloody stools


• stomach cramps


• unusual headaches


• blurred vision


• fever


• rash


• joint pain


• feeling very tired

Solodyn® may also cause:

• central nervous system effects. Symptoms include light-headedness, dizziness, and a spinning feeling (vertigo). You should not drive or operate dangerous machines if you have these symptoms.


• sun sensitivity (photosensitivity). You may get a worse sunburn with Solodyn.® Avoid sun exposure and the use of sunlamps or tanning beds. Protect your skin while out in sunlight. Stop Solodyn® and call your doctor at the first sign of redness or sunburn.


• darkening of skin, scars, teeth, and gums.

The most common side effects with Solodyn® include:

• headache


• nausea


• tiredness


• dizziness or spinning feeling


• diarrhea


• stomach area pain


• itching

Call your doctor if you have a side effect that bothers you or that does not go away.

These are not all the side effects with Solodyn.® Ask your doctor or pharmacist for more information.

How should I store Solodyn®?

• Store Solodyn® at room temperature. Keep Solodyn® Tablets in the bottle you received from the pharmacy and store away from moisture and light.


• Keep Solodyn® and all medicines out of the reach of children.

General Information about Solodyn®

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Solodyn® for a condition for which it was not prescribed. Do not give Solodyn® to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about Solodyn.® If you would like more information, talk to your doctor. You can ask your doctor or pharmacist for information about Solodyn® that is written for health professionals.

What are the Ingredients in Solodyn®?

Active Ingredient: minocycline HCl USP equivalent to 45 mg, 65 mg, 90 mg, 115 mg, or 135 mg of minocycline.

Inactive Ingredients: lactose monohydrate NF, hypromellose type 2910 USP, magnesium stearate NF, colloidal silicon dioxide NF, and carnauba wax NF. The 45 mg tablets also contain opadry II gray which contains: lactose monohydrate NF, hypromellose type 2910 USP, titanium dioxide USP, triacetin USP, and iron oxide black JPE. The 65 mg tablets also contain opadry II blue which contains: hypromellose type 2910 USP, lactose monohydrate NF, FD&C Blue #1, polyethylene glycol 3350 NF, FD&C Blue #2, titanium dioxide USP, triacetin USP, and D&C Yellow #10. The 90 mg tablets also contain opadry II yellow which contains: hypromellose type 2910 USP, lactose monohydrate NF, titanium dioxide USP, iron oxide yellow NF, polyethylene glycol 3350 NF, and triacetin USP. The 115 mg tablets also contain opadry II green which contains: hypromellose type 2910 USP, lactose monohydrate NF, D&C yellow #10, triacetin USP, FD&C Blue #1, titanium dioxide USP, FD&C Blue #2. The 135 mg tablets also contain opadry II pink which contains: hypromellose type 2910 USP, lactose monohydrate NF, titanium dioxide USP, polyethylene glycol 3350 NF, iron oxide red NF, and triacetin USP.

Solodyn® is manufactured by Wellspring Pharmaceutical Canada Corp. for Medicis, The Dermatology Company, Scottsdale, AZ, 85256.

July 2009

N4605A

17100004

PRINCIPAL DISPLAY PANEL - 45 mg Tablet Bottle Label

NDC 99207-460-30

Rx Only

45 mg*

Solodyn®

(MINOCYCLINE HCl, USP)

EXTENDED RELEASE TABLETS

30 Tablets

PRINCIPAL DISPLAY PANEL - 65 mg Tablet Bottle Label

NDC 99207-463-30

Rx Only

65 mg*

30 TABLETS

Solodyn®

(MINOCYCLINE HCl, USP)

EXTENDED RELEASE TABLETS

PRINCIPAL DISPLAY PANEL - 90 mg Tablet Bottle Label

NDC 99207-461-30

Rx Only

90 mg*

Solodyn®

(MINOCYCLINE HCl, USP)

EXTENDED RELEASE TABLETS

30 Tablets

PRINCIPAL DISPLAY PANEL - 115 mg Tablet Bottle Label

NDC 99207-464-30

Rx Only

115 mg*

30 TABLETS

Solodyn®

(MINOCYCLINE HCl, USP)

