Arava and night Sweats

Arava and Night Sweats

This page helps to understand the Arava side effects that cause sweating and night sweats commonly known as nocturnal hydrosis. this medicine has many warnings associated with it. This information is always subject to change please consult you doctor before taking Arava.

CONTRAINDICATIONS AND WARNINGS

PREGNANCY MUST BE EXCLUDED BEFORE THE START OF TREATMENT WITH THIS DRUG. THIS DRUG IS CONTRAINDICATED IN PREGNANT WOMEN, OR WOMEN OF CHILDBEARING POTENTIAL WHO ARE NOT USING RELIABLE CONTRACEPTION. (SEE CONTRAINDICATIONS AND WARNINGS .) PREGNANCY MUST BE AVOIDED DURING ARAVA TREATMENT OR PRIOR TO THE COMPLETION OF THE DRUG ELIMINATION PROCEDURE AFTER ARAVA TREATMENT.

DESCRIPTION

ARAVA ^®(leflunomide) is a pyrimidine synthesis inhibitor. The chemical name for leflunomide is N-(4'-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide. It has an empirical formula C ₁₂H ₉F ₃N ₂O ₂, a molecular weight of 270.2 and the following structural formula:

PRECAUTIONS

General

Need for Drug Elimination

The active metabolite of leflunomide is eliminated slowly from the plasma. In instances of any serious toxicity from ARAVA, including hypersensitivity, use of a drug elimination procedure as described in this section is highly recommended to reduce the drug concentration more rapidly after stopping ARAVA therapy. If hypersensitivity is the suspected clinical mechanism, more prolonged cholestyramine or charcoal administration may be necessary to achieve rapid and sufficient clearance. The duration may be modified based on the clinical status of the patient.

Cholestyramine given orally at a dose of 8 g three times a day for 24 hours to three healthy volunteers decreased plasma levels of M1 by approximately 40% in 24 hours and by 49 to 65% in 48 hours.

Administration of activated charcoal (powder made into a suspension) orally or via nasogastric tube (50 g every 6 hours for 24 hours) has been shown to reduce plasma concentrations of the active metabolite, M1, by 37% in 24 hours and by 48% in 48 hours.

These drug elimination procedures may be repeated if clinically necessary.

Respiratory

Interstitial lung disease has been reported during treatment with leflunomide and has been associated with fatal outcomes (see ADVERSE REACTIONS ). Interstitial lung disease is a potentially fatal disorder, which may occur acutely at any time during therapy and has a variable clinical presentation. New onset or worsening pulmonary symptoms, such as cough and dyspnea, with or without associated fever, may be a reason for discontinuation of the therapy and for further investigation as appropriate. If discontinuation of the drug is necessary, initiation of wash-out procedures should be considered. (See WARNINGS - Drug Elimination Procedure ).

Renal Insufficiency

Single dose studies in dialysis patients show a doubling of the free fraction of M1 in plasma. There is no clinical experience in the use of ARAVA in patients with renal impairment. Caution should be used when administering this drug in this population.

Vaccinations

No clinical data are available on the efficacy and safety of vaccinations during ARAVA treatment. Vaccination with live vaccines is, however, not recommended. The long half-life of ARAVA should be considered when contemplating administration of a live vaccine after stopping ARAVA.

Information for Patients

The potential for increased risk of birth defects should be discussed with female patients of childbearing potential. It is recommended that physicians advise women that they may be at increased risk of having a child with birth defects if they are pregnant when taking ARAVA, become pregnant while taking ARAVA, or do not wait to become pregnant until they have stopped taking ARAVA and followed the drug elimination procedure (as described in WARNINGS - Use In Women of Childbearing Potential - Drug Elimination Procedure ).
Patients should be advised of the possibility of rare, serious skin reactions. Patients should be instructed to inform their physicians promptly if they develop a skin rash or mucous membrane lesions.
Patients should be advised of the potential hepatotoxic effects of ARAVA and of the need for monitoring liver enzymes. Patients should be instructed to notify their physicians if they develop symptoms such as unusual tiredness, abdominal pain or jaundice.
Patients should be advised that they may develop a lowering of their blood counts and should have frequent hematologic monitoring. This is particularly important for patients who are receiving other immunosuppressive therapy concurrently with ARAVA, who have recently discontinued such therapy before starting treatment with ARAVA, or who have had a history of a significant hematologic abnormality. Patients should be instructed to notify their physicians promptly if they notice symptoms of pancytopenia (such as easy bruising or bleeding, recurrent infections, fever, paleness or unusual tiredness).
Patients should be informed about the early warning signs of interstitial lung disease and asked to contact their physician as soon as possible if these symptoms appear or worsen during therapy.

