Plaquenil

PLAQUENIL- hydroxychloroquine sulfate tablet
RedPharm Drug, Inc.

DESCRIPTION

PLAQUENIL ^® (hydroxychloroquine sulfate) is a white or practically white, crystalline powder, freely soluble in water; practically insoluble in alcohol, chloroform, and in ether. The chemical name for hydroxychloroquine sulfate is 2-[[4-[(7-Chloro-4-quinolyl)amino]pentyl]ethylamino] ethanol sulfate (1:1). Its structural formula is:

The molecular weight of hydroxychloroquine sulfate is 433.95, and molecular formula is C ₁₈ H ₂₆ ClN ₃ O.H ₂ SO ₄ .

PLAQUENIL (hydroxychloroquine sulfate) tablets contain 200 mg hydroxychloroquine sulfate, equivalent to 155 mg base, and are for oral administration.

Inactive Ingredients: Dibasic calcium phosphate USP, hypromellose USP, magnesium stearate NF, polyethylene glycol 400 NF, polysorbate 80 NF, corn starch, titanium dioxide USP, carnauba wax NF, shellac NF, black iron oxide NF.

CLINICAL PHARMACOLOGY

Pharmacokinetics: Following a single 200 mg oral dose of PLAQUENIL to healthy male volunteers, the mean peak blood concentration of hydroxychloroquine was 129.6 ng/mL, reached in 3.26 hours with a half-life of 537 hours (22.4 days). In the same study, the plasma peak concentration was 50.3 ng/mL reached in 3.74 hours with a half-life of 2963 hours (123.5 days). Urine hydroxychloroquine levels were still detectable after 3 months with approximately 10% of the dose excreted was parent drug. Results following a single dose of a 200 mg tablet versus i.v. infusion (155 mg), demonstrated a half-life of about 40 days and a large volume of distribution. Peak blood concentrations of metabolites were observed at the same time as peak levels of hydroxycholoquine. The mean fraction of the dose absorbed was 0.74. After administration of single 155 mg and 310 mg intravenous doses, peak blood concentrations ranged from 1161 ng/mL to 2436 ng/mL (mean 1918 ng/mL) following the 155 mg infusion and 6 months following the 3as10 mg infusion. Pharmacokinetic parameters were not significantly different over the therapeutic dose range of 155 mg and 310 mg indicating linear kinetics.

Following chronic oral administration of hydroxychloroquine, significant levels of three metabolites, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bidesethylhydroxychloroquine (BDCQ) have been found in plasma and blood, with DHCQ being the major metabolite. The absorption half-life was approximately 3 to 4 hours and the terminal half-life ranged from 40 to 50 days. The long half-life can be attributed to extensive tissue uptake rather than through decreased excretion. Peak plasma levels of hydroxychloroquine were seen in about 3 to 4 hours. Renal clearance in rheumatoid arthritis (RA) patients taking PLAQUENIL for at least six months seemed to be similar to that of the single dose studies in volunteers, suggesting that no change occurs with chronic dosing. Range for renal clearance of unchanged drug was approximately 16 to 30% and did not correlate with creatinine clearance; therefore, a dosage adjustment is not required for patients with renal impairment. In RA patients, there was large variability as to the fraction of the dose absorbed (i.e. 30 to 100%), and mean hydroxychloroquine levels were significantly higher in patients with less disease activity. Cellular levels of patients on daily hydroxychloroquine have been shown to be higher in mononuclear cells than polymorphonuclear leucocytes.

Microbiology — Malaria

Mechanism of action: The precise mechanism by which hydroxychloroquine exhibits activity against Plasmodium is not known. Hydroxychloroquine, like chloroquine, is a weak base and may exert its effect by concentrating in the acid vesicles of the parasite and by inhibiting polymerization of heme. It can also inhibit certain enzymes by its interaction with DNA.

Activity in vitro and in Clinical Infections: Hydroxychloroquine is active against the erythrocytic forms of chloroquine sensitive strains of Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, and Plasmodium vivax. Hydroxychloroquine is not active against the gametocytes and exoerythrocytic forms including the hypnozoite stage (P. vivax and P. ovale) of the Plasmodium parasites.

Drug Resistance: P. falciparum strains exhibiting reduced susceptibility to chloroquine also show reduced susceptibility to hydroxychloroquine.

Resistance of Plasmodium parasites to chloroquine is widespread (see INDICATIONS AND USAGE – Malaria).

Patients in whom chloroquine or hydroxychloroquine have failed to prevent or cure clinical malaria or parasitemia, or patients who acquired malaria in a geographic area where chloroquine resistance is known to occur should be treated with another form of antimalarial therapy (see INDICATIONS AND USAGE – Malariaand WARNINGS).

Rheumatoid Arthritis and Systemic Lupus Erythematosus

Mechanism of action: The mechanisms underlying the anti-inflammatory and immunomodulatory effects of PLAQUENIL are unknown

INDICATIONS AND USAGE

Malaria

PLAQUENIL is indicated for the treatment of uncomplicated malaria due to P. falciparum, P. malariae, P. ovale, and P. vivax.

PLAQUENIL is indicated for the prophylaxis of malaria in geographic areas where chloroquine resistance is not reported.

