4.1.1 Adjuvant Breast Cancer Doxorubicin Hydrochloride Injection/for

 

Doxorubicin Hydrochloride is indicated as a component of multi-agent adjuvant chemotherapy for treatment of women with axillary lymph node involvement following resection of primary breast cancer.

 

4.1.2 Other Cancers

 

Doxorubicin Hydrochloride is indicated for the treatment of

•           acute lymphoblastic leukemia

•           acute myeloblastic leukemia

•           Hodgkin lymphoma

•           non-Hodgkin lymphoma (NHL)

•           metastatic breast cancer

•           metastatic Wilms’ tumor

•           metastatic neuroblastoma

•           metastatic soft tissue sarcoma

•           metastatic bone sarcoma

•           metastatic ovarian carcinoma

•           metastatic transitional cell bladder carcinoma

•           metastatic thyroid carcinoma

•           metastatic gastric carcinoma

•           metastatic bronchogenic carcinoma

The total Adriblastina dose per cycle may differ according to its use within a specific treatment regimen (e.g. given as a single agent or in combination with other cytotoxic drugs) and according to the indication.

 

The solution is given via the tubing of a freely running intravenous infusion, taking not less than 3 minutes and not more than 10 minutes over the injection. This technique minimises the risk of thrombosis or perivenous extravasation which can lead to severe cellulitis, vesication and necrosis. A direct push injection is not recommended due to the risk of extravasation, which may occur even in the presence of adequate blood return upon needle aspiration (see section 4.4).

 

Dosage is usually calculated on the basis of body surface area. As a single agent, the recommended standard starting dose of doxorubicin per cycle in adults is 60-75mg/m² of body surface area. The total starting dose per cycle may be given as a single dose or divided over 3 successive days or in divided doses given on days 1 and 8. Under conditions of normal recovery from drug-induced toxicity (particularly bone marrow depression and stomatitis), each treatment cycle can be repeated every 3 to 4 weeks. If it is used in combination with other antitumour agents having overlapping toxicity, the dosage of Adriblastina may need to be reduced to 30-60mg/m² every three weeks.

 

If dosage is calculated on the basis of body weight, it has been shown that giving Adriblastina as a single dose every three weeks greatly reduces the distressing toxic effect, mucositis. However, there are still some who believe that dividing the dose over three successive days (0.4-0.8mg/kg or 20-25mg/m² on each day) gives greater effectiveness though at the cost of higher toxicity.  If dosage is to be calculated on the basis of body weight, 1.2-2.4 mg/kg should be given as a single dose every three weeks.

 

Administration of Adriblastina in a weekly regimen has been shown to be as effective as the 3-weekly regimen. The recommended dosage is 20mg/m² weekly, although, objective responses have been seen at 16mg/m². Weekly administration leads to a reduction in cardiotoxicity.

 

Dosage may also need to be reduced in children, obese patients and the elderly.

 

Lower starting doses or longer intervals between cycles may need to be considered for heavily pre-treated patients, or patients with neoplastic bone marrow infiltration (see section 4.4).

 

Hepatic dysfunction

If hepatic function is impaired, doxorubicin dosage should be reduced according to the following table:

 

Serum Bilirubin Levels	Recommended Dose
1.2 – 3.0 mg/100ml	50% Normal dose
> 3.0 mg/100ml	25% Normal dose

 

Adriblastina should not be administered to patients with severe hepatic impairment (see section 4.3).

Hypersensitivity to Adriblastina or to any of the excipients listed in section 6.1, other anthracyclines or anthracenediones. Intravenous (IV) use: • persistent myelosuppression • severe hepatic impairment • severe myocardial insufficiency • recent myocardial infarction • severe arrhythmias • previous treatment with maximum cumulative doses of Adriblasrina, daunorubicin, epirubicin, idarubicin, and/or other anthracyclines and anthracenediones (see section 4.4).

Adriblastina should be administered only under the supervision of physicians experienced in the use of cytotoxic therapy.

 

Patients should recover from the acute toxicities of prior cytotoxic treatment (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) before beginning treatment with doxorubicin.