Laboratory Tests

Hematologic Monitoring

At minimum, patients taking ARAVA should have platelet, white blood cell count and hemoglobin or hematocrit monitored at baseline and monthly for six months following initiation of therapy and every 6 to 8 weeks thereafter.

Bone Marrow Suppression Monitoring

If used with concomitantly with immunosuppressants such as methotrexate, chronic monitoring should be monthly. (See WARNINGS - Immunosuppression Potential/Bone Marrow Suppression ).

Liver Enzyme Monitoring

ALT (SGPT) must be performed at baseline and monitored at monthly intervals during the first six months then, if stable, every 6 to 8 weeks thereafter. In addition, if ARAVA and methotrexate are given concomitantly, ACR guidelines for monitoring methotrexate liver toxicity must be followed with ALT, AST, and serum albumin testing every month. (See WARNINGS - Hepatotoxicity .)

Due to a specific effect on the brush border of the renal proximal tubule, ARAVA has a uricosuric effect. A separate effect of hypophosphaturia is seen in some patients. These effects have not been seen together, nor have there been alterations in renal function.

ADVERSE REACTIONS

Adverse reactions associated with the use of leflunomide in RA include diarrhea, elevated liver enzymes (ALT and AST), alopecia and rash. In the controlled studies at one year, the following adverse events were reported, regardless of causality. (See Table 9.)

Table 9. Percentage Of Patients With Adverse Events >/=3% In Any Leflunomide Treated Group
	All RA Studies	Placebo-Controlled Trials				Active-Controlled Trials
	All RA Studies	MN 301 and US 301				MN 302 *
	LEF (N=1339) ¹	LEF (N=315)	PBO (N=210)	SSZ (N=133)	MTX (N=182)	LEF (N=501)	MTX (N=498)
BODY AS A WHOLE
Allergic Reaction	2%	5%	2%	0%	6%	1%	2%
Asthenia	3%	6%	4%	5%	6%	3%	3%
Flu Syndrome	2%	4%	2%	0%	7%	0%	0%
Infection, upper respiratory	4%	0%	0%	0%	0%	0%	0%
Injury Accident	5%	7%	5%	3%	11%	6%	7%
Pain	2%	4%	2%	2%	5%	1%	<1%
Abdominal Pain	6%	5%	4%	4%	8%	6%	4%
Back Pain	5%	6%	3%	4%	9%	8%	7%
CARDIOVASCULAR
Hypertension ²	10%	9%	4%	4%	3%	10%	4%
- New onset of hypertension		1%	<1%	0%	2%	2%	<1%
Chest Pain	2%	4%	2%	2%	4%	1%	2%
GASTROINTESTINAL
Anorexia	3%	3%	2%	5%	2%	3%	3%
Diarrhea	17%	27%	12%	10%	20%	22%	10%
Dyspepsia	5%	10%	10%	9%	13%	6%	7%
Gastroenteritis	3%	1%	1%	0%	6%	3%	3%
Abnormal Liver Enzymes	5%	10%	2%	4%	10%	6%	17%
Nausea	9%	13%	11%	19%	18%	13%	18%
GI/Abdominal Pain	5%	6%	4%	7%	8%	8%	8%
Mouth Ulcer	3%	5%	4%	3%	10%	3%	6%
Vomiting	3%	5%	4%	4%	3%	3%	3%
METABOLIC AND NUTRITIONAL
Hypokalemia	1%	3%	1%	1%	1%	1%	<1%
Weight Loss ³	4%	2%	1%	2%	0%	2%	2%
MUSCULO-SKELETAL SYSTEM
Arthralgia	1%	4%	3%	0%	9%	<1%	1%
Leg Cramps	1%	4%	2%	2%	6%	0%	0%
Joint Disorder	4%	2%	2%	2%	2%	8%	6%
Synovitis	2%	<1%	1%	0%	2%	4%	2%
Tenosynovitis	3%	2%	0%	1%	2%	5%	1%
NERVOUS SYSTEM
Dizziness	4%	5%	3%	6%	5%	7%	6%
Headache	7%	13%	11%	12%	21%	10%	8%
Paresthesia	2%	3%	1%	1%	2%	4%	3%
RESPIRATORY SYSTEM
Bronchitis	7%	5%	2%	4%	7%	8%	7%
Increased Cough	3%	4%	5%	3%	6%	5%	7%
Respiratory Infection	15%	21%	21%	20%	32%	27%	25%
Pharyngitis	3%	2%	1%	2%	1%	3%	3%
Pneumonia	2%	3%	0%	0%	1%	2%	2%
Rhinitis	2%	5%	2%	4%	3%	2%	2%
Sinusitis	2%	5%	5%	0%	10%	1%	1%
SKIN AND APPENDAGES
Alopecia	10%	9%	1%	6%	6%	17%	10%
Eczema	2%	1%	1%	1%	1%	3%	2%
Pruritus	4%	5%	2%	3%	2%	6%	2%
Rash	10%	12%	7%	11%	9%	11%	10%
Dry Skin	2%	3%	2%	2%	0%	3%	1%
UROGENITAL SYSTEM
Urinary Tract Infection	5%	5%	7%	4%	2%	5%	6%
*Only 10% of patients in MN302 received folate. All patients in US301 received folate; none in MN301 received folate.
¹ Includes all controlled and uncontrolled trials with leflunomide (duration up to 12 months).
² Hypertension as a preexisting condition was overrepresented in all leflunomide treatment groups in phase III trials.
³ In a meta-analysis of all phase II and III studies, during the first 6 months in patients receiving leflunomide, 10% lost 10-19 lbs (24 cases per 100 patient years) and 2% lost at least 20 lbs (4 cases/100 patient years). Of patients receiving leflunomide 4% lost 10% of their baseline weight during the first 6 months of treatment.