Limitations of Use in Malaria
• PLAQUENIL is not recommended for the treatment of complicated malaria.
• PLAQUENIL is not effective against chloroquine or hydroxychloroquine-resistant strains of Plasmodium species (see CLINICAL PHARMACOLOGY – Microbiology). PLAQUENIL is not recommended for the treatment of malaria acquired in geographic areas where chloroquine resistance occurs or when the Plasmodium species has not been identified.
• PLAQUENIL is not recommended for malaria prophylaxis in geographic areas where chloroquine resistance occurs.
• PLAQUENIL does not prevent relapses of P. vivax or P. ovale because it is not active against the hypnozoite forms of these parasites. For radical cure of P. vivax and P. ovale infections, concomitant therapy with an 8-aminoquinoline compound is necessary (see CLINICAL PHARMACOLOGY – Microbiology).

Prior to prescribing PLAQUENIL for the treatment or prophylaxis of malaria, consult the Centers for Disease Control and Prevention (CDC) Malaria website (http://www.cdc.gov/malaria).

Lupus Erythematosus

PLAQUENIL is indicated for the treatment of chronic discoid lupus erythematosus and systemic lupus erythematosus in adults.

Rheumatoid Arthritis

PLAQUENIL is indicated for the treatment of acute and chronic rheumatoid arthritis in adults.

CONTRAINDICATIONS

Use of PLAQUENIL is contraindicated in patients with known hypersensitivity to 4-aminoquinoline compounds.

WARNINGS

Resistant strains of malaria: PLAQUENIL is not effective against chloroquine-resistant strains of P. falciparum (see CLINICAL PHARMACOLOGY – Microbiology).

Ocular: Irreversible retinal damage has been observed in some patients who had received hydroxychloroquine sulfate. Significant risk factors for retinal damage include daily doses of hydroxychloroquine sulfate greater than 6.5 mg/kg (5 mg/kg base) of actual body weight, durations of use greater than five years, subnormal glomerular filtration, use of some concomitant drug products such as tamoxifen citrate and concurrent macular disease.

A baseline ocular examination is recommended within the first year of starting PLAQUENIL. The baseline exam should include: best corrected distance visual acuity (BCVA), an automated threshold visual field (VF) of the central 10 degrees (with retesting if an abnormality is noted), and spectral domain ocular coherence tomography (SD-OCT).

For individuals with significant risk factors (daily dose of hydroxychloroquine sulfate greater than 5.0 mg/kg base of actual body weight, subnormal glomerular filtration, use of tamoxifen citrate or concurrent macular disease) monitoring should include annual examinations which include BCVA, VF and SD-OCT. For individuals without significant risk factors, annual exams can usually be deferred until five years of treatment.

In individuals of Asian descent, retinal toxicity may first be noticed outside the macula. In patients of Asian descent, it is recommended that visual field testing be performed in the central 24 degrees instead of the central 10 degrees.

It is recommended that hydroxychloroquine be discontinued if ocular toxicity is suspected and the patient should be closely observed given that retinal changes (and visual disturbances) may progress even after cessation of therapy.

Cardiac Effects, including Cardiomyopathy and QT prolongation: Postmarketing cases of life-threatening and fatal cardiomyopathy have been reported with use of PLAQUENIL as well as with use of chloroquine. Patients may present with atrioventricular block, pulmonary hypertension, sick sinus syndrome or with cardiac complications. ECG findings may include atrioventricular, right or left bundle branch block. Signs or symptoms of cardiac compromise have appeared during acute and chronic treatment. Clinical monitoring for signs and symptoms of cardiomyopathy is advised, including use of appropriate diagnostic tools such as ECG to monitor patients for cardiomyopathy during PLAQUENIL therapy. Chronic toxicity should be considered when conduction disorders (bundle branch block/atrio-ventricular heart block) or biventricular hypertrophy are diagnosed. If cardiotoxicity is suspected, prompt discontinuation of PLAQUENIL may prevent life-threatening complications.

PLAQUENIL prolongs the QT interval. Ventricular arrhythmias and torsades de pointes have been reported in patients taking PLAQUENIL (see OVERDOSAGE). Therefore, PLAQUENIL should not be administered with other drugs that have the potential to prolong the QT interval (see DRUG INTERACTIONS).

Worsening of psoriasis and porphyria: Use of PLAQUENIL in patients with psoriasis may precipitate a severe attack of psoriasis. When used in patients with porphyria the condition may be exacerbated. The preparation should not be used in these conditions unless in the judgment of the physician the benefit to the patient outweighs the possible hazard.

Proximal Myopathy and Neuropathy: Skeletal muscle myopathy or neuropathy leading to progressive weakness and atrophy of proximal muscle groups, depressed tendon reflexes, and abnormal nerve conduction, have been reported. Muscle and nerve biopsies have been associated with curvilinear bodies and muscle fiber atrophy with vacuolar changes. Assess muscle strength and deep tendon reflexes periodically in patients on long-term therapy with PLAQUENIL.

Neuropsychiatric events, including suicidality: Suicidal behavior has been rarely reported in patients treated with PLAQUENIL.

Hypoglycemia: PLAQUENIL has been shown to cause severe hypoglycemia including loss of consciousness that could be life threatening in patients treated with or without antidiabetic medications (see DRUG INTERACTIONS and ADVERSE REACTIONS). Patients treated with PLAQUENIL should be warned about the risk of hypoglycemia and the associated clinical signs and symptoms. Patients presenting with clinical symptoms suggestive of hypoglycemia during treatment with PLAQUENIL should have their blood glucose checked and treatment reviewed as necessary.