 

The systemic clearance of Adriblastina is reduced in obese patients (i.e. >130% ideal body weight) (see section 4.2).

 

Cardiac Function

Cardiotoxicity is a risk of anthracycline treatment that may be manifested by early (i.e. acute) or late (i.e. delayed) events.

 

Early (i.e. Acute) Events: Early cardiotoxicity of Adriblastina consists mainly of sinus tachycardia and/or ECG abnormalities such as non-specific ST-T wave changes. Tachyarrhythmias, including premature ventricular contractions and ventricular tachycardia, bradycardia, as well as atrioventricular and bundle-branch block have also been reported.  These effects do not usually predict subsequent development of delayed cardiotoxicity, and are generally not a consideration for discontinuation of doxorubicin treatment.

 

Late (i.e. Delayed) Events: Delayed cardiotoxicity usually develops late in the course of therapy with doxorubicin or within 2 to 3 months after treatment termination, but later events, several months to years after completion of treatment, have also been reported.  Delayed cardiomyopathy is manifested by reduced left ventricular ejection fraction (LVEF) and/or signs and symptoms of congestive heart failure (CHF) such as dyspnoea, pulmonary oedema, dependent oedema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion and gallop rhythm.  Subacute effects such as pericarditis/myocarditis have also been reported.  Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative dose-limiting toxicity of the drug.

 

Cardiac function should be assessed before patients undergo treatment with Adriblastina and must be monitored throughout therapy to minimize the risk of incurring severe cardiac impairment.  The risk may be decreased through regular monitoring of LVEF during the course of treatment with prompt discontinuation of Adriblastina at the first sign of impaired function.  The appropriate quantitative method for repeated assessment of cardiac function (evaluation of LVEF) includes multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO).  A baseline cardiac evaluation with an ECG and either a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiotoxicity.  Repeated MUGA or ECHO determinations of LVEF should be performed, particularly with higher, cumulative anthracycline doses.  The technique used for assessment should be consistent throughout follow-up.

The probability of developing CHF, estimated around 1% to 2% at a cumulative dose of 300 mg/m² slowly increases up to the total cumulative dose of 450-550 mg/m².  Thereafter, the risk of developing CHF increases steeply and it is recommended not to exceed a maximum cumulative dose of 550 mg/m².

 

Risk factors for cardiac toxicity include active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones and concomitant use of drugs with the ability to suppress cardiac contractility or  of cardiotoxic substances (e.g. trastuzumab) and age over 70 years. Patients receiving anthracyclines after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at an increased risk of developing cardiotoxicity. The reported half-life of trastuzumab is variable. Trastuzumab may persist in the circulation for up to 7 months. Therefore, physicians should avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab when possible.  If this is not possible, the patient’s cardiac function should be monitored carefully.  

 

Cardiac function must be carefully monitored in patients receiving high cumulative doses and in those with risk factors. However, cardiotoxicity with Adriblastina may occur at lower cumulative doses whether or not cardiac risk factors are present. 

 

Children and adolescents are at an increased risk for developing delayed cardiotoxicity following Adriblastina administration.  Females may be at greater risk than males.  Follow-up cardiac evaluations are recommended periodically to monitor for this effect.

 

It is probable that the toxicity of Adriblastina and other anthracyclines or anthracenediones is additive.

 

Haematologic Toxicity

Adriblastina may produce myelosuppression.  Haematologic profiles should be assessed before and during each cycle of therapy with Adriblastina, including differential white blood cell (WBC) counts.  A dose-dependent, reversible leucopenia and/or granulocytopenia (neutropenia) is the predominant manifestation of Adriblastina haematologic toxicity and is the most common acute dose-limiting toxicity of this drug.  Leucopenia and neutropenia generally reach the nadir between days 10 and 14 after drug administration; the WBC/neutrophil counts return to normal values in most cases by day 21.  Thrombocytopenia and anaemia may also occur.  Clinical consequences of severe myelosuppression include fever, infections, sepsis/septicaemia, septic shock, haemorrhage, tissue hypoxia or death.