EXTENDED RELEASE TABLETS

PRINCIPAL DISPLAY PANEL - 135 mg Tablet Bottle Label

NDC 99207-462-30

Rx Only

135 mg*

Solodyn®

(MINOCYCLINE HCl, USP)

EXTENDED RELEASE TABLETS

30 Tablets

Solodyn  minocycline hydrochloride  tablet, film coated, extended release

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 99207-460 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength minocycline hydrochloride (minocycline) minocycline 45 mg

Inactive Ingredients Ingredient Name Strength lactose monohydrate   hypromellose 2910 (50 cps)   titanium dioxide   triacetin   ferrosoferric oxide

Product Characteristics Color GRAY Score no score Shape OVAL Size 16mm Flavor Imprint Code DYN;045 Contains

Packaging # NDC Package Description Multilevel Packaging 1 99207-460-30 30 TABLET In 1 BOTTLE None 2 99207-460-10 100 TABLET In 1 BOTTLE None 3 99207-460-01 20 BLISTER PACK In 1 CARTON contains a BLISTER PACK 3 1 TABLET In 1 BLISTER PACK This packa

Formucare Allergy Relief

loratadine

Dosage Form: tablet
Access Business Group International LLC Allergy Relief Drug Facts

Active ingredient (in each tablet)

Loratadine 10 mg

Purpose

Antihistamine

Uses

temporarily relieves these symptoms due to hay fever or other upper respiratory allergies:

• runny nose


• sneezing


• itchy, watery eyes


• itching of the nose or throat

Warnings

Do not use

if you have ever had an allergic reaction to this product or any of its ingredients

Ask a doctor before use if you have

liver or kidney disease. Your doctor should determine if you need a different dose.

When using this product

do not take more than directed. Taking more than directed may cause drowsiness.

Stop use and ask a doctor if

an allergic reaction to this product occurs. Seek medical help right away.

If pregnant or breast-feeding,

ask a health professional before use.

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away.

Directions

adults and children 6 years and over	1 tablet daily; not more than 1 tablet in 24 hours
children under 6 years of age	ask a doctor
consumers with liver or kidney disease	ask a doctor

Other information

• do not use if printed foil under cap is broken or missing


• store at 20°-25°C (68°-77°F)

Inactive ingredients

lactose monohydrate, magnesium stearate, povidone, pregelatinized starch

Questions or comments?

1-800-719-9260

Principal Display Panel

Non-Drowsy*

Allergy Relief

Loratadine Tablets, 10 mg

Antihistamine

Indoor & Outdoor Allergies

Original Prescription Strength

Relief of:

Sneezing; Runny Nose;

Itchy, Watery Eyes;

Itchy Throat or Nose

24 Hour

Actual Size

*When taken as directed. See Drug Facts Panel.

Allergy Relief Carton

Formucare Allergy Relief  loratadine  tablet

Product Information Product Type HUMAN OTC DRUG NDC Product Code (Source) 10056-612 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength LORATADINE (LORATADINE) LORATADINE 10 mg

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color WHITE Score no score Shape OVAL Size 8mm Flavor Imprint Code L612 Contains

Packaging # NDC Package Description Multilevel Packaging 1 10056-612-75 1 BOTTLE In 1 CARTON contains a BOTTLE 1 90 TABLET In 1 BOTTLE This package is contained within the CARTON (10056-612-75)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA076301	01/27/2005

Labeler - Access Business Group International LLC (609682641)

Revised: 09/2009Access Business Group International LLC

More Formucare Allergy Relief resources

• Formucare Allergy Relief Side Effects (in more detail)
• Formucare Allergy Relief Dosage
• Formucare Allergy Relief Use in Pregnancy & Breastfeeding
• Formucare Allergy Relief Drug Interactions
• 0 Reviews for Formucare Allergy Relief - Add your own review/rating

Compare Formucare Allergy Relief with other medications

• Hay Fever
• Urticaria

Haldol Injection

1. Name Of The Medicinal Product

HALDOL Injection

2. Qualitative And Quantitative Composition

Haloperidol 5 mg/ml

3. Pharmaceutical Form

Solution for injection

4. Clinical Particulars

4.1 Therapeutic Indications

Adults:

• Schizophrenia: treatment of symptoms and prevention of relapse.