Adverse events during a second year of treatment with leflunomide in clinical trials were consistent with those observed during the first year of treatment and occurred at a similar or lower incidence.

In addition, the following adverse events have been reported in 1% to <3% of the RA patients in the leflunomide treatment group in controlled clinical trials.

Body as a Whole: abscess, cyst, fever, hernia, malaise, pain, neck pain, pelvic pain;

Cardiovascular: angina pectoris, migraine, palpitation, tachycardia, varicose vein, vasculitis, vasodilatation;

Gastrointestinal: cholelithiasis, colitis, constipation, esophagitis, flatulence, gastritis, gingivitis, melena, oral moniliasis, pharyngitis, salivary gland enlarged, stomatitis (or aphthous stomatitis), tooth disorder;

Endocrine: diabetes mellitus, hyperthyroidism;

Hemic and Lymphatic System: anemia (including iron deficiency anemia), ecchymosis;

Metabolic and Nutritional: creatine phosphokinase increased, hyperglycemia, hyperlipidemia, peripheral edema;

Musculo-Skeletal System: arthrosis, bone necrosis, bone pain, bursitis, muscle cramps, myalgia, tendon rupture;

Nervous System: anxiety, depression, dry mouth, insomnia, neuralgia, neuritis, sleep disorder, sweating increased, vertigo;

Respiratory System: asthma, dyspnea, epistaxis, lung disorder;

Skin and Appendages: acne, contact dermatitis, fungal dermatitis, hair discoloration, hematoma, herpes simplex, herpes zoster, maculopapular rash, nail disorder, skin discoloration, skin disorder, skin nodule, subcutaneous nodule, ulcer skin;

Special Senses: blurred vision, cataract, conjunctivitis, eye disorder, taste perversion;

Urogenital System: albuminuria, cystitis, dysuria, hematuria, menstrual disorder, prostate disorder, urinary frequency, vaginal moniliasis.

Other less common adverse events seen in clinical trials include: 1 case of anaphylactic reaction occurred in Phase 2 following rechallenge of drug after withdrawal due to rash (rare); urticaria; eosinophilia; transient thrombocytopenia (rare); and leukopenia <2000 WBC/mm ³(rare).

In post-marketing experience, the following have been reported rarely:

Body as a whole: opportunistic infections, severe infections including sepsis that may be fatal;

Gastrointestinal: pancreatitis;

Hematologic: agranulocytosis, leukopenia, neutropenia, pancytopenia, thrombocytopenia;

Hypersensitivity: angioedema;

Hepatic: hepatitis, jaundice/cholestasis, severe liver injury such as hepatic failure and acute hepatic necrosis that may be fatal;

Respiratory: interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis, which may be fatal;

Nervous system: peripheral neuropathy;

Skin and Appendages: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Adverse Reactions (Pediatric Patients)

The safety of ARAVA was studied in 74 patients with polyarticular course juvenile rheumatoid arthritis ranging in age from 3-17 years (47 patients from the active-controlled study and 27 from the open-label safety and pharmacokinetic study). The most common adverse events included abdominal pain, diarrhea, nausea, vomiting, oral ulcers, upper respiratory tract infections, alopecia, rash, headache, and dizziness. Less common adverse events included anemia, hypertension, and weight loss. Fourteen pediatric patients experienced ALT and/or AST elevations, nine between 1.2 and 3-fold the upper limit of normal, five between 3 and 8-fold the upper limit of normal.