 

Secondary Leukaemia

Secondary leukaemia, with or without a preleukaemic phase, has been reported in patients treated with anthracyclines.  Secondary leukaemia is more common when such drugs are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs or when doses of the anthracyclines have been escalated.  These leukaemias can have a 1 to 3 year latency period.

 

Carcinogenesis, Mutagenesis and Impairment of Fertility

Adriblastina was genotoxic and mutagenic in vitro and in vivo tests.

 

In women, Adriblastina may cause infertility during the time of drug administration.  Adriblastina may cause amenorrhoea.  Ovulation and menstruation appear to return after termination of therapy, although premature menopause can occur.

 

Adriblastina is mutagenic and can induce chromosomal damage in human spermatozoa.  Oligospermia or azoospermia may be permanent; however, sperm counts have been reported to return to normospermic levels in some instances.  This may occur several years after the end of therapy.  Men undergoing Adriblastina treatment should use effective contraceptive methods.

 

Liver function

The major route of elimination of Adriblastina is the hepatobiliary system.  Serum total bilirubin should be evaluated before and during treatment with Adriblastina.  Patients with elevated bilirubin may experience slower clearance of the drug with an increase in overall toxicity.  Lower doses are recommended in these patients (see section 4.2).  Patients with severe hepatic impairment should not receive Adriblastina (see section 4.3).

 

Other

Adriblastina may potentiate the toxicity of other anticancer therapies.  Exacerbation of cyclophosphamide-induced haemorrhagic cystitis and enhanced hepatotoxicity of 6-mercaptopurine have been reported.  Radiation-induced toxicities (myocardium, mucosae, skin and liver) have also been reported.

 

As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena including pulmonary embolism (in some cases fatal) have been coincidentally reported with the use of Adriblastina.

 

Tumour-Lysis Syndrome

Adriblastina may induce hyperuricaemia as a consequence of the extensive purine catabolism that accompanies drug-induced rapid lysis of neoplastic cells (tumour-lysis syndrome).  Blood uric acid levels, potassium, calcium phosphate and creatinine should be evaluated after initial treatment.  Hydration, urine alkalinization, and prophylaxis with allopurinol to prevent hyperuricaemia may minimize potential complications of tumour lysis syndrome.

 

Vaccinations

Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including Adriblastina, may result in serious or fatal infections.  Vaccination with a live vaccine should be avoided in patients receiving doxorubicin.  Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

 

Excipient Information

Adriblastina 10 mg/5ml, and 50 mg/25 ml contain 17.7 mg, and 88.5 mg sodium per each vial, equivalent to 0.9%, and 4.43% of the WHO maximum recommended daily intake (RDI) of 2 g sodium for an adult, respectively.

Adriblastina is a major substrate of cytochrome P450 CYP3A4 and CYP2D6, and P‑glycoprotein (P-gp).  Clinically significant interactions have been reported with inhibitors of CYP3A4, CYP2D6, and/or P-gp (e.g, verapamil), resulting in increased concentration and clinical effect of Adriblastina.  Inducers of CYP3A4 (e.g, phenobarbital, phenytoin, St. John’s Wort) and P-gp inducers may decrease the concentration of doxorubicin.

The addition of cyclosporine to Adriblastina may result in increases in area under the concentration-time curve (AUC) for both Adriblastina and doxorubicinol, possibly due to a decrease in clearance of the parent drug and a decrease in metabolism of doxorubicinol. Literature reports suggest that adding cyclosporine to Adriblastina results in more profound and prolonged haematologic toxicity than that observed with Adriblastina alone.  Coma and seizures have also been described with concomitant administration of cyclosporine and Adriblastina.

 

High dose cyclosporine increases the serum levels and myelotoxicity of Adriblastina.

 

Adriblastina is mainly used in combination with other cytotoxic drugs. Additive toxicity may occur especially with regard to bone marrow/haematologic and gastrointestinal effects (see section 4.4). The use of Adriblastina in combination chemotherapy with other potentially cardiotoxic drugs, as well as the concomitant use of other cardioactive compounds (e.g. calcium channel blockers), require monitoring of cardiac function throughout treatment. Changes in hepatic function induced by concomitant therapies may affect Adriblastina metabolism, pharmacokinetics, therapeutic efficacy and/or toxicity.