• Other psychoses; especially paranoid.

• Mania and hypomania.

• Mental or behavioural problems such as aggression, hyperactivity and self-mutilation in the mentally retarded and in patients with organic brain damage.

• As an adjunct to short term management of moderate to severe psychomotor agitation, excitement, violent or dangerously impulsive behaviour.

• Nausea and vomiting.

4.2 Posology And Method Of Administration

Haldol Injection is recommended for IM administration only.

Dosage for all indications should be individually determined and is best initiated and titrated under close clinical supervision. To determine the initial dose, consideration should be given to the patient's age, severity of symptoms and previous response to other neuroleptics.

Patients who are elderly or debilitated or those with previously reported adverse reactions to neuroleptic drugs may require less haloperidol. The normal starting dose should be halved, followed by a gradual titration to achieve optimal response.

Haldol injection should be used at the minimum dose that is clinically effective.

Adults:

Schizophrenia, psychoses, mania and hypomania, mental or behavioural problems, psychomotor agitation, excitement, violent or dangerously impulsive behaviour, organic brain damage:

For control of acutely agitated patients with moderate symptoms: 2-10 mg IM. Depending on the response of the patient, subsequent doses may be given every 4-8 hours, up to a maximum of 18 mg/day.

Infrequently, severely disturbed patients may require an initial dose of up to 18 mg.

Oral treatment should succeed intramuscular administration as soon as practicable. Bioavailability from the oral route is about 60% of that from the IM route, and readjustment of dose may be required.

Nausea and vomiting

1-2 mg IM

Children:

Not recommended for parenteral use in children.

4.3 Contraindications

Comatose states, CNS depression, Parkinson's disease, known hypersensitivity to haloperidol, lesions of basal ganglia.

In common with other neuroleptics, haloperidol has the potential to cause rare prolongation of the QT interval. Use of haloperidol is therefore contra-indicated in patients with clinically significant cardiac disorders e.g. recent acute myocardial infarction, uncompensated heart failure, arrhythmias treated with class IA and III antiarrhythmic medicinal products, QTc interval prolongation, history of ventricular arrhythmia or torsades de pointes clinically significant bradycardia, second or third degree heart block and uncorrected hypokalaemia. Haloperidol should not be used concomitantly with other QT prolonging drugs (see section 4.5, Interactions)

4.4 Special Warnings And Precautions For Use

Cases of sudden death have been reported in psychiatric patients receiving antipsychotic drugs, including haloperidol.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10 week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

Haldol is not licensed for the treatment of dementia-related behavioural disturbances.

Cardiovascular effects

Very rare reports of QT prolongation and/or ventricular arrhythmias, in addition to rare reports of sudden death, have been reported with haloperidol. They may occur more frequently with high doses and in predisposed patients.

The risk-benefit of haloperidol treatment should be fully assessed before treatment is commenced and patients with risk factors for ventricular arrhythmias such as cardiac disease; family history of sudden death and/or QT prolongation; uncorrected electrolyte disturbances; subarachnoid haemorrhage; starvation; or alcohol abuse should be monitored carefully (ECGs and potassium levels), particularly during the initial phase of treatment, to obtain steady plasma levels. The risk of QT prolongation and/or ventricular arrhythmias may be increased with higher doses (see Sections 4.8 and 4.9) or with parenteral use, particularly intravenous administration. Continuous ECG monitoring should be performed for QT interval prolongation and for serious cardiac dysrhythmias if Haldol is administered intravenously.

Haldol Injection is recommended for IM administration only.

Haloperidol should be used with caution in patients known to be slow metabolisers of CYP2D6, and during use of cytochrome P450 inhibitors. Concomitant use of antipsychotics should be avoided. (See Section 4.5)

Baseline ECG is recommended prior to treatment in all patients, especially in the elderly and patients with a positive personal or family history of cardiac disease or abnormal findings on cardiac clinical examination. During therapy, the need for ECG monitoring (e.g. at dose escalation) should be assessed on an individual basis. Whilst on therapy, the dose should be reduced if QT is prolonged, and haloperidol should be discontinued if the QTc exceeds 500 ms.