 

Paclitaxel can cause increased plasma-concentrations of Adriblastina and/or its metabolites when given prior to Adriblastina. Certain data indicate that a smaller increase is observed when Adriblastina is administered prior to paclitaxel.

 

The use of trastuzumab in combination with anthracyclines (such as doxorubicin hydrochloride) is associated with an increased cardiotoxic risk. Trastuzumab and anthracyclines should currently not be used in combination, except for well controlled clinical studies with monitoring of cardiac function (see section 4.4).

 

In a clinical study, an increase in Adriblastina AUC of 21% was observed when given with sorafenib 400 mg twice daily.  The clinical significance of this finding is unknown.

Pregnancy

Adriblastina has harmful pharmacological effects on pregnancy and/or the foetus/newborn child.

 

Due to the embryotoxic potential of Adriblastina, this drug should not be used during pregnancy unless clearly necessary. If a woman receives Adriblastina during pregnancy or becomes pregnant whilst taking the drug, she should be warned of the potential hazard to the foetus. Women of childbearing potential have to use effective contraception during treatment (see section 4.4).

 

Breast-feeding

Adriblastina is secreted into breast milk. Women should not breastfeed while undergoing treatment with Adriblastina.

The effect of Adriblastina on the ability to drive or use machinery has not been systematically evaluated.

Adverse reactions reported in association with Adriblastina therapy are listed below by MedDRA System Organ Class and by frequency. Frequencies are defined as: Very common (≥10%), Common (³1%, <10%), Uncommon (³0.1%, <1%), Rare (≥0.01%, <0.1%), Very rare (<0.01%), and Not known (cannot be estimated from available data).

 

Adverse Reactions Table
Infections and Infestations
Very common	Infection
Common	Sepsis
Neoplasms Benign, Malignant and Unspecified (including cysts and polyps)
Not known	Acute lymphocytic leukaemia, Acute myeloid leukaemia
Blood and Lymphatic System Disorders
Very common	Leukopenia, Neutropenia, Anaemia, Thrombocytopenia
Immune System Disorders
Not known	Anaphylactic reaction
Metabolism and Nutrition Disorders
Very common	Decreased appetite
Not known	Dehydration, Hyperuricaemia
Eye Disorders
Common	Conjunctivitis
Not known	Keratitis, Lacrimation increased
Cardiac Disorders
Common	Cardiac failure congestive, Sinus tachycardia
Not known	Atrioventricular block, Tachyarrhythmia, Bundle branch block
Vascular Disorders
Uncommon	Embolism
Not known	Shock, Haemorrhage, Thrombophlebitis, Phlebitis, Hot flush
Gastrointestinal Disorders
Very common	Mucosal inflammation/Stomatitis, Diarrhoea, Vomiting, Nausea
Common	Oesophagitis, Abdominal pain
Not known	Gastrointestinal haemorrhage, Gastritis erosive, Colitis, Mucosal discolouration
Skin and Subcutaneous Tissue Disorders
Very common	Palmar-plantar erythrodysaesthesia syndrome, Alopecia
Common	Urticaria, Rash, Skin hyperpigmentation, Nail hyperpigmentation
Not known	Photosensitivity reaction, Recall phenomenon, Pruritus, Skin disorder
Renal and Urinary Disorders
Not known	Chromaturiaa
Reproductive System and Breast Disorders
Not known	Amenorrhoea, Azoospermia, Oligospermia
General Disorders and Administration Site Conditions
Very common	Pyrexia, Asthenia, Chills
Common	Infusion site reaction
Not known	Malaise
Investigations
Very common	Ejection fraction decreased, Electrocardiogram abnormal, Transaminases abnormal, Weight increasedb
aFor one to two days after administration bReported in patients with early breast cancer receiving doxorubicin-containing adjuvant therapy (NSABP B-15 trial)

 

Reporting of suspected adverse reactions
 

Reporting suspected adverse reactions after marketing authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions according to their local requirements.