Periodic electrolyte monitoring is recommended, especially for patients taking diuretics, or during intercurrent illness.

An approximately 3-fold increase risk of cerebrovascular adverse events have been seen in randomised placebo controlled clinical trials in the dementia population with some atypical antipsychotics. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Haloperidol should be used with caution in patients with risk factors for stroke.

Neuroleptic malignant syndrome

In common with other antipsychotic drugs, Haldol has been associated with neuroleptic malignant syndrome: a rare idiosyncratic response characterised by hyperthermia, generalised muscle rigidity, autonomic instability, altered consciousness. Hyperthermia is often an early sign of this syndrome. Antipsychotic treatment should be withdrawn immediately and appropriate supportive therapy and careful monitoring instituted.

Tardive dyskinesia

As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long-term therapy or after drug discontinuation. The syndrome is mainly characterised by rhythmic involuntary movements of the tongue, face, mouth or jaw. The manifestations may be permanent in some patients. The syndrome may be masked when treatment is reinstituted, when the dosage is increased or when a switch is made to a different antipsychotic drug. Treatment should be discontinued as soon as possible.

Extrapyramidal symptoms

In common with all neuroleptics, extrapyramidal symptoms may occur, e.g. tremor, rigidity, hypersalivation, bradykinesia, akathisia, acute dystonia.

Antiparkinson drugs of the anticholinergic type may be prescribed as required, but should not be prescribed routinely as a preventive measure. If concomitant antiparkinson medication is required, it may have to be continued after stopping Haldol if its excretion is faster than that of Haldol in order to avoid the development or aggravation of extrapyramidal symptoms. The physician should keep in mind the possible increase in intraocular pressure when anticholinergic drugs, including antiparkinson agents, are administered concomitantly with Haldol.

Seizures/Convulsions

It has been reported that seizures can be triggered by Haldol. Caution is advised in patients suffering from epilepsy and in conditions predisposing to convulsions (e.g., alcohol withdrawal and brain damage).

Hepatobiliary concerns

As Haldol is metabolised by the liver, caution is advised in patients with liver disease. Isolated cases of liver function abnormalities or hepatitis, most often cholestatic, have been reported.

Endocrine system concerns

Thyroxin may facilitate Haldol toxicity. Antipsychotic therapy in patients with hyperthyroidism should be used only with great caution and must always be accompanied by therapy to achieve a euthyroid state.

Hormonal effects of antipsychotic neuroleptic drugs include hyperprolactinaemia, which may cause galactorrhoea, gynaecomastia and oligo- or amenorrhoea. Very rare cases of hypoglycaemia and of Syndrome of Inappropriate ADH Secretion have been reported.

Venous thromboembolism

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Haldol and preventive measures undertaken.

Additional considerations

In schizophrenia, the response to antipsychotic drug treatment may be delayed. Also, if drugs are withdrawn, recurrence of symptoms may not become apparent for several weeks or months. Acute withdrawal symptoms including nausea, vomiting and insomnia have very rarely been described after abrupt cessation of high doses of antipsychotic drugs. Relapse may also occur and gradual withdrawal is advisable.

As with all antipsychotic agents, Haldol should not be used alone where depression is predominant. It may be combined with antidepressants to treat those conditions in which depression and psychosis coexist.

Caution is advised in patients with renal failure and phaeochromocytoma.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use of haloperidol with drugs known to prolong the QT interval may increase the risk of ventricular arrhythmias, including torsade de pointes. Therefore concomitant use of these products is not recommended (see section 4.3-Contraindications).

Examples include certain antiarrhythmics, such as those of Class 1A (such as quinidine, disopyramide and procainamide) and class III (such as amiodarone, sotalol and dofetilide), certain antimicrobials (sparfloxacin, moxifloxacin, erythromycin IV), tricyclic antidepressants (such as amitriptyline), certain tetracyclic antidepressants (such as maprotiline), other neuroleptics (e.g. phenothiazines, pimozide and sertindole), certain antihistamines (such as terfenadine), cisapride, bretylium and certain antimalarials such as quinine and mefloquine. This list is not comprehensive.

Concurrent use of drugs causing electrolyte imbalance may increase the risk of ventricular arrhythmias and is not recommended (see section 4.4-Special Warnings and Precautions for Use). Diuretics, in particular those causing hypokalaemia, should be avoided but, if necessary, potassium-sparing diuretics are preferred.

Haloperidol is metabolised by several routes, including glucuronidation and the cytochrome P450 enzyme system (particularly CYP 3A4 or CYP 2D6). Inhibition of these routes of metabolism by another drug or a decrease in CYP 2D6 enzyme activity may result in increased haloperidol concentrations and an increased risk of adverse events, including QT-prolongation. In pharmacokinetic studies, mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with drugs characterised as substrates or inhibitors of CYP 3A4 or CYP 2D6 isozymes, such as, itraconazole, buspirone, venlafaxine, alprazolam, fluvoxamine, quinidine, fluoxetine, sertraline, chlorpromazine, and promethazine. A decrease in CYP2D6 enzyme activity may result in increased haloperidol concentrations. Increases in QTc and extrapyramidal symptoms have been observed when haloperidol was given with a combination of the metabolic inhibitors ketoconazole (400 mg/day) and paroxetine (20 mg/day). It may be necessary to reduce the haloperidol dosage.

Effect of Other Drugs on Haloperidol

When prolonged treatment with enzyme-inducing drugs such as carbamazepine, phenobarbital, rifampicin is added to Haldol therapy, this results in a significant reduction of haloperidol plasma levels. Therefore, during combination treatment, the Haldol dose should be adjusted, when necessary. After stopping such drugs, it may be necessary to reduce the dosage of Haldol.

Sodium valproate, a drug known to inhibit glucuronidation, does not affect haloperidol plasma concentrations.

Effect of Haloperidol on Other Drugs

In common with all neuroleptics, Haldol can increase the central nervous system depression produced by other CNS-depressant drugs, including alcohol, hypnotics, sedatives or strong analgesics. An enhanced CNS effect, when combined with methyldopa, has also been reported.

Haldol may antagonise the action of adrenaline and other sympathomimetic agents and reverse the blood-pressure-lowering effects of adrenergic-blocking agents such as guanethidine.

Haldol may impair the antiparkinson effects of levodopa.

Haloperidol is an inhibitor of CYP 2D6. Haldol inhibits the metabolism of tricyclic antidepressants, thereby increasing plasma levels of these drugs.

Other Forms of Interaction

In rare cases, an encephalopathy-like syndrome has been reported in combination with lithium and haloperidol. It remains controversial whether these cases represent a distinct clinical entity or whether they are in fact cases of NMS and/or lithium toxicity. Signs of encephalopathy-like syndrome include confusion, disorientation, headache, disturbances of balance and drowsiness. One report showing symptomless EEG abnormalities on the combination has suggested that EEG monitoring might be advisable. When lithium and haloperidol therapy are used concomitantly, haloperidol should be given in the lowest effective dose and lithium levels should be monitored and kept below 1 mmol/l. If symptoms of encephalopathy-like syndrome occur, therapy should be stopped immediately.

Antagonism of the effect of the anticoagulant phenindione has been reported.

The dosage of anticonvulsants may need to be increased to take account of the lowered seizure threshold.

4.6 Pregnancy And Lactation

The safety of haloperidol in pregnancy has not been established. There is some evidence of harmful effects in some but not all animal studies. Neonates exposed to antipsychotic drugs (including haloperidol) during the third trimester of pregnancy are at risk of adverse effects including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.

There have been a number of reports of birth defects following foetal exposure to haloperidol for which a causal role for haloperidol cannot be excluded. Haldol should be used during pregnancy only if the anticipated benefit outweighs the risk and the administered dose and duration of treatment should be as low and as short as possible.