 

To report any side effect:

 

·        Saudi Arabia

 

National Pharmacovigilance and Drug Safety Centre (NPC) SFDA Call center: 19999 E-mail: npc.drug@sfda.gov.sa Website: https://ade.sfda.gov.sa/

 

·        Other GCC States

 

-    Please contact the relevant competent authority.

Adverse Reactions Table
Infections and Infestations
Very common	Infection
Common	Sepsis
Neoplasms Benign, Malignant and Unspecified (including cysts and polyps)
Not known	Acute lymphocytic leukaemia, Acute myeloid leukaemia
Blood and Lymphatic System Disorders
Very common	Leukopenia, Neutropenia, Anaemia, Thrombocytopenia
Immune System Disorders
Not known	Anaphylactic reaction
Metabolism and Nutrition Disorders
Very common	Decreased appetite
Not known	Dehydration, Hyperuricaemia
Eye Disorders
Common	Conjunctivitis
Not known	Keratitis, Lacrimation increased
Cardiac Disorders
Common	Cardiac failure congestive, Sinus tachycardia
Not known	Atrioventricular block, Tachyarrhythmia, Bundle branch block
Vascular Disorders
Uncommon	Embolism
Not known	Shock, Haemorrhage, Thrombophlebitis, Phlebitis, Hot flush
Gastrointestinal Disorders
Very common	Mucosal inflammation/Stomatitis, Diarrhoea, Vomiting, Nausea
Common	Oesophagitis, Abdominal pain
Not known	Gastrointestinal haemorrhage, Gastritis erosive, Colitis, Mucosal discolouration
Skin and Subcutaneous Tissue Disorders
Very common	Palmar-plantar erythrodysaesthesia syndrome, Alopecia
Common	Urticaria, Rash, Skin hyperpigmentation, Nail hyperpigmentation
Not known	Photosensitivity reaction, Recall phenomenon, Pruritus, Skin disorder
Renal and Urinary Disorders
Not known	Chromaturiaa
Reproductive System and Breast Disorders
Not known	Amenorrhoea, Azoospermia, Oligospermia
General Disorders and Administration Site Conditions
Very common	Pyrexia, Asthenia, Chills
Common	Infusion site reaction
Not known	Malaise
Investigations
Very common	Ejection fraction decreased, Electrocardiogram abnormal, Transaminases abnormal, Weight increasedb
aFor one to two days after administration bReported in patients with early breast cancer receiving doxorubicin-containing adjuvant therapy (NSABP B-15 trial)

 

Reporting of suspected adverse reactions
 

Reporting suspected adverse reactions after marketing authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions according to their local requirements.

 

 

To report any side effect:

 

 

• Saudi Arabia

 

National Pharmacovigilance and Drug Safety Centre ( NPC ) Fax: +966 11 205 7662 ·   Call NPC at +966-11-2038222, Ext 2317-2356-2340 ·   Call center : 19999 E-mail: npc.drug@sfda.gov.sa Website: https://ade.sfda.gov.sa/

 

Single doses of 250mg and 500mg of Adriblastina have proved fatal. Such doses may cause acute myocardial degeneration within 24 hours and severe myelosupression (mainly leucopenia and thromobocytopenia), the effects of which are greatest between 10 and 15 days after administration. Treatment should aim to support the patient during this period and should utilise such measures as blood transfusions and reverse barrier nursing.

 

Acute overdose with Adriblastina will result in gastrointestinal toxic effects (mainly mucositis).  This generally appears early after drug administration, but most patients recover from this within three weeks.

 

Delayed cardiac failure may occur up to six months after the overdosage. Patients should be observed carefully and should signs of cardiac failure arise, be treated along conventional lines.

Pharmacotherapeutic group: Anthracyclines and related substances, ATC code: L01DB01

 

Adriblastina is an antitumour agent.  Tumour cells are probably killed through drug-induced alterations of nucleic acid synthesis although the exact mechanism of action has not yet been clearly elucidated.