Haloperidol is excreted in breast milk. There have been isolated cases of extrapyramidal symptoms in breast-fed children. If the use of Haldol is essential, the benefits of breast feeding should be balanced against its potential risks.

4.7 Effects On Ability To Drive And Use Machines

Some degree of sedation or impairment of alertness may occur, particularly with higher doses and at the start of treatment, and may be potentiated by alcohol or other CNS depressants. Patients should be advised not to undertake activities requiring alertness such as driving or operating machinery during treatment, until their susceptibility is known.

4.8 Undesirable Effects

The data provided below covers all haloperidol formulations including the Haldol Decanoate formulations.

The safety of Haldol was evaluated in 284 haloperidol-treated subjects who participated in 3 placebo-controlled, and in 1295 haloperidol-treated subjects who participated in sixteen double-blind active comparator- controlled clinical trials. The safety of Haldol decanoate was evaluated in 410 subjects who participated in 3 comparator trials (one comparing haloperidol vs. fluphenazine and two comparing the decanoate formulation to the oral formulation), 9 open label trials and 1 dose responsive trial. Based on pooled safety data from these clinical trials, the most commonly reported (% incidence) Adverse Drug Reactions (ADRs) were: Extrapyramidal disorder (34), Insomnia (19), Agitation (15), Hyperkinesia (13), Headache (12), Psychotic disorder (9), Depression (8), Weight increased (8), Orthostatic hypotension (7) and Somnolence (5).

Including the above mentioned ADRs, the following ADRs have been observed from clinical trials and post-marketing experiences reported with the use of Haldol and Haldol decanoate. Frequencies displayed use the following convention:

Very common (

System Organ Class	Adverse Drug Reactions
Frequency Category
Very Common (	Common (	Uncommon (	Rare (	Not Known
Blood and lymphatic System Disorders			Leukopenia		Agranulocytosis; Neutropenia; Pancytopenia; Thrombocytopenia
Immune System Disorders			Hypersensitivity		Anaphylactic reaction
Endocrine Disorders				Hyperprolactinaemia	Inappropriate antidiuretic hormone secretion
Metabolic and Nutritional Disorders					Hypoglycaemia
Psychiatric Disorders	Agitation; Insomnia	Depression; Psychotic disorder	Confusional state; Libido Decreased; Loss of libido; Restlessness
Nervous System Disorders	Extrapyramidal disorder; Hyperkinesia; Headache	Tardive dyskinesia; Oculogyric Crisis; Dystonia; Dyskinesia; Akathisia; Bradykinesia; Hypokinesia; Hypertonia; Somnolence; Masked Facies, Tremor; Dizziness	Convulsion; Parkinsonism; Akinesia; Cogwheel rigidity; Sedation; Muscle Contractions Involuntary	Motor dysfunction; Neuroleptic malignant syndrome; Nystagmus;
Eye Disorders		Visual disturbance;	Vision blurred
Cardiac Disorders			Tachycardia		Ventricular Fibrillation; Torsade de pointes; Ventricular Tachycardia; Extrasystoles
Vascular Disorders		Orthostatic Hypotension; Hypotension
Respiratory, thoracic and mediastinal Disorders			Dyspnoea	Bronchospasm	Laryngeal Oedema; Laryngospasm
Gastrointestinal Disorders		Constipation; Dry mouth; Salivary hypersecretion; Nausea; Vomiting
Hepatobiliary Disorders		Liver function test abnormal	Hepatitis; Jaundice		Acute Hepatic Failure; Cholestasis
Skin and subcutaneous tissue disorders		Rash	Photosensitivity Reaction; Urticaria; Pruritis; Hyperhidrosis		Leukocytoclastic Vasculitis; Dermatitis Exfoliative
Musculoskeletal and Connective Tissue Disorders			Torticollis; Muscle rigidity; Muscle Spasms; Musculoskeletal stiffness	Trismus; Muscle Twitching
Renal and Urinary Disorders		Urinary retention
Pregnancy, Puerperium and Perinatal Conditions					Drug withdrawal syndrome neonatal (see section 4.6)
Reproductive System and Breast Disorders		Erectile dysfunction	Amenorrhoea; Dysmenorrhoea; Galactorrhoea; Breast Discomfort; Breast Pain;	Menorrhagia; Menstrual Disorder; Sexual Dysfunction	Gynaecomastia, Priapism
General Disorders and Administration Site Conditions		Injection Site Reaction	Gait disturbance; Hyperthermia; Oedema		Sudden Death; Face Oedema; Hypothermia
Investigations		Weight increased; Weight decreased		Electrocardiogram QT prolonged