 

Proposed mechanism of action include:

 

DNA intercalation (leading to an inhibition of synthesis of DNA, RNA and proteins), formation of highly reactive free-radicals and superoxides, chelation of divalent cations, the inhibition of Na-K ATPase and the binding of Adriblastina to certain constituents of cell membranes (particularly to the membrane lipids, spectrin and cardiolipin).  Highest drug concentrations are attained in the lung, liver, spleen, kidney, heart, small intestine and bone-marrow.  Adriblastina does not cross the blood-brain barrier.

After IV administration, the plasma disappearance curve of Adriblastina is triphasic with half-lives of 12 minutes, 3.3 hours and 30 hours.  The relatively long terminal elimination half-life reflects Adriblastina’s distribution into a deep tissue compartment.  Only about 33 to 50% of fluorescent or tritiated drug (or degradation products), respectively, can be accounted for in urine, bile and faeces for up to 5 days after IV administration.  The remainder of the Adriblastina and degradation products appear to be retained for long periods of time in body tissues.

 

In cancer patients, Adriblastina is reduced to adriamycinol, which is an active cytotoxic agent.  This reduction appears to be catalysed by cytoplasmic and pH-dependent aldo-keto reductases that are found in all tissues and play an important role in determining the overall pharmacokinetics of Adriblastina.

 

Microsomal glycosidases present in most tissues split Adriblastina and adriamycinol into inactive aglycones.  The aglycones may then undergo 0-demethylation, followed by conjugation to sulphate or glucuronide esters, and excretion in the bile.

No information in addition to that presented elsewhere in this Summary of Product Characteristics is available.

Water for Injections

Sodium chloride

Hydrochloric acid

 

            The dilution diluents:

             Sodium Chloride (0.9% w/v) and Glucose (5% w/v).

Adriblastina should not be mixed with heparin as a precipitate may form and it is not recommended that doxorubicin be mixed with other drugs.  Prolonged contact with any solution of an alkaline pH should be avoided as it will result in hydrolysis of the drug.

 

Adriblastina should not be mixed with fluorouracil (e.g. in the same IV infusion bag or at the Y-site of an IV infusion line) since it has been reported that these drugs are incompatible to the extent that a precipitate might form. If concomitant therapy with Adriblastina and fluorouracil is required, it is recommended that the IV line be flushed between the administration of these drugs

2 years Do not use Adriblastina after the expiry date which is stated on the Vial label after EXP: The expiry date refers to the last day of that month. In-use shelf-life and in-use storage instructions: From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 °C, unless reconstitution/dilution (etc) has taken place in controlled and validated aseptic conditions.

Store refrigerated between 2 - 8°C.

Do not freeze. Protect from light.

Discard any unused solution.

Single glass vials of 5ml (10mg) and 25ml (50mg)

 

Single Cytosafe polypropylene vials of 5ml (10mg) and 25ml (50mg)

 

Not all pack sizes may be marketed.

The following protective recommendations are given due to the toxic nature of this substance:

 

·          Personnel should be trained in good technique for reconstitution and handling.

 

·          Pregnant staff should be excluded from working with this drug.

 

·          Personnel handling doxorubicin should wear protective clothing: goggles, gowns, disposable gloves and masks.

 

·          A designated area should be defined for reconstitution (preferably under a laminar flow system). The work surface should be protected by disposable, plastic-backed and absorbent paper.

 

·          All items for reconstitution, administration or cleaning, including gloves, should be placed in high-risk waste-disposal bags for high temperature incineration.

 

·          Spillage or leakage should be treated with dilute sodium hypochlorite (1% available chlorine)

solution, preferably soaking and then water. 

 

·          All cleaning materials should be disposed of as indicated previously.

 

·          In case of skin contact, thoroughly wash the affected area with soap and water or sodium

·          bicarbonate solution. However, do not graze the skin by using a scrubbing brush.

 

·          In case of contact with eye(s), hold back the eyelid(s) and flush the affected eyes with copious amounts of water for at least 15 minutes. Then seek medical evaluation by a physician.

 

·          Always wash hands after removing gloves.