Additional Information

Cardiac effects such as QT-interval prolongation, torsade de pointes, ventricular arrhythmias, including ventricular fibrillation and ventricular tachycardia), and cardiac arrest have been reported. These effects may occur more frequently with high doses, and in predisposed patients.

Toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported in patients taking haloperidol. The true incidence of these reports is not known.

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs- Frequency unknown.

4.9 Overdose

Symptoms: In general, the manifestations of haloperidol overdosage are an extension of its pharmacological actions, the most prominent of which would be severe extrapyramidal symptoms, hypotension and psychic indifference with a transition to sleep. The risk of ventricular arrhythmias possibly associated with QT-prolongation should be considered. The patient may appear comatose with respiratory depression and hypotension which could be severe enough to produce a shock-like state. Paradoxically hypertension rather than hypotension may occur. Convulsions may also occur.

Treatment: There is no specific antidote to haloperidol. A patent airway should be established and maintained with mechanically assisted ventilation if necessary. In view of isolated reports of arrhythmia, ECG monitoring is strongly advised. Hypotension and circulatory collapse should be treated by plasma volume expansion and other appropriate measures. Adrenaline should not be used. The patient should be monitored carefully for 24 hours or longer, body temperature and adequate fluid intake should be maintained.

In cases of severe extrapyramidal symptoms, appropriate anti-Parkinson medication should be administered.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Haloperidol is a central dopamine antagonist. It also has some anticholinergic properties and is an opiate receptor antagonist, and acts at peripheral dopamine receptors.

5.2 Pharmacokinetic Properties

A 10 mg IV dose of haloperidol given over 2 mins produced a peak serum concentration of 34μg/ml at the end of infusion, declining to 1μg/ml by 40 hours. Following IM administration of 2 mg, peak plasma concentrations were similar to after oral ie. 10μg/ml but are reached within 20 minutes.

Haloperidol is rapidly distributed throughout the body.

Haloperidol is excreted in human breast milk, milk concentrations being 59-69% of maternal plasma.

Haloperidol is extensively metabolised by oxidative dealkylation. Metabolites are ultimately conjugated with glycine.

5.3 Preclinical Safety Data

Only limited data are available, however these show no specific hazards apart from decreased fertility, limited teratogenicity as well as embryo-toxic effects in rodents.

Haloperidol has been shown to block the cardiac hERG channel in several published studies in vitro. In a number of in vivo studies intravenous administration of haloperidol in some animal models has caused significant QTc prolongation, at doses around 0.3 mg/kg i.v., giving C_max plasma levels 3 to 7 times higher than the effective human plasma concentrations of 4 to 20 ng/ml. These intravenous doses which prolonged QTc did not cause arrhythmias. In some studies higher intravenous doses of 1 to 5 mg/kg haloperidol i.v. caused QTc prolongation and/or ventricular arrhythmias at C_max plasma levels 19 to 68 times higher than the effective human plasma concentrations.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactic Acid

Water for Injections

6.2 Incompatibilities

None known.

6.3 Shelf Life

5 years

6.4 Special Precautions For Storage

Keep the ampoule in the outer carton.

6.5 Nature And Contents Of Container

Amber glass ampoules containing 1 or 2ml of solution for injection. Boxes of 5 ampoules.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

Janssen-Cilag Limited

50-100 Holmers Farm Way

High Wycombe

Bucks

HP12 4EG

UK

8. Marketing Authorisation Number(S)

PL 00242/0036R

9. Date Of First Authorisation/Renewal Of The Authorisation

23 November 1988/25 May 2004

10. Date Of Revision Of The Text

16 Nov 2011

LEGAL CATEGORY

POM